**Combined Pulmonary Fibrosis and Emphysema (CPFE)**

Keisaku Fujimoto1 and Yoshiaki Kitaguchi2 *1Department of Clinical Laboratory Sciences, Shinshu University School of Health Sciences. 21st Department of Internal Medicine, Shinshu University School of Medicine. Nagano, Japan* 

### **1. Introduction**

78 Emphysema

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Combined pulmonary fibrosis and emphysema (CPFE) is one of smoking-related lung diseases.

Emphysema is characterized by the permanent abnormal enlargement of airspaces distal to the terminal bronchioles, accompanied by destruction of their walls. The characteristics of emphysema do not, by definition, include thickening of the alveolar septa and fibrosis. However, coincidental idiopathic pulmonary fibrosis (IPF) and emphysema was firstly reported in 1990 by Wiggins et al (Wiggins J, et al., 1990) in London. Smoking-related interstitial lung diseases (SRILD) include desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-related interstitial lung disease (RB-ILD), pulmonary Langerhans' cell histiocytosis (LCH) and idiopathic pulmonary fibrosis (IPF) (Ryu JH, et al., 2001). Tobacco smoking is also major course of emphysema and chronic obstructive pulmonary disease (COPD). Smoking is a common risk factor for both emphysema and pulmonary fibrosis. Recently, the occurrence of both emphysema and pulmonary fibrosis in the same patient has received increased attention as the syndrome of combined pulmonary fibrosis and emphysema (CPFE) (Cottin V, et al., 2005). It has been demonstrated that CPFE syndrome is not rare because on a series of 110 patients with IPF, 28% of them with at least 10% of the lung affected with emphysema, and thus are considered to have CPFE (Mejia M, et al., 2009).

#### **2. Clinical characteristics of CPFE**

In Japan Hiwatari *et al* (Hiwatari N, et al., 1993) reported nine patients with pulmonary emphysema and IPF among 152 pulmonary emphysema patients in 1993. Those patients were all men and heavy smokers. Odani *et al* (Odani K, et al., 2004) reported 31 patients combined with pulmonary emphysema and IPF among 14900 patients who underwent chest CT from January 1996 to March 2001 at Kochi Medical School Hospital in Japan. The CT of all patients showed the coexistence of emphysema with upper lung field predominance and diffuse parenchymal lung disease with significant pulmonary fibrosis predominantly in the lower lung fields (Figure 1). Centriacinar emphysema was present in 24 of the 31 (77%)

Combined Pulmonary Fibrosis and Emphysema (CPFE) 81

Fig. 2. Total survival of patients with combined pulmonary fibrosis and emphysema (CPFE)

We retrospectively examined the clinical characteristics of 47 patients with CPFE based on the findings of chest HRCT consecutively recruited from outpatients attending Shinshu University Hospital between October 2004 and June 2007 (Kitaguchi Y, et al., 2010). The clinical characteristics of CPFE patients were compared with those of emphysema-dominant COPD patients without parenchymal lung disease (COPD without fibrosis). Forty-six of the 47 CPFE patients were male. Paraseptal emphysema was particularly common in the CPFE group, although centriacinar was dominant in the COPD without fibrosis (Table 1). All CPFE patients showed the coexistence of emphysema with upper lung fields predominance and diffuse parenchymal lung disease with significant pulmonary fibrosis with lower lung

(a); 5-yr survival was 55%. Survival for subjects with CPFE stratified on the basis of pulmonary hypertension (PH) (b); 5-yr survival was significantly less in patients with pulmonary hypertension (25%) compared with those without pulmonary hypertension

(75%) at diagnosis.

patients and paraseptal emphysema in 11 of 31 patients (35%). Honeycombing, which is one of the most common findings of usual interstitial pneumonia, was present in 24 of the 31 patients (77%). In 2005 Cottin *et al* (Cottin V, et al., 2005) conducted a retrospective study of 61 patients with CPFE and characterized this association as a distinct entity. They reported that sixty patients were male, dyspnea on exertion was present in all patients, basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests showed preserved lung volumes and strongly impaired lung diffusing capacity for carbon monoxide (DLCO). They showed that pulmonary hypertension was frequent in patients with CPFE with 47% of patients with estimated systolic right ventricular pressure ≧45 mmHg at echocardiography and the 5-yr probability of survival was 25% in patients with pulmonary hypertension compared with 75% in those without pulmonary hypertension at diagnosis (Figure 2). They also confirmed these findings by right heart catheterization on a retrospective multicenter study and concluded that the patients with CPFE and pulmonary hypertension have a dismal prognosis despite moderately altered lung volume and flows (Cottin V, et al., 2010). The risk of developing pulmonary hypertension is much higher in CPFE than in IPF without emphysema (Mejia M, et al., 2009). Pulmonary hypertension was a critical determinant of the prognosis.

Fig. 1. Imaging in a 66-year-old male with combined pulmonary fibrosis and emphysema (CPFE). Chest high-resolution computed tomography of the bilateral upper lung fields (a) shows centriaciner + paraseptal emphysema with thick walled bulla and of the bilateral lower lung fields (b) shows reticular opacities and traction bronchiectasis.

patients and paraseptal emphysema in 11 of 31 patients (35%). Honeycombing, which is one of the most common findings of usual interstitial pneumonia, was present in 24 of the 31 patients (77%). In 2005 Cottin *et al* (Cottin V, et al., 2005) conducted a retrospective study of 61 patients with CPFE and characterized this association as a distinct entity. They reported that sixty patients were male, dyspnea on exertion was present in all patients, basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests showed preserved lung volumes and strongly impaired lung diffusing capacity for carbon monoxide (DLCO). They showed that pulmonary hypertension was frequent in patients with CPFE with 47% of patients with estimated systolic right ventricular pressure ≧45 mmHg at echocardiography and the 5-yr probability of survival was 25% in patients with pulmonary hypertension compared with 75% in those without pulmonary hypertension at diagnosis (Figure 2). They also confirmed these findings by right heart catheterization on a retrospective multicenter study and concluded that the patients with CPFE and pulmonary hypertension have a dismal prognosis despite moderately altered lung volume and flows (Cottin V, et al., 2010). The risk of developing pulmonary hypertension is much higher in CPFE than in IPF without emphysema (Mejia M, et al., 2009). Pulmonary hypertension was a critical determinant of

Fig. 1. Imaging in a 66-year-old male with combined pulmonary fibrosis and emphysema (CPFE). Chest high-resolution computed tomography of the bilateral upper lung fields (a) shows centriaciner + paraseptal emphysema with thick walled bulla and of the bilateral

lower lung fields (b) shows reticular opacities and traction bronchiectasis.

the prognosis.

Fig. 2. Total survival of patients with combined pulmonary fibrosis and emphysema (CPFE) (a); 5-yr survival was 55%. Survival for subjects with CPFE stratified on the basis of pulmonary hypertension (PH) (b); 5-yr survival was significantly less in patients with pulmonary hypertension (25%) compared with those without pulmonary hypertension (75%) at diagnosis.

We retrospectively examined the clinical characteristics of 47 patients with CPFE based on the findings of chest HRCT consecutively recruited from outpatients attending Shinshu University Hospital between October 2004 and June 2007 (Kitaguchi Y, et al., 2010). The clinical characteristics of CPFE patients were compared with those of emphysema-dominant COPD patients without parenchymal lung disease (COPD without fibrosis). Forty-six of the 47 CPFE patients were male. Paraseptal emphysema was particularly common in the CPFE group, although centriacinar was dominant in the COPD without fibrosis (Table 1). All CPFE patients showed the coexistence of emphysema with upper lung fields predominance and diffuse parenchymal lung disease with significant pulmonary fibrosis with lower lung

Combined Pulmonary Fibrosis and Emphysema (CPFE) 83

 CPFE COPD number 47 82 Sex, female/male 1/46 8/74 Body mass index, kg/m2 22.9±0.4\*\* 20.5±0.3 Smoking history, packs・year 58.7±4.4 59.4±3.0 Non-COPD 27 (57.4%) 0 (0.0%) COPD 20 (42.6%) 82 (100.0%) StageⅠ 8 (17.0%) 8 (9.8%) StageⅡ 8 (17.0%)\*\* 34 (41.5%) StageⅢ 4 (8.5%)\*\* 30 (36.6%) StageⅣ 0 (0.0%)\* 10 (12.2%) Complication of lung cancer、n (%) 22 (46.8%)\*\* 6 (7.3%) squamous cell carcinoma 12 (54.5%)\*\* 3 (50.0%) small cell carcinoma 2 (9.1%) 0 (0.0%) adenocarcinoma 7 (31.8%) 3 (50.0%) LCNEC 1 (4.5%) 0 (0.0%)

n (%), Values are the mean±SEM. \*p<0.05 and \*\*p<0.01 vs. COPD.

Table 2. Clinical characteristics in patients with combined pulmonary fibrosis and emphysema (CPFE) and emphysema dominant COPD without fibrosis (COPD).

 CPFE COPD %VC, % 94.7±3.5 96.6±2.4 FEV1, % of pred. 79.0±3.1\*\* 54.7±2.7 FEV1/FVC, % 71.8±2.0\*\* 48.0±1.2 FRC, % of pred. 89.9±5.8\*\* 112.5±2.7 RV, % of pred. 114.7±10.3\*\* 181.7±5.5 RV/TLC, % 37.3±1.9\*\* 50.5±1.1 %DLco, % 39.6±2.5\*\* 57.7±2.2 PaO2, torr 68.6±2.3 70.0±1.3 PaCO2, torr 39.3±0.9 40.5±0.6 α1-AT, mg/dl 153±15 190±38 CRP, mg/dl 1.1±0.3 0.5±0.1

KL-6, U/ml 1058±166 -

Table 3. Pulmonary function tests and laboratory data in patients with combined pulmonary fibrosis and emphysema (CPFE, n=47) and emphysema dominant COPD without fibrosis

Values are the mean±SEM. \*\*p<0.01 vs. COPD.

(COPD, n=82).

fields predominance. Honeycombing, ground-glass opacities and reticular opacities were present in 75.6%, 62.2% and 84.4% of CPFE patients, respectively. Thick-walled bullae were characteristic in CPFE and observed in more than one half of the CPFE patients.

Twenty-seven of the 47 CPFE patients (57.4%) showed a FEV1/FVC ratio within the normal range and the other patients showed milder airflow limitation, although the presence of severe emphysema (Table 2, 3). All CPFE patients showed lower lung volume and DLCO than the patients with COPD without fibrosis as previously reported. Desaturation during 6-min walking test in CPFE patients tended to be more severe than in COPD without fibrosis patients, if the level of FEV1 or 6-minute walking distance was equal (Figure 3). These findings suggest that CPFE patients show severe dyspnea and severe hypoxemia on effort in spite of subnormal spirometry findings.


Values are the mean±SEM. \*p<0.05 and \*\*p<0.01 vs. COPD.

Table 1. Chest HRCT findings in patients with combined pulmonary fibrosis and emphysema (CPFE, n=47) and emphysema dominant COPD without fibrosis (COPD, n=82).

fields predominance. Honeycombing, ground-glass opacities and reticular opacities were present in 75.6%, 62.2% and 84.4% of CPFE patients, respectively. Thick-walled bullae were

Twenty-seven of the 47 CPFE patients (57.4%) showed a FEV1/FVC ratio within the normal range and the other patients showed milder airflow limitation, although the presence of severe emphysema (Table 2, 3). All CPFE patients showed lower lung volume and DLCO than the patients with COPD without fibrosis as previously reported. Desaturation during 6-min walking test in CPFE patients tended to be more severe than in COPD without fibrosis patients, if the level of FEV1 or 6-minute walking distance was equal (Figure 3). These findings suggest that CPFE patients show severe dyspnea and severe hypoxemia on

characteristic in CPFE and observed in more than one half of the CPFE patients.

 CPFE COPD LAA score 13.2±0.9\*\* 18.9±0.7 Upper lobe 5.6±0.3\*\* 6.7±0.2 Middle lobe 4.3±0.3\*\* 6.2±0.2 Lower lobe 3.3±0.4\*\* 5.9±0.3

centriacinar, % 11 (24.4%)\*\* 49 (59.8%) panacinar+centriacinar, % 7 (15.6%)\* 26 (31.7%) paraseptal, % 15 (33.3%)\*\* 7 (8.5%) paraseptal+centriacinar, % 12 (26.7%)\*\* 0 (0.0%)

effort in spite of subnormal spirometry findings.

Upper lobe 8 (17.0%) Middle lobe 18 (38.3%) Lower lobe 47 (100.0%)

Thick-walled bulla, n (%) 26 (57.8%) honeycombing, n (%) 34 (75.6%) reticular opacity, n (%) 38 (84.4%) ground glass opacity, n (%) 28 (62.2%) consolidation, n (%) 6 (13.3%) traction bronchiectasis, n (%) 18 (40.0%) peribronchovascular thickening, n (%) 4 (8.9%) architectural distortion, n (%) 7 (15.6%)

Values are the mean±SEM. \*p<0.05 and \*\*p<0.01 vs. COPD.

Table 1. Chest HRCT findings in patients with combined pulmonary fibrosis and

emphysema (CPFE, n=47) and emphysema dominant COPD without fibrosis (COPD, n=82).

Emphysema type

IP distribution

IP pattern


n (%), Values are the mean±SEM. \*p<0.05 and \*\*p<0.01 vs. COPD.

Table 2. Clinical characteristics in patients with combined pulmonary fibrosis and emphysema (CPFE) and emphysema dominant COPD without fibrosis (COPD).


Values are the mean±SEM. \*\*p<0.01 vs. COPD.

Table 3. Pulmonary function tests and laboratory data in patients with combined pulmonary fibrosis and emphysema (CPFE, n=47) and emphysema dominant COPD without fibrosis (COPD, n=82).

Combined Pulmonary Fibrosis and Emphysema (CPFE) 85

According to a clinical study of IPF based on autopsy studies in elderly patients performed in Japan, lung cancer developed in approximately 23% of the IPF patients (Araki T, et al., 2003). Therefore, the complicated ratio of lung cancer might be higher in CPFE patients than in COPD and IPF patients. However, the evidence is poor because of retrospective study and a single institution study may have some selection bias. Further investigations are needed to clarify whether CPFE is an independent risk factor for lung cancer, its role in

Fig. 4. Imaging in a 78-year-old male with CPFE complicated with lung cancer (squamous cell carcinoma) in the left lung S4. Chest HRCT images before left upper lobectomy (A, B) and after upper lobectomy (C, D). Two months later, the patients developed exacerbation of interstitial pneumonia, new diffuse bilateral ground-glass opacities superimposed on a background of reticular opacities and honeycombing with basal and peripheral

When the patients with CPFE are complicated with lung cancer, it may have a profound influence on their prognosis because of poor operability and difficulties in chemotherapy. Usui et al (Usui K, et al., 2011) retrospectively reviewed the data for 1143 patients with lung

susceptibility to lung cancer.

predominance (E, F).

Fig. 3. Relationship between ΔSpO2 during a 6-minute walking test and FEV1 or 6 minutewalking distance (6MWD) in patients with combined pulmonary fibrosis and emphysema (CPFE) and emphysema dominant COPD without fibrosis (COPD).

#### **3. Higher incidence of lung cancer**

In the series of our retrospective study, twenty-two of the 47 CPFE patients (46.8%) had lung cancer whereas only 7.3% of the patients with COPD without fibrosis had (Table 2) (Kitaguchi Y, et al., 2010). There were no significant differences in histological type of cancer between CPFE and COPD without fibrosis group. Odani *et al* (Odani K, et al., 2004) also reported higher incidence of lung cancer and 42% (13 patients) of CPFE were complicated lung cancer as well as our report and squamous cell carcinoma was the most common histological type. On the other hand, Nakayama et al reported that 18 of 127 patients with COPD (14%) were complicated with lung cancer in Japan (Nakayama M, et al., 2003).

Fig. 3. Relationship between ΔSpO2 during a 6-minute walking test and FEV1 or 6 minutewalking distance (6MWD) in patients with combined pulmonary fibrosis and emphysema

In the series of our retrospective study, twenty-two of the 47 CPFE patients (46.8%) had lung cancer whereas only 7.3% of the patients with COPD without fibrosis had (Table 2) (Kitaguchi Y, et al., 2010). There were no significant differences in histological type of cancer between CPFE and COPD without fibrosis group. Odani *et al* (Odani K, et al., 2004) also reported higher incidence of lung cancer and 42% (13 patients) of CPFE were complicated lung cancer as well as our report and squamous cell carcinoma was the most common histological type. On the other hand, Nakayama et al reported that 18 of 127 patients with COPD (14%) were complicated with lung cancer in Japan (Nakayama M, et al., 2003).

(CPFE) and emphysema dominant COPD without fibrosis (COPD).

**3. Higher incidence of lung cancer** 

According to a clinical study of IPF based on autopsy studies in elderly patients performed in Japan, lung cancer developed in approximately 23% of the IPF patients (Araki T, et al., 2003). Therefore, the complicated ratio of lung cancer might be higher in CPFE patients than in COPD and IPF patients. However, the evidence is poor because of retrospective study and a single institution study may have some selection bias. Further investigations are needed to clarify whether CPFE is an independent risk factor for lung cancer, its role in susceptibility to lung cancer.

Fig. 4. Imaging in a 78-year-old male with CPFE complicated with lung cancer (squamous cell carcinoma) in the left lung S4. Chest HRCT images before left upper lobectomy (A, B) and after upper lobectomy (C, D). Two months later, the patients developed exacerbation of interstitial pneumonia, new diffuse bilateral ground-glass opacities superimposed on a background of reticular opacities and honeycombing with basal and peripheral predominance (E, F).

When the patients with CPFE are complicated with lung cancer, it may have a profound influence on their prognosis because of poor operability and difficulties in chemotherapy. Usui et al (Usui K, et al., 2011) retrospectively reviewed the data for 1143 patients with lung

Combined Pulmonary Fibrosis and Emphysema (CPFE) 87

cancer and acute exacerbation may occur after lung surgery in CPFE. HRCT plays an important role in diagnose CPFE and evaluating the occurrence of lung cancer and an acute exacerbation of CPFE. CPFE syndrome is an important entity and is a matter of growing

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**6. References**

cancer. CPFE, emphysema and fibrosis were identified in 8.9%, 35.3% and 1.3% patients with lung cancer, retrospectively. The median overall survival of CPFE patients was significantly less than that of normal patients or that of patients with emphysema alone. Of interest, 76% of lung cancers in patients with CPFE were diagnosed at an advanced stage. Also, fatal severe acute lung injury occurred more frequently (19.8%) in CPFE, irrespective of the treatment modality. Especially, postoperative lung injury occurred in nine of 33 patients with CPFE. Therefore, the presence of CPFE may be higher risk for postoperative lung injury as well as the presence of interstitial lung disease (Chiyo M, et al., 2003). Figure 4 shows imaging in a 78-year-old male with CPFE complicated with lung cancer (squamous cell carcinoma) in the segment 4 of left lung admitted to our hospital. He was underwent left upper lobectomy for lung cancer. However, two months later, he developed severe exacerbation of interstitial pneumonia, and dies due to respiratory failure.

#### **4. Pathogenesis**

Little is known about the pathogenesis of CPFE. Concerning with parenchymal lung disease in CPFE, usual interstitial pneumonia (UIP) has been the most common histopathological finding, and there are no differences in histological findings from IPF. IPF and pulmonary emphysema have distinct clinical and pathological characteristics, and have been considered to be separate disorders. In spite of such differences, animal experiments have suggested that the same lung injury might result in either fibrosis or emphysema. Connective tissue synthesis during the healing phase may be the critical determinant (Niewoehner DE, et al., 1982). Hoyle *et al*. (Hoyle GW, et al., 1999) reported that the overexpression of plateletderived growth factor-B induced both emphysema and fibrotic lung disease in the developing and adult lung of transgenic mice. It has been also shown that the overexpression of TNF-alpha driven by the surfactant protein C promoter (Lundblad LK, et al., 2005), IL-13 (Fulkerson PC, et al., 2006), and transforming growth factor-beta 1 (Lee CG, et al., 2006) in transgenic mice induces pathological changes consistent with both emphysema and pulmonary fibrosis. These pathological changes might represent an experimental animal model of CPFE. The tissue effects of these factors might depend on the balance of apoptosis, proteolysis and fibrosis and might regulate the degree of emphysema and/or fibrosis in the injured lung. It has been recently reported a 32-year-old women, never smokers, with CPFE and her daughter at 3 months of age showed having fibrosing interstitial pneumonia, and both the mother and daughter had a mutation of the surfactant protein-C (SFTPC) gene (Cottin V, et al., 2011). It is suggested that an individual's genetic background may predispose some smokers to the development of CPFE. Further studies are needed to elucidate these phenomena.

#### **5. Conclusion**

CPFE patients had some different clinical characteristics in comparison with emphysema and interstitial lung disease and should be included as a smoking-related lung disease. The patients with CPFE show severe dyspnea, unexpected subnormal spirometry findings, severely impaired DLCO, hypoxemia at exercise, characteristic imaging feature, and a high probability of severe pulmonary hypertension and lung cancer. A strict follow-up is therefore required because of higher rate of complicated pulmonary hypertension and lung cancer and acute exacerbation may occur after lung surgery in CPFE. HRCT plays an important role in diagnose CPFE and evaluating the occurrence of lung cancer and an acute exacerbation of CPFE. CPFE syndrome is an important entity and is a matter of growing interest by respiratory clinicians.

#### **6. References**

86 Emphysema

cancer. CPFE, emphysema and fibrosis were identified in 8.9%, 35.3% and 1.3% patients with lung cancer, retrospectively. The median overall survival of CPFE patients was significantly less than that of normal patients or that of patients with emphysema alone. Of interest, 76% of lung cancers in patients with CPFE were diagnosed at an advanced stage. Also, fatal severe acute lung injury occurred more frequently (19.8%) in CPFE, irrespective of the treatment modality. Especially, postoperative lung injury occurred in nine of 33 patients with CPFE. Therefore, the presence of CPFE may be higher risk for postoperative lung injury as well as the presence of interstitial lung disease (Chiyo M, et al., 2003). Figure 4 shows imaging in a 78-year-old male with CPFE complicated with lung cancer (squamous cell carcinoma) in the segment 4 of left lung admitted to our hospital. He was underwent left upper lobectomy for lung cancer. However, two months later, he developed severe

Little is known about the pathogenesis of CPFE. Concerning with parenchymal lung disease in CPFE, usual interstitial pneumonia (UIP) has been the most common histopathological finding, and there are no differences in histological findings from IPF. IPF and pulmonary emphysema have distinct clinical and pathological characteristics, and have been considered to be separate disorders. In spite of such differences, animal experiments have suggested that the same lung injury might result in either fibrosis or emphysema. Connective tissue synthesis during the healing phase may be the critical determinant (Niewoehner DE, et al., 1982). Hoyle *et al*. (Hoyle GW, et al., 1999) reported that the overexpression of plateletderived growth factor-B induced both emphysema and fibrotic lung disease in the developing and adult lung of transgenic mice. It has been also shown that the overexpression of TNF-alpha driven by the surfactant protein C promoter (Lundblad LK, et al., 2005), IL-13 (Fulkerson PC, et al., 2006), and transforming growth factor-beta 1 (Lee CG, et al., 2006) in transgenic mice induces pathological changes consistent with both emphysema and pulmonary fibrosis. These pathological changes might represent an experimental animal model of CPFE. The tissue effects of these factors might depend on the balance of apoptosis, proteolysis and fibrosis and might regulate the degree of emphysema and/or fibrosis in the injured lung. It has been recently reported a 32-year-old women, never smokers, with CPFE and her daughter at 3 months of age showed having fibrosing interstitial pneumonia, and both the mother and daughter had a mutation of the surfactant protein-C (SFTPC) gene (Cottin V, et al., 2011). It is suggested that an individual's genetic background may predispose some smokers to the development of CPFE. Further studies are

CPFE patients had some different clinical characteristics in comparison with emphysema and interstitial lung disease and should be included as a smoking-related lung disease. The patients with CPFE show severe dyspnea, unexpected subnormal spirometry findings, severely impaired DLCO, hypoxemia at exercise, characteristic imaging feature, and a high probability of severe pulmonary hypertension and lung cancer. A strict follow-up is therefore required because of higher rate of complicated pulmonary hypertension and lung

exacerbation of interstitial pneumonia, and dies due to respiratory failure.

**4. Pathogenesis** 

needed to elucidate these phenomena.

**5. Conclusion** 


**1. Introduction** 

inspiratory muscle strength [5].

**6** 

*Germany* 

 **Endoscopic Lung Volume Reduction** 

*Pneumology and Respiratory Care Medicine, Thoraxklinik, Heidelberg* 

Chronic obstructive pulmonary disease (COPD) that presents a growing cause for mortality worldwide [1, 2] is characterized by chronic bronchitis, obstructive bronchiolitis and emphysema. The most important etiologic factor is cigarette smoking, but occupational and environmental dusts as well as genetic factors contribute to COPD developing. The exposure to these noxious inhaled agents lead to abnormal pathogenic reactions like a permanent airway inflammation, imbalance between proteinases and antiproteinases, impairment of elastin repair and increased oxidative stress with subsequent lung parenchyma destruction [3]. The progressive permanent enlargement of airspaces distal to terminal bronchioles results in a decrease in lung elastic recoil, air trapping and hyperinflation, thus leading to airflow limitation and increased residual volume. These alterations of respiratory mechanics cause the symptoms of dyspnoea, limited exercise capacitiy and reduced quality of life. Therapeutic recommendations for COPD consisting of bronchodilators, glucocorticosteroids, long term oxygen therapy and rehabilitation are common insufficient in advanced COPD [4]. Therefore, surgical treatments like Lung Volume Reduction Surgery (LVRS) and lung transplantation should be considered in advanced disease. The resection of emphysematous lung tissue results in improvement of lung elastic recoil with subsequent increased expiratory flow. Furthermore, the reduction of hyperinflation allows the diaphragm to function more effectively and increases the global

Already in the 1950s, the first lung volume reduction surgery has been performed to achieve lung volume reduction with subsequent improvement of respiratory mechanics leading to decreased breathlessness on exertion and increased exercise capacity. Although a physiological improvement could be observed, the surgical treatment did not attract attention due to high perioperative mortality [6]. Just in the 1990s the surgical treatment was reintroduced and the positive results have been confirmed in several trials [7-10]. The most known trial related to LVRS is the multicenter "National Emphysema Treatment Trial" (NETT) [10] comparing the surgical treatment to standard medical care in 1.218 patients with severe emphysema. The results of NETT showed that patients with predominantly upper lobe emphysema experienced significant improvement in clinical outcome measurements. However, the 90-day mortality rate in the surgery group was 7.9% and thus significant higher than in the medical-therapy group. Particularly, in patients with non upper lobe predominant emphysema and poor lung function, a high mortality could be

Daniela Gompelmann and Felix J.F. Herth

*University of Heidelberg, Thoraxklinik,* 


### **Endoscopic Lung Volume Reduction**

Daniela Gompelmann and Felix J.F. Herth

*University of Heidelberg, Thoraxklinik, Pneumology and Respiratory Care Medicine, Thoraxklinik, Heidelberg Germany* 

#### **1. Introduction**

88 Emphysema

Usui K, Tanai C, Tanaka Y, et al. The prevalence of pulmonary fibrosis combined with emphysema in patients with lung cancer. Respirology 2011; 16: 326-331. Wiggins J, Strickland B, Turner-Warwick M. Combined cryptogenic fibrosing alveolitis

assessment. Respir Med 1990; 84: 365-369.

and emphysema: the value of high resolution computed tomography in

Chronic obstructive pulmonary disease (COPD) that presents a growing cause for mortality worldwide [1, 2] is characterized by chronic bronchitis, obstructive bronchiolitis and emphysema. The most important etiologic factor is cigarette smoking, but occupational and environmental dusts as well as genetic factors contribute to COPD developing. The exposure to these noxious inhaled agents lead to abnormal pathogenic reactions like a permanent airway inflammation, imbalance between proteinases and antiproteinases, impairment of elastin repair and increased oxidative stress with subsequent lung parenchyma destruction [3]. The progressive permanent enlargement of airspaces distal to terminal bronchioles results in a decrease in lung elastic recoil, air trapping and hyperinflation, thus leading to airflow limitation and increased residual volume. These alterations of respiratory mechanics cause the symptoms of dyspnoea, limited exercise capacitiy and reduced quality of life. Therapeutic recommendations for COPD consisting of bronchodilators, glucocorticosteroids, long term oxygen therapy and rehabilitation are common insufficient in advanced COPD [4]. Therefore, surgical treatments like Lung Volume Reduction Surgery (LVRS) and lung transplantation should be considered in advanced disease. The resection of emphysematous lung tissue results in improvement of lung elastic recoil with subsequent increased expiratory flow. Furthermore, the reduction of hyperinflation allows the diaphragm to function more effectively and increases the global inspiratory muscle strength [5].

Already in the 1950s, the first lung volume reduction surgery has been performed to achieve lung volume reduction with subsequent improvement of respiratory mechanics leading to decreased breathlessness on exertion and increased exercise capacity. Although a physiological improvement could be observed, the surgical treatment did not attract attention due to high perioperative mortality [6]. Just in the 1990s the surgical treatment was reintroduced and the positive results have been confirmed in several trials [7-10]. The most known trial related to LVRS is the multicenter "National Emphysema Treatment Trial" (NETT) [10] comparing the surgical treatment to standard medical care in 1.218 patients with severe emphysema. The results of NETT showed that patients with predominantly upper lobe emphysema experienced significant improvement in clinical outcome measurements. However, the 90-day mortality rate in the surgery group was 7.9% and thus significant higher than in the medical-therapy group. Particularly, in patients with non upper lobe predominant emphysema and poor lung function, a high mortality could be

Endoscopic Lung Volume Reduction 91

Fig. 1. Endobronchial valve.

Fig. 2. Intrabronchial valve.

observed. Therefore, different bronchoscopic approaches have been developed imitating the LVRS but with less morbidity and mortality.

Until now, there are various techniques of Endoscopic Lung VolumeReduction (ELVR) extending the therapeutic strategies in patients withsevere emphysema. In general, reversible blocking techniques and irreversible, non-blocking techniques can be distinguished. The application of these different techniques is dependent on the emphysema distribution and degree of collateral ventilation. Therefore, an accurate patient selection has great importance.

#### **2. Reversible, blocking techniques**

The first and most known method of endoscopic lung volume reduction is the implantation of valves in targeted most destroyed lung compartments in patients with heterogeneous emphysema [11]. These blocking devices allow the air to be expelled during expiration but prevent the air entering the target lobe during inspiration and so facilitating atelectasis to achieve lung volume reduction. Two different valves are available: endobronchial valves (EBV, Zephyr ®, Pulmonx, Inc., Palo Alto, Calif., USA) and intrabronchial valves (IBV, Spiration®, Olympus Medical Co., Tokio, Japan).

#### **2.1 Implantation technique**

The endobronchial (figure 1) and intrabronchial valves (figure 2) only differentiate in shape, but the implantation technique and their functional principle is very similar. The endobronchial valves consist of a cylindrical nitinol framework, whereas the intrabonchial valves have got an umbrella shaped nitinol skeleton. Both valves are covered by a silicone membrane. Endobronchial valves are available in two different sizes, intrabronchial valves in three different sizes. Prior to valve implantation, the diameter of the bronchus that is considered to be blocked by the valves is estimated by using the measurement wings of the delivery system or a special balloon catheter. Afterwards, the appropriately sized valves are preloaded in a delivery catheter that can be introduced through a 2.8 mm or larger working channel of a standard flexible bronchoscope. The catheter is placed in the airway of the target lobe and by retracting the sheath, the valve can be deployed easily that expanded against the bronchial wall. The procedure can be performed under general anesthesia as well as under conscious sedation and takes generally 10 to 30 minutes depending on the number of valves that are placed.

#### **2.2 Endobronchial valves (EBV)**

The first published trials related to endoscopic lung volume reduction by valves were about the implantation of EBV in patients with severe heterogeneous emphysema by Toma et al. and Snell et al. in 2003 [12; 13]. Since then, several series have been published [14; 15]. The biggest and most noted trail however is the "Endobronchial Valve for Emphysema Palliation Trial" (VENT) that has been published by Sciurba et al. in 2007 [16]. In this prospective trial, 321 patients with severe emphysema were randomly assigned in a 2:1 ratio to receive endobronchial valve treatment or standard medical care. 6 months following the treatment, the results referring to the lung function test revealed a mean between groupdifference of 6.8% in FEV1.

observed. Therefore, different bronchoscopic approaches have been developed imitating the

Until now, there are various techniques of Endoscopic Lung VolumeReduction (ELVR) extending the therapeutic strategies in patients withsevere emphysema. In general, reversible blocking techniques and irreversible, non-blocking techniques can be distinguished. The application of these different techniques is dependent on the emphysema distribution and degree of collateral ventilation. Therefore, an accurate patient selection has

The first and most known method of endoscopic lung volume reduction is the implantation of valves in targeted most destroyed lung compartments in patients with heterogeneous emphysema [11]. These blocking devices allow the air to be expelled during expiration but prevent the air entering the target lobe during inspiration and so facilitating atelectasis to achieve lung volume reduction. Two different valves are available: endobronchial valves (EBV, Zephyr ®, Pulmonx, Inc., Palo Alto, Calif., USA) and intrabronchial valves (IBV,

The endobronchial (figure 1) and intrabronchial valves (figure 2) only differentiate in shape, but the implantation technique and their functional principle is very similar. The endobronchial valves consist of a cylindrical nitinol framework, whereas the intrabonchial valves have got an umbrella shaped nitinol skeleton. Both valves are covered by a silicone membrane. Endobronchial valves are available in two different sizes, intrabronchial valves in three different sizes. Prior to valve implantation, the diameter of the bronchus that is considered to be blocked by the valves is estimated by using the measurement wings of the delivery system or a special balloon catheter. Afterwards, the appropriately sized valves are preloaded in a delivery catheter that can be introduced through a 2.8 mm or larger working channel of a standard flexible bronchoscope. The catheter is placed in the airway of the target lobe and by retracting the sheath, the valve can be deployed easily that expanded against the bronchial wall. The procedure can be performed under general anesthesia as well as under conscious sedation and takes generally 10 to 30 minutes depending on the

The first published trials related to endoscopic lung volume reduction by valves were about the implantation of EBV in patients with severe heterogeneous emphysema by Toma et al. and Snell et al. in 2003 [12; 13]. Since then, several series have been published [14; 15]. The biggest and most noted trail however is the "Endobronchial Valve for Emphysema Palliation Trial" (VENT) that has been published by Sciurba et al. in 2007 [16]. In this prospective trial, 321 patients with severe emphysema were randomly assigned in a 2:1 ratio to receive endobronchial valve treatment or standard medical care. 6 months following the treatment, the results referring to the lung function test revealed a mean between group-

LVRS but with less morbidity and mortality.

**2. Reversible, blocking techniques** 

Spiration®, Olympus Medical Co., Tokio, Japan).

**2.1 Implantation technique** 

number of valves that are placed.

**2.2 Endobronchial valves (EBV)** 

difference of 6.8% in FEV1.

great importance.

Fig. 1. Endobronchial valve.

Fig. 2. Intrabronchial valve.

Endoscopic Lung Volume Reduction 93

[22]. The results demonstrated a greater benefit in patients receiving the unilateral endoscopic lung volume reduction with complete occlusion of one lobe. Significant differences were evaluated in FEV1 (+32.5% vs. +2.5%) as well as in the 6-minute-walk test (+43m vs. -19m). In conclusion, unilateral treatment with complete occlusion appears

Fig. 3. Catheter-based measurement of collateral ventilation. At the tip of the catheter, there is a balloon, that is be inflated within the airway to isolate the target lobe. The air is directed

Besides the blocking devices, there are various non-blocking techniques for bronchoscopic emphysema therapy. Implantation of lung volume reduction coils, polymeric lung volume reduction, bronchoscopic thermal vapour ablation and creation of airway bypasses can be

through the catheter to the console for measurement of air flow and air pressure.

**3. Irreversible, non-blocking techniques** 

superior to bilateral incomplete treatment but with higher risk of pneumothorax.

Furthermore, a mean between-group difference of 5.8% in the 6-minute-walk distance could be detected. Among the patients who received EBV, there was a greater reduction in the lung volume of the target lobe measured by high-resolution computed tomography (HRCT). At 12 months, the complication rate was 10.3% in the EBV group versus 4.2% in the control group. Some predictive characteristics were observed in sub analysis of this study. The beneficial effects were greatest in patients with presence of high heterogeneity of their emphysema distribution and an accurate lobar exclusion by the valves. Furthermore, interlobar fissure integrity that was analyzed as a surrogate for collateral ventilation (CV) in the computed tomography has also been observed as an independent predictor of treatment response. Therefore it is thought that CV is one of the most relevant factors responsible for valve therapy failure. Nowadays, there are two different options to predict the CV and thus the success of valve treatment. On the one hand, fissure integrity can be assessed in the HRCT, on the other hand, a catheter-based endobronchial approach providing quantitatively measurement of collateral resistance has been proposed (figure 3). In one double-blind prospective study in 2010 evaluating the safety and feasibility of this catheter-based system 25 patients with heterogeneous emphysema underwent the endobronchial determination of collateral resistance by using the catheter-based system followed by an EBV treatment [17]. In all patients, the resistance measurement was safely and successfully achieved. A correlation of the measurements with the event of atelectasis after ELVR was found in 90% of the analyzable cases. In a following multicenter study covering patients with severe heterogeneous upper lobe or lower lobe predominant emphysema, the accuracy of this catheter-based system in correctly predicting the target lobe volume reduction was evaluated [18]. Following the CV measurement by using the catheter-based system a complete occlusion of the target lobe by EBV was performed. The target lobe volume reduction after the valve implantation was assessed by HRCT 30 days following the intervention. Out of 80 patients, CV assessment prospectively showed a low CV in 51 patients and a high CV in 29 patients. The accuracy of the catheter-based system in correctly predicting the target lobe volume reduction was found to be 75%. Therefore, this quantitatively measurement of collateral ventilation predicts of whether endoscopic lung volume reduction would be successfully or not.

#### **2.3 Intrabronchial valves (IBV)**

There are also several published trials confirming the efficacy of the treatment with intrabronchial valves in patients with heterogeneous emphysema. In most of these studies a bilateral incomplete occlusion of both lobes in patients with upper lobe predominant emphysema was performed to minimize the risk of pneumothorax. The results showed an improvement in health-related quality of life and regional lung volume changes measured by quantitative and qualitative analysis of HRCT [19; 20; 21]. However, in all these studies no significant change in lung function test or 6-minute-walk test could be observed. Therefore, it is thought, that bilateral partial closure leads to redistribution of ventilation but avoid atelectasis with subsequent absence of improvement of these objective clinical outcome measures. To evaluate this hypothesis, a randomized prospective study comparing unilateral complete versus bilateral incomplete endoscopic lung volume reduction by IBV implantation in 20 patients with severe upper lobe predominant emphysema was performed

Furthermore, a mean between-group difference of 5.8% in the 6-minute-walk distance could be detected. Among the patients who received EBV, there was a greater reduction in the lung volume of the target lobe measured by high-resolution computed tomography (HRCT). At 12 months, the complication rate was 10.3% in the EBV group versus 4.2% in the control group. Some predictive characteristics were observed in sub analysis of this study. The beneficial effects were greatest in patients with presence of high heterogeneity of their emphysema distribution and an accurate lobar exclusion by the valves. Furthermore, interlobar fissure integrity that was analyzed as a surrogate for collateral ventilation (CV) in the computed tomography has also been observed as an independent predictor of treatment response. Therefore it is thought that CV is one of the most relevant factors responsible for valve therapy failure. Nowadays, there are two different options to predict the CV and thus the success of valve treatment. On the one hand, fissure integrity can be assessed in the HRCT, on the other hand, a catheter-based endobronchial approach providing quantitatively measurement of collateral resistance has been proposed (figure 3). In one double-blind prospective study in 2010 evaluating the safety and feasibility of this catheter-based system 25 patients with heterogeneous emphysema underwent the endobronchial determination of collateral resistance by using the catheter-based system followed by an EBV treatment [17]. In all patients, the resistance measurement was safely and successfully achieved. A correlation of the measurements with the event of atelectasis after ELVR was found in 90% of the analyzable cases. In a following multicenter study covering patients with severe heterogeneous upper lobe or lower lobe predominant emphysema, the accuracy of this catheter-based system in correctly predicting the target lobe volume reduction was evaluated [18]. Following the CV measurement by using the catheter-based system a complete occlusion of the target lobe by EBV was performed. The target lobe volume reduction after the valve implantation was assessed by HRCT 30 days following the intervention. Out of 80 patients, CV assessment prospectively showed a low CV in 51 patients and a high CV in 29 patients. The accuracy of the catheter-based system in correctly predicting the target lobe volume reduction was found to be 75%. Therefore, this quantitatively measurement of collateral ventilation predicts of whether endoscopic lung

There are also several published trials confirming the efficacy of the treatment with intrabronchial valves in patients with heterogeneous emphysema. In most of these studies a bilateral incomplete occlusion of both lobes in patients with upper lobe predominant emphysema was performed to minimize the risk of pneumothorax. The results showed an improvement in health-related quality of life and regional lung volume changes measured by quantitative and qualitative analysis of HRCT [19; 20; 21]. However, in all these studies no significant change in lung function test or 6-minute-walk test could be observed. Therefore, it is thought, that bilateral partial closure leads to redistribution of ventilation but avoid atelectasis with subsequent absence of improvement of these objective clinical outcome measures. To evaluate this hypothesis, a randomized prospective study comparing unilateral complete versus bilateral incomplete endoscopic lung volume reduction by IBV implantation in 20 patients with severe upper lobe predominant emphysema was performed

volume reduction would be successfully or not.

**2.3 Intrabronchial valves (IBV)** 

[22]. The results demonstrated a greater benefit in patients receiving the unilateral endoscopic lung volume reduction with complete occlusion of one lobe. Significant differences were evaluated in FEV1 (+32.5% vs. +2.5%) as well as in the 6-minute-walk test (+43m vs. -19m). In conclusion, unilateral treatment with complete occlusion appears superior to bilateral incomplete treatment but with higher risk of pneumothorax.

Fig. 3. Catheter-based measurement of collateral ventilation. At the tip of the catheter, there is a balloon, that is be inflated within the airway to isolate the target lobe. The air is directed through the catheter to the console for measurement of air flow and air pressure.

### **3. Irreversible, non-blocking techniques**

Besides the blocking devices, there are various non-blocking techniques for bronchoscopic emphysema therapy. Implantation of lung volume reduction coils, polymeric lung volume reduction, bronchoscopic thermal vapour ablation and creation of airway bypasses can be

Endoscopic Lung Volume Reduction 95

preformed shape leading to parenchymal compression. Figure 4 shows a chest x-ray following implantation of coils in the right upper lobe. In a pilot study using coils in heterogeneous as well as in homogeneous emphysema, the patients with predominant heterogeneous disease appeared to show more substantial improvements in pulmonary function, lung volumes, 6 minute walk test and quality of life measures than patients with homogeneous disease [23]. According to these results, a study investigating the efficacy of LVRC treatment in 16 patients with only severe heterogeneous emphysema was performed [24]. 12 patients were treated bilaterally, 4 patients underwent treatment in one lobe. A median of 10 coils per lobe were placed. LVRC treatment in all patients resulted in significant improvements in pulmonary function, exercise capacity and quality of life, with

Polymeric lung volume reduction (PLVR, Aeris therapeutics, Inc. Woburn, Mass., USA) consists of administration of a foam sealant in the destroyed lung compartment resulting in local inflammatory reaction. This inflammation leads to fibrosis and scarring with subsequent lung volume reduction (figure 5a and 5b). PLVR can be offered to patients with heterogeneous disease, but also patients with homogeneous disease experience improvement after PLVR. However, further trials evaluating the efficacy of PLVR in

The sealant is administered via a special single lumen catheter that is inserted through the working channel of a standard flexible bronchoscope until its tip extends approximately 4 cm from the tip of the scope. During the administration of the sealant, the bronchoscope is maintained in wedge position preventing backflow of the sealant at the airway subsegment. The injection time of the sealant that is prepared in a syringe takes about 10-20 seconds. The bronchoscope should be maintained in wedge position for one minute following delivery to allow complete in situ polymerization. Afterwards, the bronchoscope is repositioned at the

The first studies related to PLVR showed encouraging results with beneficial effects in selected patients with heterogeneous emphysema [26; 27] as well as with homogeneous emphysema [28]. Furthermore, a multicenter dose-ranging study revealed, that patients who received high dose treatment with 20 ml per subsegment experienced greater improvement in clinical outcomes than patients with a low dose treatment with 10 ml per subsegment [27]. In these trials, biological reagents were instillated to initiate an inflammatory reaction and a collapse of targeted lung portions, but it then was replaced by synthetic AeriSeal foam

In one recently published multicenter trial, 25 patients with severe upper lobe predominant emphysema underwent PLVR by using AeriSeal foam [29]. All patients tolerated the treatment without significant adverse events. However, a flu-like reaction following the procedure could be detected in all patients. 24 weeks after the PLVR, physiological and clinical benefits were observed. Furthermore, efficacy responses were better among the patients with COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage

an acceptable safety.

**3.2 Polymeric Lung Volume Reduction (PLVR)** 

patients with severe homogeneous emphysema are needed.

next subsegment and the procedure is repeated [25].

that allows a simpler production without blood products.

III than among patients with COPD GOLD stage IV.

distinguished. These techniques seem to be independent of collateral ventilation, however these methods are irreversible.

Fig. 4. Chest x-ray following the implantation of lung volume reduction coils in the right upper lobe. In courtesy of Prof. Dr. med. CP Heussel, Thoraxklinik Heidelberg.

#### **3.1 Lung Volume Reduction Coils (LVRC)**

One of these non-blocking endoscopic techniques is the implantation of lung volume reduction coils (LVRC, PneumRx, Inc., Mountain View, Calif., USA). These coils consisting of a nitinol wire have got a preformed shape that results in parenchymal compression and thus achieving a lung volume reduction. For implantation, the airway is identified bronchoscopically. Afterwards a low stiffness guidewire is advanced into the airway under fluoroscopic guidance with a distance of 15 mm between the distal end of the guidewire and the pleura. Next, a catheter is passed over the guidewire. Then the guidewire is removed and a straightened LVRC is introduced. As the catheter is pulled back, the coil assumes its

distinguished. These techniques seem to be independent of collateral ventilation, however

Fig. 4. Chest x-ray following the implantation of lung volume reduction coils in the right

One of these non-blocking endoscopic techniques is the implantation of lung volume reduction coils (LVRC, PneumRx, Inc., Mountain View, Calif., USA). These coils consisting of a nitinol wire have got a preformed shape that results in parenchymal compression and thus achieving a lung volume reduction. For implantation, the airway is identified bronchoscopically. Afterwards a low stiffness guidewire is advanced into the airway under fluoroscopic guidance with a distance of 15 mm between the distal end of the guidewire and the pleura. Next, a catheter is passed over the guidewire. Then the guidewire is removed and a straightened LVRC is introduced. As the catheter is pulled back, the coil assumes its

upper lobe. In courtesy of Prof. Dr. med. CP Heussel, Thoraxklinik Heidelberg.

**3.1 Lung Volume Reduction Coils (LVRC)** 

these methods are irreversible.

preformed shape leading to parenchymal compression. Figure 4 shows a chest x-ray following implantation of coils in the right upper lobe. In a pilot study using coils in heterogeneous as well as in homogeneous emphysema, the patients with predominant heterogeneous disease appeared to show more substantial improvements in pulmonary function, lung volumes, 6 minute walk test and quality of life measures than patients with homogeneous disease [23]. According to these results, a study investigating the efficacy of LVRC treatment in 16 patients with only severe heterogeneous emphysema was performed [24]. 12 patients were treated bilaterally, 4 patients underwent treatment in one lobe. A median of 10 coils per lobe were placed. LVRC treatment in all patients resulted in significant improvements in pulmonary function, exercise capacity and quality of life, with an acceptable safety.

#### **3.2 Polymeric Lung Volume Reduction (PLVR)**

Polymeric lung volume reduction (PLVR, Aeris therapeutics, Inc. Woburn, Mass., USA) consists of administration of a foam sealant in the destroyed lung compartment resulting in local inflammatory reaction. This inflammation leads to fibrosis and scarring with subsequent lung volume reduction (figure 5a and 5b). PLVR can be offered to patients with heterogeneous disease, but also patients with homogeneous disease experience improvement after PLVR. However, further trials evaluating the efficacy of PLVR in patients with severe homogeneous emphysema are needed.

The sealant is administered via a special single lumen catheter that is inserted through the working channel of a standard flexible bronchoscope until its tip extends approximately 4 cm from the tip of the scope. During the administration of the sealant, the bronchoscope is maintained in wedge position preventing backflow of the sealant at the airway subsegment. The injection time of the sealant that is prepared in a syringe takes about 10-20 seconds. The bronchoscope should be maintained in wedge position for one minute following delivery to allow complete in situ polymerization. Afterwards, the bronchoscope is repositioned at the next subsegment and the procedure is repeated [25].

The first studies related to PLVR showed encouraging results with beneficial effects in selected patients with heterogeneous emphysema [26; 27] as well as with homogeneous emphysema [28]. Furthermore, a multicenter dose-ranging study revealed, that patients who received high dose treatment with 20 ml per subsegment experienced greater improvement in clinical outcomes than patients with a low dose treatment with 10 ml per subsegment [27]. In these trials, biological reagents were instillated to initiate an inflammatory reaction and a collapse of targeted lung portions, but it then was replaced by synthetic AeriSeal foam that allows a simpler production without blood products.

In one recently published multicenter trial, 25 patients with severe upper lobe predominant emphysema underwent PLVR by using AeriSeal foam [29]. All patients tolerated the treatment without significant adverse events. However, a flu-like reaction following the procedure could be detected in all patients. 24 weeks after the PLVR, physiological and clinical benefits were observed. Furthermore, efficacy responses were better among the patients with COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage III than among patients with COPD GOLD stage IV.

Endoscopic Lung Volume Reduction 97

Bronchoscopic thermal vapor ablation (BTVA, Uptake Medical, Seattle, Wash., USA) is an alternative method that is very similar to PLVR. This technique consists of a vapor generator and a special InterVapor catheter used to deliver heated water vapor bronchoscopically to the most destroyed lung regions. The vapor induces an inflammatory reaction with subsequent fibrosis and scarring leading to lung volume reduction (figure 6a and 6b).

(a)

(b) Fig. 6. Computed tomography taken prior to bronchoscopic thermal vapor ablation (a) in the

right upper lobe. 6 months following the treatment a lobar volume reduction can be observed (b). In courtesy of Prof. Dr. med. CP Heussel, Thoraxklinik Heidelberg.

**3.3 Bronchoscopic Thermal Vapor Ablation (BTVA)** 

(b)

Fig. 5. Computed tomography acquired prior to polymeric lung volume reduction (a) in the left upper lobe and matched CT scan (b) taken 6 months following the treatment. The shift of the interlobar fissure shows the target lobe volume reduction. In courtesy of Prof. Dr. med. CP Heussel, Thoraxklinik Heidelberg.

(a)

(b) Fig. 5. Computed tomography acquired prior to polymeric lung volume reduction (a) in the left upper lobe and matched CT scan (b) taken 6 months following the treatment. The shift of the interlobar fissure shows the target lobe volume reduction. In courtesy of Prof. Dr.

med. CP Heussel, Thoraxklinik Heidelberg.

#### **3.3 Bronchoscopic Thermal Vapor Ablation (BTVA)**

Bronchoscopic thermal vapor ablation (BTVA, Uptake Medical, Seattle, Wash., USA) is an alternative method that is very similar to PLVR. This technique consists of a vapor generator and a special InterVapor catheter used to deliver heated water vapor bronchoscopically to the most destroyed lung regions. The vapor induces an inflammatory reaction with subsequent fibrosis and scarring leading to lung volume reduction (figure 6a and 6b).

(a)

(b)

Fig. 6. Computed tomography taken prior to bronchoscopic thermal vapor ablation (a) in the right upper lobe. 6 months following the treatment a lobar volume reduction can be observed (b). In courtesy of Prof. Dr. med. CP Heussel, Thoraxklinik Heidelberg.

Endoscopic Lung Volume Reduction 99

Patients with severe emphysema have to undergo a screening basic examination programme including lung function testing (spirometry, bodyplethysmography, diffusing capacity measurements), blood gases and exercise tests (6-minute-walk test). Electrocardiogramm, echocardiogram, chest x-ray as well as laboratory testing provide to evaluate patient´s clinical status prior to bronchoscopic intervention. To determine the emphysema distribution as well as fissure integrity, high resolution computed tomography scan at full inspiration and perfusion scan are necessary. Different visual scoring systems e.g. YACTA®, Pulmo® or Volume® can be used for detailed quantitative emphysema analysis. As alternative method to fissure analysis by HRCT, the catheter-based

According to the VENT, following inclusion criteria should be fulfilled: forced expiratory volume in 1 s (FEV1) < 45%, total lung capacity (TLC) > 100%, residual volume (RV) > 150 %, a partial pressure of arterial carbon dioxide of 50 mm Hg or less, a partial pressure of arterial oxygen of at least 45 mm Hg (without oxygen therapy), a 6-minute-walk distance of > 140 m. Greatest beneficial effects can be observed in patients with a severe hyperinflation with a RV > 200% and a high RV/TLC. Depending on the emphysema distribution and the fissure integrity, the method of endoscopic lung volume reduction is chosen (see figure 1).

measurement can be performed to evaluate the degree of collateral ventilation.

Fig. 7. Patient selection and therapy algorithm.

After identifying the target airway bronchoscopically, the InterVapor catheter is introduced through the working channel of the flexible bronchoscope. At the tip of the catheter there is a balloon that can be inflated within the airway so that the target lung region is isolated. Next, a predetermined dose of 125° C heated water vapor is delivered via the special InterVapor catheter.

In a 2009 reported study, 11 patients with heterogeneous emphysema treated by unilateral BTVA confirmed the feasibility and an acceptable safety profile [30]. Furthermore, an improvement of health-related quality of life could be observed. A recently published multinational single arm study evaluated the efficacy of the bronchoscopic thermal vapor ablation in 44 patients with upper lobe predominant emphysema. 24 patients received BTVA in the right upper lobe, 20 patients were treated in the left upper lobe in a single procedure with a target vapor dose of 10 cal/g. During the procedure, no adverse events could be observed. The most common adverse events following the treatment were COPD exacerbations, pneumonia and haemoptysis. 6 months following the treatment, efficacy data showed a 48% reduction of treated lobar volume assessed by HRCT measurement. Furthermore, the patients experienced significant improvement in lung function, exercise capacity and health-related quality of life [31].

#### **3.4 Airway bypass**

The creation of extra-anatomic passageways through the normal bronchial wall allowing the trapped air to escape presents a method of endoscopic lung volume reduction in patients with severe homogeneous emphysema (EASE, Broncus Technologies, Inc. Mountain View, USA).

The procedure is performed by using a standard flexible bronchoscope. After identifying the appropriate airway, a Doppler probe is used to confirm the absence of vessels behind the airway wall. Afterwards, the wall is punctured by a transbronchial needle. A balloon catheter is advanced into this hole and the balloon is inflated to enlarge the hole. After repeated confirmation of absence of vessels, a drug-eluting stent (DES) is placed to keep the bypass open over time. The trapped air can escape by bypassing the small airways leading to a lung volume reduction.

In one large prospective, sham-controlled study - EASE trial (Exhale Airway Stents for Emphysema) - 315 patients with severe homogeneous emphysema were subdivided into two groups [32]: only 208 patients out of the 315 patients received the airway bypasses. Immediately post procedure, reductions in lung volume could be evaluated demonstrating proof of concept for airway bypass. However, for the overall group, the initial benefit decreases by 6 months so that at least no sustainable benefit could be recorded with airway bypass in the patients with homogeneous emphysema. The most probable cause for loss of initial benefit is stent occlusion by mucus. Therefore, improvement of durability is required before airway bypasses could be recommend as beneficial therapy.

#### **4. Patient selection**

An accurate patient selection is the most important and most difficult issue in the area of endoscopic lung volume reduction. The various approaches require different conditions that must be fulfilled to achieve beneficial outcome. Therefore a treatment algorithm is necessary for identifying the best candidates for the different techniques of endoscopic lung volume reduction.

After identifying the target airway bronchoscopically, the InterVapor catheter is introduced through the working channel of the flexible bronchoscope. At the tip of the catheter there is a balloon that can be inflated within the airway so that the target lung region is isolated. Next, a predetermined dose of 125° C heated water vapor is delivered via the special

In a 2009 reported study, 11 patients with heterogeneous emphysema treated by unilateral BTVA confirmed the feasibility and an acceptable safety profile [30]. Furthermore, an improvement of health-related quality of life could be observed. A recently published multinational single arm study evaluated the efficacy of the bronchoscopic thermal vapor ablation in 44 patients with upper lobe predominant emphysema. 24 patients received BTVA in the right upper lobe, 20 patients were treated in the left upper lobe in a single procedure with a target vapor dose of 10 cal/g. During the procedure, no adverse events could be observed. The most common adverse events following the treatment were COPD exacerbations, pneumonia and haemoptysis. 6 months following the treatment, efficacy data showed a 48% reduction of treated lobar volume assessed by HRCT measurement. Furthermore, the patients experienced significant improvement in lung function, exercise

The creation of extra-anatomic passageways through the normal bronchial wall allowing the trapped air to escape presents a method of endoscopic lung volume reduction in patients with severe homogeneous emphysema (EASE, Broncus Technologies, Inc. Mountain View, USA). The procedure is performed by using a standard flexible bronchoscope. After identifying the appropriate airway, a Doppler probe is used to confirm the absence of vessels behind the airway wall. Afterwards, the wall is punctured by a transbronchial needle. A balloon catheter is advanced into this hole and the balloon is inflated to enlarge the hole. After repeated confirmation of absence of vessels, a drug-eluting stent (DES) is placed to keep the bypass open over time. The trapped air can escape by bypassing the small airways leading

In one large prospective, sham-controlled study - EASE trial (Exhale Airway Stents for Emphysema) - 315 patients with severe homogeneous emphysema were subdivided into two groups [32]: only 208 patients out of the 315 patients received the airway bypasses. Immediately post procedure, reductions in lung volume could be evaluated demonstrating proof of concept for airway bypass. However, for the overall group, the initial benefit decreases by 6 months so that at least no sustainable benefit could be recorded with airway bypass in the patients with homogeneous emphysema. The most probable cause for loss of initial benefit is stent occlusion by mucus. Therefore, improvement of durability is required

An accurate patient selection is the most important and most difficult issue in the area of endoscopic lung volume reduction. The various approaches require different conditions that must be fulfilled to achieve beneficial outcome. Therefore a treatment algorithm is necessary for identifying the best candidates for the different techniques of endoscopic lung volume

before airway bypasses could be recommend as beneficial therapy.

InterVapor catheter.

**3.4 Airway bypass** 

to a lung volume reduction.

**4. Patient selection** 

reduction.

capacity and health-related quality of life [31].

Patients with severe emphysema have to undergo a screening basic examination programme including lung function testing (spirometry, bodyplethysmography, diffusing capacity measurements), blood gases and exercise tests (6-minute-walk test). Electrocardiogramm, echocardiogram, chest x-ray as well as laboratory testing provide to evaluate patient´s clinical status prior to bronchoscopic intervention. To determine the emphysema distribution as well as fissure integrity, high resolution computed tomography scan at full inspiration and perfusion scan are necessary. Different visual scoring systems e.g. YACTA®, Pulmo® or Volume® can be used for detailed quantitative emphysema analysis. As alternative method to fissure analysis by HRCT, the catheter-based measurement can be performed to evaluate the degree of collateral ventilation.

Fig. 7. Patient selection and therapy algorithm.

According to the VENT, following inclusion criteria should be fulfilled: forced expiratory volume in 1 s (FEV1) < 45%, total lung capacity (TLC) > 100%, residual volume (RV) > 150 %, a partial pressure of arterial carbon dioxide of 50 mm Hg or less, a partial pressure of arterial oxygen of at least 45 mm Hg (without oxygen therapy), a 6-minute-walk distance of > 140 m. Greatest beneficial effects can be observed in patients with a severe hyperinflation with a RV > 200% and a high RV/TLC. Depending on the emphysema distribution and the fissure integrity, the method of endoscopic lung volume reduction is chosen (see figure 1).

Endoscopic Lung Volume Reduction 101

or lower lobe predominant emphysema and low collateral ventilation. Irreversible, nonblocking techniques that seem to be independent of collateral ventilation are minimally invasive endoscopic approaches for patients with upper lobe predominant emphysema.

[1] Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S.

[2] Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL- Global Burden of Disease

[3] Macnee W. Chronic Obstructive Pulmonary Disease: Epidemiology, Physiology and

[5] Marchand E, Gavan-Ramirez G, De Leyn P, Decramer M. Physiological basis of

[6] Fessler, HE, Reilly JR, Sugarbaker DJ. Lung Volume Reduction Surgery for Emphysema.

[7] Cooper JD, Patterson GA, Sundaresan RS et al. Results of 150 consecutive bilateral lung

[8] Sciurba FC, Rogers RM, Keenan RJ, Slivka WA, Gorcsan J 3rd, Ferson PF, Holbert JM,

[9] Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P,

[10] Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood

[12] Toma TP, Hopkinson NS, Hillier J, Hansell DM, Morgan C, Goldstraw PG, Polkey MI,

[13] Snell GI, Holsworth L, Borrill ZL, Thomson KR, Kalff V, Smith JA, Williams TJ. The

[14] Venuta F, de Giacomo T, Rendina EA et al. Bronchoscopic lung-volume reduction with

[15] Wan IY, Toma TP, Geddes DM et al. Bronchoscopic lung volume reduction for endstage emphysema: report on the first 98 patients. Chest 2006; 129: 518-526. [16] Sciurba FC, Ernst A, Herth FJF, Strange C, Criner GJ, Marquette CH, Kovitz KL,

therapy for severe emphysema. N Engl J Med 2003; 348: 2059–2073. [11] Herth FJF, Gompelmann D, Ernst A, Eberhardt R. Endoscopic Lung Volume Reduction.

and Risk Factors. In: Washington (DC): World Bank. 2006.

diagnosis, management and prevention of COPD.

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improvement after lung volume reduction surgery for severe emphysema: where

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Brown ML, Landreneau RJ. Improvement in pulmonary function and elastic recoil after lung-volume reduction surgery for diffuse emphysema. N Engl J Med 1996.

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DE: A randomized trial comparing lung-volume-reduction surgery with medical

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Chiacchierini RP, Goldin J, McLennan G; VENT Study Research Group. A

**7. References** 

Respi J 2006. 27:397-412.

### **5. Complications**

#### **5.1 Valve Implantation**

The most common adverse event following valve implantation is pneumonia distal the valves despite the valves allow secretion to pass. The VENT revealed a pneumonia rate of 4.2% [16]. In 1/3 of these cases, valve removal was necessary for recovery. In very rare cases, development of bronchiectasis can be observed distal the valves requiring valve removal. Another frequent risk is pneumothorax after valve treatment. Therefore, pneumothorax must be ruled out by chest x-ray 2 hours and 24 h following the intervention. Pneumothorax occurs particularly in patients who experience a great improvement in clinical outcome following valve placement due to a rapid atelectasis. Chest tube drainage is required in some patients with lung collapse. In case of persistent fistula, the removal of one of the implanted valves provides lung expanding and thus sealing fistula. Surgical intervention is only needed to treat fistula that remains persistent despite of adequate chest tube drainage and valve removal. Development of granulation tissue formation that is often associated with bleeding complication is another side effect related to valves due to the pressure of the valves on the mucosa. Cryotherapy is recommended for the treatment of severe granulation tissue formation. New or worsening hypercapnia is another adverse event. Therefore, repeated blood gas analysis following the valve implantation is required. Only in few cases non-invasive ventilation and/or valve removal is necessary. COPD exacerbation, mild haemoptysis, chest pain and valve migration are other anticipated complications to valve treatment.

#### **5.2 Coil Implantation**

Side effects rated as possibly related to either the procedure or the device are haemoptysis, dyspnoea, cough, COPD exacerbations, peumonia and chest pain. Pneumothorax can also occur following coil implantation. To minimize risk of pneumothorax, a distance of at least 15 mm to pleura should be kept.

#### **5.3 Polymeric Lung Volume Reduction and Bronchoscopic Thermal Vapor Ablation**

The effect of PLVR and BTVA is based on an inflammatory reaction that results in fibrosis, scarring and shrinking. Due to this inflammation, the majority of the patients experience a "flu-like" reaction with dyspnoea, transient fever, pleuritic chest pain, leucocytosis, elevated C-reactive protein and infiltration in chest x-ray. This inflammatory response is self-limiting and resolves within 24-96 h with supportive care. Especially, systemic application of glucocorticosteroids is useful to diminish the symptoms following PLVR. Furthermore, a 7 day course of antibiotic prophylaxis for one week is required in each patient. Other adverse effects following PLVR and BTVA include COPD exacerbation, pneumonia, bronchitis or haemoptysis.

### **6. Conclusion**

Endoscopic lung volume reduction presents an encouraging therapy modality for patients with advanced emphysema. However, efficacy depends strictly on patient selection requiring an appropriate diagnostic and treatment algorithm for identifying the best candidates for each of the various ELVR techniques. Complete lobar occlusion by valve implantation provides an effective option for patients with severe heterogeneous upper lobe or lower lobe predominant emphysema and low collateral ventilation. Irreversible, nonblocking techniques that seem to be independent of collateral ventilation are minimally invasive endoscopic approaches for patients with upper lobe predominant emphysema.

#### **7. References**

100 Emphysema

The most common adverse event following valve implantation is pneumonia distal the valves despite the valves allow secretion to pass. The VENT revealed a pneumonia rate of 4.2% [16]. In 1/3 of these cases, valve removal was necessary for recovery. In very rare cases, development of bronchiectasis can be observed distal the valves requiring valve removal. Another frequent risk is pneumothorax after valve treatment. Therefore, pneumothorax must be ruled out by chest x-ray 2 hours and 24 h following the intervention. Pneumothorax occurs particularly in patients who experience a great improvement in clinical outcome following valve placement due to a rapid atelectasis. Chest tube drainage is required in some patients with lung collapse. In case of persistent fistula, the removal of one of the implanted valves provides lung expanding and thus sealing fistula. Surgical intervention is only needed to treat fistula that remains persistent despite of adequate chest tube drainage and valve removal. Development of granulation tissue formation that is often associated with bleeding complication is another side effect related to valves due to the pressure of the valves on the mucosa. Cryotherapy is recommended for the treatment of severe granulation tissue formation. New or worsening hypercapnia is another adverse event. Therefore, repeated blood gas analysis following the valve implantation is required. Only in few cases non-invasive ventilation and/or valve removal is necessary. COPD exacerbation, mild haemoptysis, chest

pain and valve migration are other anticipated complications to valve treatment.

Side effects rated as possibly related to either the procedure or the device are haemoptysis, dyspnoea, cough, COPD exacerbations, peumonia and chest pain. Pneumothorax can also occur following coil implantation. To minimize risk of pneumothorax, a distance of at least

**5.3 Polymeric Lung Volume Reduction and Bronchoscopic Thermal Vapor Ablation**  The effect of PLVR and BTVA is based on an inflammatory reaction that results in fibrosis, scarring and shrinking. Due to this inflammation, the majority of the patients experience a "flu-like" reaction with dyspnoea, transient fever, pleuritic chest pain, leucocytosis, elevated C-reactive protein and infiltration in chest x-ray. This inflammatory response is self-limiting and resolves within 24-96 h with supportive care. Especially, systemic application of glucocorticosteroids is useful to diminish the symptoms following PLVR. Furthermore, a 7 day course of antibiotic prophylaxis for one week is required in each patient. Other adverse effects following PLVR and BTVA include COPD exacerbation, pneumonia, bronchitis or

Endoscopic lung volume reduction presents an encouraging therapy modality for patients with advanced emphysema. However, efficacy depends strictly on patient selection requiring an appropriate diagnostic and treatment algorithm for identifying the best candidates for each of the various ELVR techniques. Complete lobar occlusion by valve implantation provides an effective option for patients with severe heterogeneous upper lobe

**5. Complications 5.1 Valve Implantation** 

**5.2 Coil Implantation** 

haemoptysis.

**6. Conclusion** 

15 mm to pleura should be kept.


**7** 

**Surgical Management of Prolonged Air Leak** 

Prolonged air leak is one of the most common post-operative complications encountered after thoracic surgical operations involving mobilization or resection of lung parenchyma. Air leak typically manifests as persistent bubbling in a chest tube drainage system, but may also present with increasing subcutaneous emphysema or pneumothorax in a post-operative patient. No universal consensus exist as to the exact duration of air leak which constitutes a prolonged air leak, but it is generally regarded to exist if it is present for more than 5 days(1- 4) or 7 days(2, 5-7) after initial surgery. It is an important complication that results in increased length of stay(8-15) and has been associated with other post-operative complications such as pneumonia(12, 14, 16), empyema(9, 10, 16) and ICU re-admission(12). Patients with emphysema form a significant proportion of patients which will undergo thoracic surgical operations. Chronic smoking and emphysema predisposes an individual to developing a pneumothorax(17, 18) or carcinoma of the lung(19, 20) that may require surgical intervention for treatment. In addition, lung volume reduction surgery plays a role in the management of certain patients with advanced emphysema(21). Conversely, emphysema is regarded as a risk factor for developing prolonged air leak in cases where patients with emphysema require an operation(7). This is presumably because the underlying lung substrate in patients with emphysema is more easily injured during

The role of emphysema as a risk factor for prolonged air leak has been inferred from numerous surgical case series which reliably demonstrate that patients noted preoperatively to have emphysema will have a higher incidence of prolonged air leak. However, a major weakness of these studies, is that they are heterogenous in their definition of prolonged air leak, patient population (eg age, definition of impaired lung function), type of operation performed (eg video assisted vs open, chemical vs mechanical pleurodesis, type/extent of resection) and methods used to prevent air leak (eg use of pleural tenting), which limits the ability to compare between individual studies. In addition, several studies analyzing the specific risk factors for developing this complication have consistently shown

**1. Introduction** 

surgery and takes longer to heal.

**in Patients with Underlying Emphysema** 

Boon-Hean Ong1, Bien-Keem Tan2 and Chong-Hee Lim1

*2Department of Plastic, Reconstructive and Aesthetic Surgery,* 

*1Department of Cardiothoracic Surgery, National Heart Centre Singapore* 

 *Singapore General Hospital* 

*Singapore* 

Randomized Study of Endobronchial Valves for Advanced Emphysema. N Engl J Med 2010; 363(13): 1233-1244.


## **Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema**

Boon-Hean Ong1, Bien-Keem Tan2 and Chong-Hee Lim1 *1Department of Cardiothoracic Surgery, National Heart Centre Singapore 2Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital Singapore* 

#### **1. Introduction**

102 Emphysema

[17] Gompelmann D, Eberhardt R, Michaud G, Ernst A, Herth FJ. Predicting atelectasis by

[18] Gompelmann D, Eberhardt R, Slebos DJ, Ficker J, Reichenberger F, Schmidt B, Ek L,

[19] Wood DE, McKenna RJ, Yusan RD et al. A Multi-Center Trial of an intrabronchial Valve

[20] Springmeyer SC, Bolliger SC, Waddell TK et al. Treatment of heterogeneous emphysema using the Spiration IBV Valves. Thorac Surg Clinic 2009. [21] Sterman DH, Mehta AC, Wood De et al. A Multicenter Pilot Study of a Bronchial Valve

[22] Eberhardt R, Gompelmann D, Schuhmann M, Heussel CP, Herth FJF. Unilateral vs.

[23] Herth FJF, Eberhardt R, Ernst A: Pilot study of an improved lung volume reduction coil for the treatment of emphysema. Am J Respir Crit Care Med 2009; 179:A6160. [24] Slebos DJ, Kerstjens HAM, Ernst A, Blaas SH, Gesierich WJ, Herth F. Bronchoscopic lung volume reduction coil treatment of severe heterogeneous emphysema. ERS 2010. [25] Herth FJ, Eberhardt R, Ingenito EP, Gompelmann D. Assessment of a novel lung sealant

[26] Reilly J, Washko G, Pinto-Plata V, Velez E, Kenney L, Berger R, Celli B. Biological lung

[27] Criner GJ, Pinot-Plata V, Strange C et al. Biologic lung volume reduction in advanced upper lobe emphysema: Phase 2 results. Am J Respir Crit Care 2009. 179:791-798. [28] Refaely Y, Dransfield M, Kramer MR, Gotfried M, Leeds W, McLennan G, Tewari S,

[29] Herth FJ, Gompelmann D, Stanzel F, Bonnet R, Behr J, Schmidt B, Magnussen H, Ernst

[30] Snell GI, Hopkins P, Wetsall G, Holsworth L, Carle A, Williams TJ. A feasibility and

[31] Snell G, Herth FJF, Hopkins P, Baker K, Witt Christian, Gotfried MH, Valipour A,

randomized, sham-controlled, multicentre trial. Lancet 2011. 378:997-1005.

for the Treatment of Severe Emphysema. Respiration 2010.

emphysema. Expert Rev Med Devices 2011. 8:307-312.

homogeneous emphysema. Eur Respir J 2010. 36:20-27.

Sealant (AeriSeal®). Epub ahead of print.

Ann Thorac Surg 2009. 88:1993-1998.

emphysema: A comparative randomised case study. ERS 2010.

Med 2010; 363(13): 1233-1244.

2007. 133:65-73.

2007. 131:1108-1113.

a feasibility study. Respiration 2010. 80:419-425

subgroup analysis. ERS 2011. Abstract 373.

Randomized Study of Endobronchial Valves for Advanced Emphysema. N Engl J

assessment of collateral ventilation prior to endobronchial lung volume reduction:

Herth FJF. Study of the use of Chartis® pulmonary assessment system to optimize subject selection for endobronchial lung volume reduction (ELVR) – Results and

for Treatment of Severe Emphysema. Journal of Thoracic and Cardiovasc Surg

bilateral endoscopic lung volume reduction in patients with severe heterogeneous

for performing endoscopic volume reduction therapy in patients with advanced

volume reduction: a new bronchoscopic therapy for advanced emphysema. Chest

Krasna M, Criner GJ. Biological lung volume reduction therapy for advanced

A, Eberhardt R. Treatment of Advanced Emphysema with Emphysematous Lung

safety study of bronchoscopic thermal vapor ablation: a novel emphysema therapy.

Wagner M, Stanzel F, Egan J, Kesten S, Ernst A. Bronchoscopic Thermal Vapor Ablation Therapy in the Management of Heterogeneous Emphysema. Submitted. [32] Shah P, Slebos DJ, Cardoso PF, Cetti E, Voelker K, Levine B, Russell ME, Goldin J,

Brown M, Cooper JD, Sybrecht GW; EASE trial study group. Bronchoscopic lungvolume reduction with Exhale airway stents for emphysema (EASE trial): Prolonged air leak is one of the most common post-operative complications encountered after thoracic surgical operations involving mobilization or resection of lung parenchyma. Air leak typically manifests as persistent bubbling in a chest tube drainage system, but may also present with increasing subcutaneous emphysema or pneumothorax in a post-operative patient. No universal consensus exist as to the exact duration of air leak which constitutes a prolonged air leak, but it is generally regarded to exist if it is present for more than 5 days(1- 4) or 7 days(2, 5-7) after initial surgery. It is an important complication that results in increased length of stay(8-15) and has been associated with other post-operative complications such as pneumonia(12, 14, 16), empyema(9, 10, 16) and ICU re-admission(12).

Patients with emphysema form a significant proportion of patients which will undergo thoracic surgical operations. Chronic smoking and emphysema predisposes an individual to developing a pneumothorax(17, 18) or carcinoma of the lung(19, 20) that may require surgical intervention for treatment. In addition, lung volume reduction surgery plays a role in the management of certain patients with advanced emphysema(21). Conversely, emphysema is regarded as a risk factor for developing prolonged air leak in cases where patients with emphysema require an operation(7). This is presumably because the underlying lung substrate in patients with emphysema is more easily injured during surgery and takes longer to heal.

The role of emphysema as a risk factor for prolonged air leak has been inferred from numerous surgical case series which reliably demonstrate that patients noted preoperatively to have emphysema will have a higher incidence of prolonged air leak. However, a major weakness of these studies, is that they are heterogenous in their definition of prolonged air leak, patient population (eg age, definition of impaired lung function), type of operation performed (eg video assisted vs open, chemical vs mechanical pleurodesis, type/extent of resection) and methods used to prevent air leak (eg use of pleural tenting), which limits the ability to compare between individual studies. In addition, several studies analyzing the specific risk factors for developing this complication have consistently shown

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 105

Definition of prolonged air leak (PAL)

>7 days 0

>7 days 1.7%

Incidence of PAL in primary spontaneous pneumothorax

>2 days 2.1% 7.1%

(excluded 1 patient who required conversion to open thoracotomy)

>24 hours 0 26%

(excluded 6 patients who required conversion to open thoracotomy)

>5 days 3.8% 14.9%

Incidence of PAL in secondary spontaneous pneumothorax

16.7% (excluded 4 patients who required conversion to open thoracotomy)

16.6% (excluded 10 patients who required conversion to open thoracotomy)

pleurodesis

VATS, excision of blebs, pleurectomy or talc powder (mechanical or chemical pleurodesis)

VATS, excision of blebs, pleural abrasion or pleurectomy (mechanical pleurodesis)

VATS, bleb ablation by electrocautery, talc powder (chemical pleurodesis)

VATS, excision of blebs, pleural abrasion ± pleurectomy (mechanical pleurodesis)

VATS, excision of blebs, pleural abrasion, pleurectomy or talc powder (mechanical or chemical pleurodesis)

Author Patient population Type of

95 patients with primary spontaneous pneumothorax requiring surgery 14 patients with secondary spotaneous pneumothorax requiring surgery (5 COPD patients)

75 patients with primary spontaneous pneumothorax requiring surgery 22 patients with secondary spontaneous pneumothorax requiring surgery (13 COPD patients)

28 patients with 31 episodes primary spontaneous pneumothorax requiring surgery 20 patients with 23 episodes of secondary

spontaneous pneumothorax requiring surgery (6 COPD patients)

65 patients with primary spontaneous pneumothorax requiring surgery 34 patients with secondary spontaneous pneumothorax requiring surgery (24 COPD patients)

480 patients with 550 episodes of primary spontaneous pneumothorax requiring surgery 89 patients with 94 episodes of secondary

spontaneous pneumothorax requiring surgery (all patients with COPD)

Hatz et al. (22)

Mouroux et al. (23)

Noppen et al. (24)

Passlick et al. (25)

Shaikhreza et al. (26)

that low FEV1 or FEV1/FVC will increase the risk of developing prolonged air leak after either pulmonary resection or lung volume reduction surgery (see below for details).

Fig. 1. Severe subcutaneous emphysema in a patient with underlying emphysema with prolonged air-leak.

For surgical pleurodesis, several authors have described their experience in performing this operation on both primary spontaneous pneumothorax and secondary spontaneous pneumothorax (which mainly consist of patients with underlying emphysema). The reported incidence of prolonged air leak in patients with primary spontaneous pneumothorax undergoing surgical pleurodesis has been reported to range from 0-3.8%, while it has been reported to range from 7.1-29.1% for patients with secondary spontaneous pneumothorax. A similar trend is also demonstrable in patients undergoing pulmonary resection for carcinoma of the lung, with an incidence of prolonged air leak of 4.2-18.2% in patients without underlying emphysema, compared to 5.4-44% in patients with underlying emphysema.

that low FEV1 or FEV1/FVC will increase the risk of developing prolonged air leak after

either pulmonary resection or lung volume reduction surgery (see below for details).

Fig. 1. Severe subcutaneous emphysema in a patient with underlying emphysema with

For surgical pleurodesis, several authors have described their experience in performing this operation on both primary spontaneous pneumothorax and secondary spontaneous pneumothorax (which mainly consist of patients with underlying emphysema). The reported incidence of prolonged air leak in patients with primary spontaneous pneumothorax undergoing surgical pleurodesis has been reported to range from 0-3.8%, while it has been reported to range from 7.1-29.1% for patients with secondary spontaneous pneumothorax. A similar trend is also demonstrable in patients undergoing pulmonary resection for carcinoma of the lung, with an incidence of prolonged air leak of 4.2-18.2% in patients without underlying emphysema, compared to 5.4-44% in patients with underlying emphysema.

prolonged air-leak.


Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 107

Type of intraoperative adjuncts used

Variety of methods (not standardized) including buttressing, sealants, tenting and pleurodesis

Buttressed staple

lines

Table 3. Studies reporting the incidence of prolonged air leak in patients undergoing lung

For lung volume reduction surgery, the incidence of prolonged air leak is much higher, ranging from 39-45.2%. This is expected, as the operation is conducted on both lungs, and

This review will discuss the pathogenesis, risk factors, intra-operative and post-operative management strategies for prolonged air leak in patients with emphysema based on current available literature. In addition, we propose an algorithm for the management of prolonged air leak in this group of patients based on this discussion, and also define specific criteria for surgical intervention for prolonged air leak that we follow at our institution. Several recent reviews have previously discussed the problem of prolonged air leaks, but do not focus specifically on patients with emphysema(3, 4) or neglect to discuss the utility of surgical intervention in greater detail(2, 34) which we believe plays an important role for this challenging clinical problem, particularly in the small number (but no less important) of

**2. Pathogenesis and factors influencing incidence of prolonged air leak in** 

Some degree of post-operative air leak is generally unavoidable in operations involving pulmonary resection or mobilization, usually reflective of an alveolo-pleural fistula arising from exposed alveoli, whereas more severe leaks suggest fistulas arising from larger, more proximal bronchi(5, 7). The duration of the leak is related to the severity of the air leak as

Definition of prolonged air leak (PAL)

>7 days 45%

>7 days 39%

Pleural tenting >7 days 45.2%

Incidence of PAL

Type of lung volume reduction surgery

Bilateral LVRS via median sternotomy

Bilateral VATS

Bilateral LVRS via median sternotomy (70%)

Bilateral VATS

Bilateral LVRS via median sternotomy (39%)

(30%)

(61%)

usually on patients with more advanced underlying lung disease.

patients who are refractory to all other forms of therapy.

Author Patient

Ciccone et al.

DeCamp et al.

Ledrer et al. (33)

(32)

(12)

population

250 patients, mean pre-op FEV1 26% of predicted

580 patients, mean pre-op FEV1 26.8% of predicted

23 patients, mean pre-op FEV1 25% of predicted

volume reduction surgery.

**patients with emphysema** 


Table 1. Studies comparing the incidence of prolonged air leak in patients with primary versus secondary spontaneous pneumothorax undergoing surgical pleurodesis.


Table 2. Studies comparing the incidence of prolonged air leak in patients with COPD versus those without COPD undergoing pulmonary resection.

Definition of prolonged air leak (PAL)

Definition of prolonged air leak (PAL)

Not defined 6.7%

Incidence of PAL in primary spontaneous pneumothorax

>5 days 3% 29.1%

Incidence of PAL in patients without COPD

(excludes pneumonectomy patients)

>7 days 13.3% 16.2%

pneumonectomy patients)

pneumonectomy patients)

>10 days 4.2% (excludes

Not defined 18.2% (excludes

Incidence of PAL in secondary spontaneous pneumothorax

Incidence of PAL in patients with

18.8% (excludes pneumonectomy patients)

44% (excludes pneumonectomy patients)

COPD

5.4% (excludes pneumonectomy patients)

pleurodesis

Table 1. Studies comparing the incidence of prolonged air leak in patients with primary

versus secondary spontaneous pneumothorax undergoing surgical pleurodesis.

Type of pulmonary

Pneumonectomy (9.8% vs 10.6%), bilobectomy (4.5% vs 6.7%), lobectomy (84.2% vs 81.7%), wedge resection (1.5% vs 1.0%)

Upper lobectomy (64.4% vs 58.1%), other lobectomy (35.6% vs 41.9%)

Pneumonectomy (13.9% vs 18%), bilobectomy (13.9%

segmentectomy and wedge resection (2.4% vs 3.9%)

Pneumonectomy (53.2% vs 28.6%), upper lobectomy (23.4% vs 34.3%), other lobectomy (23.4% vs 37.1%)

Table 2. Studies comparing the incidence of prolonged air leak in patients with COPD

vs 19.2%), lobectomy (68.7% vs 58.8%),

versus those without COPD undergoing pulmonary resection.

resection

Open thoracotomy, excision of blebs, pleural abrasion

Author Patient population Type of

130 patients with 100 episodes of primary spontaneous pneumothorax requiring surgery 67 patients with 24 episodes of secondary

spontaneous pneumothorax requiring surgery (22 COPD patients)

population

133 patients with FEV1 >80% predicted 104 patients with FEV1<80% predicted

45 patients with FEV1 >80% predicted 43 patients with FEV1 <80% predicted

166 patients with FEV1 >70% predicted & FEV1/FVC>70% 78 patients with FEV1 <70% predicted & FEV/FVC<70%

47 patients with FEV1/FVC >70%

35 patient with FEV1/FVC<70%

Tanaka et al. (27)

Author Patient

Lee et al. (28)

Santambrogio

Sekine et al. (30)

Subotic et al. (31)

et al. (29)


Table 3. Studies reporting the incidence of prolonged air leak in patients undergoing lung volume reduction surgery.

For lung volume reduction surgery, the incidence of prolonged air leak is much higher, ranging from 39-45.2%. This is expected, as the operation is conducted on both lungs, and usually on patients with more advanced underlying lung disease.

This review will discuss the pathogenesis, risk factors, intra-operative and post-operative management strategies for prolonged air leak in patients with emphysema based on current available literature. In addition, we propose an algorithm for the management of prolonged air leak in this group of patients based on this discussion, and also define specific criteria for surgical intervention for prolonged air leak that we follow at our institution. Several recent reviews have previously discussed the problem of prolonged air leaks, but do not focus specifically on patients with emphysema(3, 4) or neglect to discuss the utility of surgical intervention in greater detail(2, 34) which we believe plays an important role for this challenging clinical problem, particularly in the small number (but no less important) of patients who are refractory to all other forms of therapy.

#### **2. Pathogenesis and factors influencing incidence of prolonged air leak in patients with emphysema**

Some degree of post-operative air leak is generally unavoidable in operations involving pulmonary resection or mobilization, usually reflective of an alveolo-pleural fistula arising from exposed alveoli, whereas more severe leaks suggest fistulas arising from larger, more proximal bronchi(5, 7). The duration of the leak is related to the severity of the air leak as

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 109

Incidence of prolonged air

>7 days 18.6% - low FEV1 predicted

>5 days 5.6% - female gender

>7 days 6.9% - male gender

>7 days 9.7% - FEV1 <70% and

Risk factors identified






FEV/FVC<70%

leak

prolonged air

Table 4. Studies analyzing risk factors for prolonged air leak in patients undergoing

**3. Intra-operative strategies for prevention of prolonged air leak** 

maximal re-expansion of remaining lung tissue after pulmonary resection.

only using staplers for division of lung parenchyma when it is required(40, 41).

Based on the above mentioned factors, methods geared to the prevention of prolonged air leaks aim to minimize intra-operative surgical trauma or ensure more complete lung expansion. These approaches can be broadly divided into intra-operative and post-operative

The thoracic surgeon should ensure that lung tissue is handled as carefully as possible during dissection and manipulation to ensure minimal trauma, particularly in patients with emphysema, where the underlying lung is fragile. Any obvious parenchymal tears that are identified during surgery should be repaired meticulously. In addition, the remaining lung should be completely mobilized and decortication should be performed if necessary to aid

Conventional lobectomy involves dissection of lung parenchyma within the fissures by sharp or blunt dissection for exposure of the pulmonary artery that may result in air leaks. The fissureless technique involves exposing the pulmonary artery without such dissection,

Although the efficacy of this technique has not been studied in patients with emphysema specifically, two previous studies on a general population of patients undergoing

leak

Author Patient population Definition of

1393 patients undergoing open lobectomy or bilobectomy

Lee et al. (38) 580 patients undergoing

Liberman et al. (14)

Rivera et al. (39)

open lobectomy or segmentectomy

24,113 patients undergoing open lobectomy, bilobectomy, segmentectomy, bulla resection or LVRS

Stolz et al.(13) 134 patients undergoing open loebectomy

**3.2 Fissureless technique for lobectomy** 

pulmonary resection.

strategies.

**3.1 General** 

well as the time taken for the exposed parenchyma to heal, which occurs via an inflammatory reaction that results in granulation tissue formation and fibrin deposition(7). Moreover, this process is widely accepted to be facilitated by re-expansion of the lung to allow contact between the lung and parietal pleura.

Thus, it would follow that factors that would increase the risk of prolonged air leak include impaired wound healing (older age, more severe underlying emphysema), greater intraoperative surgical trauma (re-operations, extensive adhesions) and incomplete lung expansion post-operatively. This has been confirmed by a number of studies on patients undergoing pulmonary resection which have looked at specific factors that influence the incidence of prolonged air leak, summarized below.

Though no study looked specifically at risk factors for prolonged air leak in patients with emphysema undergoing pulmonary resection, DeCamp and colleagues(12) analyzed the data from the surgical arm of the National Emphysema Treatment Trial and found that the following factors increase the risk developing air leak after lung volume reduction surgery:


Whether this can be extrapolated to patients with emphysema undergoing other forms of thoracic operations has not been demonstrated.



Table 4. Studies analyzing risk factors for prolonged air leak in patients undergoing pulmonary resection.

Based on the above mentioned factors, methods geared to the prevention of prolonged air leaks aim to minimize intra-operative surgical trauma or ensure more complete lung expansion. These approaches can be broadly divided into intra-operative and post-operative strategies.

### **3. Intra-operative strategies for prevention of prolonged air leak**

#### **3.1 General**

108 Emphysema

well as the time taken for the exposed parenchyma to heal, which occurs via an inflammatory reaction that results in granulation tissue formation and fibrin deposition(7). Moreover, this process is widely accepted to be facilitated by re-expansion of the lung to

Thus, it would follow that factors that would increase the risk of prolonged air leak include impaired wound healing (older age, more severe underlying emphysema), greater intraoperative surgical trauma (re-operations, extensive adhesions) and incomplete lung expansion post-operatively. This has been confirmed by a number of studies on patients undergoing pulmonary resection which have looked at specific factors that influence the

Though no study looked specifically at risk factors for prolonged air leak in patients with emphysema undergoing pulmonary resection, DeCamp and colleagues(12) analyzed the data from the surgical arm of the National Emphysema Treatment Trial and found that the following factors increase the risk developing air leak after lung volume reduction surgery: Caucasian race (however, only 4.7% of trial participants were from minorities, so there

Whether this can be extrapolated to patients with emphysema undergoing other forms of

Incidence of prolonged air

>7 days 26% - FEV1/FVC <50%

>7 days 15.6% - low predicted post-

Risk factors identified





operative FEV1 - pleural adhesions - upper lobectomy

leak

>5 days 13% - age >65

>4 days 8% - male gender

>10 days 18.1% - diabetes

prolonged air

leak

Poorer pulmonary function (lower FEV1 predicted or DLCO predicted)

allow contact between the lung and parietal pleura.

incidence of prolonged air leak, summarized below.

may be an element of selection bias)

thoracic operations has not been demonstrated.

Author Patient population Definition of

100 patients undergoing open upper lobectomy

588 patients undergoing open lobectomy or bilobectomy

658 patients undergoing open lobectomy

669 patients undergoing

segmentectomy or wedge

138 patients undergoing open lobectomy or segmentectomy

lobectomy,

resection

Inhaled (but not oral) steroid use

 Upper lobe disease Pleural adhesions

Abolhoda et al. (11)

Brunelli et al.

Brunelli et al.

Cerfolio et al.

Isowa et al. (37)

(16)

(35)

(36)

The thoracic surgeon should ensure that lung tissue is handled as carefully as possible during dissection and manipulation to ensure minimal trauma, particularly in patients with emphysema, where the underlying lung is fragile. Any obvious parenchymal tears that are identified during surgery should be repaired meticulously. In addition, the remaining lung should be completely mobilized and decortication should be performed if necessary to aid maximal re-expansion of remaining lung tissue after pulmonary resection.

#### **3.2 Fissureless technique for lobectomy**

Conventional lobectomy involves dissection of lung parenchyma within the fissures by sharp or blunt dissection for exposure of the pulmonary artery that may result in air leaks. The fissureless technique involves exposing the pulmonary artery without such dissection, only using staplers for division of lung parenchyma when it is required(40, 41).

Although the efficacy of this technique has not been studied in patients with emphysema specifically, two previous studies on a general population of patients undergoing

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 111

Another area of study in the intra-operative prevention of air leaks during thoracic surgery has been the use of buttress material for staple lines, which in theory would help reinforce the fragile staple lines and thus prevent air leak from these areas of weakness. A variety of buttress materials have been described for this purpose, both synthetic (eg polytetrafluoroethylene(51), polydioxanone(52)) and biological [bovine pericardial strips(53- 56), bovine collagen(57), autologous parietal pleura(58)]. However, only a few have been investigated in clinical practice, the most widely studied of which are bovine pericardial strips. Unfortunately, the cost of using these are high(57), and the few small studies that have been performed on a general population of patients undergoing pulmonary resection have not shown a clear benefit(53, 54). Several studies directed at emphysema patients specifically have been performed with more consistent results, but these are limited to those undergoing lung volume reduction surgery or bullectomy(55, 56, 58). On the other hand, an analysis of factors influencing post-operative air leak in patients undergoing lung volume reduction surgery in the National Emphsema Treatment Trial did not find that use of staple line buttressing

(regardless of material) helpful in preventing or shortening duration of air leak(12).

In summary, current evidence suggest that the use of buttressing staple lines in patients with emphysema undergoing lung volume reduction surgery or bullectomy may be useful in reducing incidence of prolonged air leak, but its use in other operations, particularly

A table summarizing the results of the various studies mentioned above is presented below.

prolonged air leak

Incidence of prolonged air

N/A N/A 5.9 vs 6.3

N/A N/A 7.9 vs 10.4

Time to chest tube removal (mean)

days, p=0.62

days, p=0.04

7.6 vs 9.7 days, p=0.045

Length of stay (mean)

8 vs 9 days, p=0.24

vs 7.2 days

8.6 vs 11.4 days, p=0.03

12.7 vs 15.7 days, p=0.14

N/A 4.4 vs 7.8

leak

>7 days 0% vs 20% vs 10%

Not defined 15.6% vs

21.2%

Patient population Definition of

80 patients undergoing open lobectomy (65) or segmentectomy (15)

30 patients undergoing open lobectomy

123 patients with emphysema undergoing unilateral VATS

65 patients with emphysema undergoing bilateral VATS

LVRS

LVRS

**3.4 Buttress material for staple lines** 

pulmonary resection has not been demonstrated.

Author Butress

Miller et al.(53)

Venuta et al.(54)

Hazelrigg et al.(55)

Stammberger et al.(56)

material

Bovine pericardial strips + stapler vs stapler alone

Bovine pericardial strips + stapler vs stapler alone

Bovine pericardial strips + stapler vs stapler alone

Bovine pericardial strips + staplers vs stapler alone

conventional cautery, clamp and ties

vs

pulmonary resection have shown that this technique significantly decreases the incidence of prolonged air leak. Gomez-Caro and associates(42) demonstrated in a randomized prospective study of 63 patients undergoing either lobectomy or bilobectomy, that the incidence of prolonged air leak (>5 days) in patients whom a fissureless technique was employed was 3.2%, compared to 21.8% for those in whom conventional dissection was performed. A more recent retrospective case control study by Ng et al.(43) looking at 93 patients undergoing right upper lobectomy only, revealed similar results, with patients in the fissureless technique group having an incidence of prolonged air leak (>7 days) of 7.6%, compared to 22.2% in patients in the conventional lobectomy group.

#### **3.3 No cut plication (non-resectional) technique for lung volume reduction surgery**

For lung volume reduction surgery, an alternative technique involving no cut plication has been described by various authors as having lower rates of prolonged air leak while having short to intermediate term improvement in pulmonary function comparable to conventional lung volume reduction surgery(44-47). With this alternative technique, lung tissue is folded up or pushed down onto itself before being stapled together instead of performing staple excision of lung tissue in traditional lung volume reduction surgery.

Swanson and colleagues reported that in their series of 50 procedures performed on 32 patients, the incidence of prolonged air leak (>7 days) was only 8.6%(44). In a series of 20 patients operated by Iwasaki and associates, they reported that no patient had an air leak beyond 5 days(45). The largest reported series of 66 patients at Tor Vergata University by Tacconi, Pompeo and Mineo, demonstrated an incidence of prolonged air leak (>7 days) of 18% in patients undergoing non-resectional lung volume reduction surgery under thoracic epidural anaesthesia, compared to 40% of patients in a control group undergoing conventional lung volume reduction surgery under general anaesthesia(48).

Moreover, Pompeo and colleagues at the Tor Vergata University also recently published a randomized control trial comparing 32 patients undergoing non-resectional lung volume reduction surgery with thoracic epidural anaesthesia against 31 patients undergoing conventional lung volume reduction surgery with general anaesthesia and found that the incidence of prolonged air leak in the former was 18.8% compared to 48.4% for the latter, while survival and improvement in post-operative pulmonary function were similar in both groups (49). The same group also compared the results of 41 patients undergoing nonresectional lung volume reduction surgery under thoracic epidural anaesthesia against 19 patients undergoing non-resectional lung volume reduction surgery under general anaesthesia, and found that the occurrence of prolonged air leak was similar between the two groups (12.1% vs 26.3%, p=0.26), which suggests that the type of lung volume reduction surgery rather than the type of anaesthesia was the main factor in determining risk of prolonged air leak(50).

The above published data indicate that this technique may potentially be superior to the traditional lung volume reduction surgical approach in terms of reducing morbidity from prolonged air leak. However, the long-term durability of pulmonary function improvement after plication is still not known, as the studies so far have only involved small numbers of patients and only limited follow-up, thus more research on this technique is required before its widespread adoption can be recommended.

#### **3.4 Buttress material for staple lines**

110 Emphysema

pulmonary resection have shown that this technique significantly decreases the incidence of prolonged air leak. Gomez-Caro and associates(42) demonstrated in a randomized prospective study of 63 patients undergoing either lobectomy or bilobectomy, that the incidence of prolonged air leak (>5 days) in patients whom a fissureless technique was employed was 3.2%, compared to 21.8% for those in whom conventional dissection was performed. A more recent retrospective case control study by Ng et al.(43) looking at 93 patients undergoing right upper lobectomy only, revealed similar results, with patients in the fissureless technique group having an incidence of prolonged air leak (>7 days) of 7.6%,

**3.3 No cut plication (non-resectional) technique for lung volume reduction surgery**  For lung volume reduction surgery, an alternative technique involving no cut plication has been described by various authors as having lower rates of prolonged air leak while having short to intermediate term improvement in pulmonary function comparable to conventional lung volume reduction surgery(44-47). With this alternative technique, lung tissue is folded up or pushed down onto itself before being stapled together instead of performing staple

Swanson and colleagues reported that in their series of 50 procedures performed on 32 patients, the incidence of prolonged air leak (>7 days) was only 8.6%(44). In a series of 20 patients operated by Iwasaki and associates, they reported that no patient had an air leak beyond 5 days(45). The largest reported series of 66 patients at Tor Vergata University by Tacconi, Pompeo and Mineo, demonstrated an incidence of prolonged air leak (>7 days) of 18% in patients undergoing non-resectional lung volume reduction surgery under thoracic epidural anaesthesia, compared to 40% of patients in a control group undergoing

Moreover, Pompeo and colleagues at the Tor Vergata University also recently published a randomized control trial comparing 32 patients undergoing non-resectional lung volume reduction surgery with thoracic epidural anaesthesia against 31 patients undergoing conventional lung volume reduction surgery with general anaesthesia and found that the incidence of prolonged air leak in the former was 18.8% compared to 48.4% for the latter, while survival and improvement in post-operative pulmonary function were similar in both groups (49). The same group also compared the results of 41 patients undergoing nonresectional lung volume reduction surgery under thoracic epidural anaesthesia against 19 patients undergoing non-resectional lung volume reduction surgery under general anaesthesia, and found that the occurrence of prolonged air leak was similar between the two groups (12.1% vs 26.3%, p=0.26), which suggests that the type of lung volume reduction surgery rather than the type of anaesthesia was the main factor in determining risk of

The above published data indicate that this technique may potentially be superior to the traditional lung volume reduction surgical approach in terms of reducing morbidity from prolonged air leak. However, the long-term durability of pulmonary function improvement after plication is still not known, as the studies so far have only involved small numbers of patients and only limited follow-up, thus more research on this technique is required before

compared to 22.2% in patients in the conventional lobectomy group.

excision of lung tissue in traditional lung volume reduction surgery.

conventional lung volume reduction surgery under general anaesthesia(48).

prolonged air leak(50).

its widespread adoption can be recommended.

Another area of study in the intra-operative prevention of air leaks during thoracic surgery has been the use of buttress material for staple lines, which in theory would help reinforce the fragile staple lines and thus prevent air leak from these areas of weakness. A variety of buttress materials have been described for this purpose, both synthetic (eg polytetrafluoroethylene(51), polydioxanone(52)) and biological [bovine pericardial strips(53- 56), bovine collagen(57), autologous parietal pleura(58)]. However, only a few have been investigated in clinical practice, the most widely studied of which are bovine pericardial strips. Unfortunately, the cost of using these are high(57), and the few small studies that have been performed on a general population of patients undergoing pulmonary resection have not shown a clear benefit(53, 54). Several studies directed at emphysema patients specifically have been performed with more consistent results, but these are limited to those undergoing lung volume reduction surgery or bullectomy(55, 56, 58). On the other hand, an analysis of factors influencing post-operative air leak in patients undergoing lung volume reduction surgery in the National Emphsema Treatment Trial did not find that use of staple line buttressing (regardless of material) helpful in preventing or shortening duration of air leak(12).

In summary, current evidence suggest that the use of buttressing staple lines in patients with emphysema undergoing lung volume reduction surgery or bullectomy may be useful in reducing incidence of prolonged air leak, but its use in other operations, particularly pulmonary resection has not been demonstrated.


A table summarizing the results of the various studies mentioned above is presented below.

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 113

prolonged air

>6 days 13% vs

>7 days 14% vs

Incidence of prolonged air leak

22%, p=not significant

>7 days 2.5% vs 7% 4.5 vs 5.2

12%, p=0.813

N/A N/A 3.90 vs 3.92

N/A N/A 6.1 vs 6.9

>7 days 8% vs 20% 5.6 vs 10

N/A N/A 4 vs 3 days

3.2%

32.46%, p=0.282

Not defined 4.2% vs

>7 days 24% vs

N/A N/A N/A 5.7 vs 6.2

Time to chest tube removal (mean)

days, p=0.41

6.8 vs 6.2 days, p=0.679 (median)

days, p=0.559 (median)

days, p=0.9

days, p=0.03

(median)

5.1 vs 6.3 days, p=0.022

N/A N/A

N/A 9.2 vs 8.6

Length of stay (mean)

days, p=not significant

7.4 vs 10.1 days, p=0.78

6 vs 7 days, p=0.04 (median)

13 vs 12 days, p=0.292 (median)

13 vs 14.4 days, p=0.4

8 vs 11.6 days, p=0.009

days, p=0.18

6 vs 7 days (median)

6.2 to 7.7 days, p=0.01

leak

Patient population Definition of

124 patients undergoing open bilobectomy or lobectomy

172 patients undergoing open bilobectomy, lobectomy, segmentectomy or wedge resection

161 patients undergoing open bilobectomy, lobectomy, segmentectomy, wedge resection, decortications or

LVRS

121 patients undergoing open lobectomy or segmentectomy

24 patients undergoing open bilobectomy, lobectomy or wedge resection

50 patients undergoing lobectomy

203 patients undergoing open bilobectomy, lobectomy, segmentectomy or wedge resection

121 patients undergoing open bilobectomy, lobectomy or wedge resection

189 patients undergoing open lobectomy

173 patients undergoing open lobectomy or segmentectomy

Author Surgical

Porte et al.(63) PEG

Wain et al.(64) PEG

Allen et al.(65) PEG

De Leyn et al.(66)

Macchiarini et al.(67)

Venuta et al.(68)

D'Andrilli et al.(69)

Tan et al.(70) PEG

Lang et al.(71) Coated

Anegg et al.(72)

sealant

based sealant vs none

based sealant vs none

based sealant vs none

PEG based sealant vs none

PEG based sealant vs none

PEG based sealant vs none

PEG based sealant vs none

based sealant vs none

collagen patch vs none

Coated collagen patch vs none


Table 5. Studies comparing the utility of buttressing staple lines in preventing prolonged air leak.

### **3.5 Pulmonary sealants**

Pulmonary sealants have been the focus of a large amount of research in the area of intraoperative prevention air leaks, with over a dozen studies on various types of sealants including fibrin glue(59-62), PEG-based sealants(63-70) and coated collagen patches(71-73). However, as with studies on other strategies, these papers have generally not focused on patients with emphysema, and individually these studies each have small cohort sizes with very mixed patient populations as well as varying methods for reporting efficacy.

Moreover, the overall results of these studies so far have found no clear advantage in their routine use on all patients(74). Thus, the use of sealants should best be reserved for patients at highest risk for developing post-operative prolonged air leak(35, 38), especially since rare complications, particularly empyema(63, 67, 75) may arise from the use of pulmonary sealants. Indeed, the studies which have focused on patients with emphysema have more consistently shown a significant reduction in the incidence of post-operative prolonged air leak and length of stay(62, 73).


Table 5. Studies comparing the utility of buttressing staple lines in preventing prolonged air

Pulmonary sealants have been the focus of a large amount of research in the area of intraoperative prevention air leaks, with over a dozen studies on various types of sealants including fibrin glue(59-62), PEG-based sealants(63-70) and coated collagen patches(71-73). However, as with studies on other strategies, these papers have generally not focused on patients with emphysema, and individually these studies each have small cohort sizes with

Moreover, the overall results of these studies so far have found no clear advantage in their routine use on all patients(74). Thus, the use of sealants should best be reserved for patients at highest risk for developing post-operative prolonged air leak(35, 38), especially since rare complications, particularly empyema(63, 67, 75) may arise from the use of pulmonary sealants. Indeed, the studies which have focused on patients with emphysema have more consistently shown a significant reduction in the incidence of post-operative prolonged air

prolonged air

>7 days 14.3% vs

>7 days 2% vs 16%,

Incidence of prolonged air leak

7.1%

N/A N/A 6 vs 6 days,

p=0.015

Time to chest tube removal (mean)

6.0 vs 5.9 days, p=0.95

p=0.8 (median)

3.5 vs 5.0 days, p=0.02 Length of stay (mean)

9.8 vs 11.5 days, p=0.21

8 vs 9 days, p=0.57 (median)

4.6 vs 4.9 days, p=0.318

leak

very mixed patient populations as well as varying methods for reporting efficacy.

Patient population Definition of

28 patients undergoing open lobectomy

66 patients undergoing open lobectomy, segmentectomy or decortication

100 patients undergoing open bilobectomy, lobectomy, segmentectomy or wedge resection

prolonged air leak

Incidence of prolonged air

>7 days 0% vs 8.3% 2.7 vs 4.8

Time to chest tube removal (mean)

days, p=0.04

8.6 vs 10.4 days

Length of stay (mean)

4.2 vs 5.9 days, p=0.09

N/A

leak

44.6%

>7 days 35.7% vs

Patient population Definition of

22 patients with emphysema undergoing open bullectomy

56 patients with emphysema undergoing bilateral VATS

LVRS

Author Butress

Baysungur et al.(58)

Fischel et al.(57)

leak.

material

Autologous pleura + stapler vs stapler alone

Bovine pericardial strips + staples vs Bovine collagen + staples

**3.5 Pulmonary sealants** 

leak and length of stay(62, 73).

sealant

Fibrin glue vs none

Fibrin glue vs none

Fibrin glue vs none

Author Surgical

Fleisher et al.(59)

Wong et al.(60)

Fabian et al.(61)


Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 115

controlling the size of the potential space post-pulmonary resection in the upper thoracic cavity, and thus has been predominantly studied in patients undergoing upper lobectomy. In a retrospective review on risk factors for prolonged post-operative air leak, Brunelli and associates(16) noted that patients with upper lobectomies who underwent a pleural tent had a significantly decreased duration of air leak compared to those who did not undergo a similar adjunctive procedure. Nevertheless, he later published a retrospective case matched analysis comparing patients with prolonged air leak after pulmonary resection and those without, which did not demonstrate that pleural tenting conferred any protective effect(9). DeCamp et al.(12) in reviewing the factors influencing air leak post-lung volume reduction surgery in patients from the National Emphysema Treatment Trial also did not find a significant decrease in incidence or duration of air leak in patients who underwent tenting

In addition, a number of randomized prospective studies have also been performed to assess its efficacy, and in general, the studies conducted on pleural tenting have shown an overall beneficial effect in terms of decreasing incidence of air leak, time to chest tube removal and length of stay. However, this procedure adds to operative time and may cause bleeding(35) though these were not shown to be significantly increased compared to

The table below summarizes the results of the randomized prospective studies performed to

Incidence of prolonged air Time to chest tube removal (mean)

7 vs 11.2 days, p<0.0001

4.6 vs 5.6 days, p=0.11

p<0.0001

Length of stay (mean)

8.2 vs 11.6 days, p<0.0001

4.96 vs 5.7 days,

7.6 vs 9.35 days, p=0.024

p=0.05

leak

p=0.003

p=0.02

>5 days 0 vs 30% 4.3 vs 7.4 days,

>7 days 14% vs 32%

>5 days 9% vs 40%,

Table 7. Studies comparing the utility of pleural tenting in preventing prolonged air leak.

Conversely, the creation a pneumoperitoneum has been utilized to minimize the postresectional space in the lower thoracic cavity. This has been described as both an intraoperative adjunct to prevent prolonged air leak(80) as well as a post-operative technique(81- 83) to treat it. It can be accomplished through instillation of air into the peritoneal cavity by

Definition of prolonged air

leak

compared to those who did not undergo tenting.

controls in the studies below.

population

200 patients undergoing open upper lobectomy or bilobectomy (100 with tenting vs 100 without)

48 patients undergoing open upper lobectomy (23 with tenting vs 25 without)

undergoing open upper lobectomy or bilobectomy (20 with tenting vs 20 without)

evaluate this technique.

Okur et al.(79) 40 patients

Author Patient

Brunelli et al.(77)

Allama et al.(78)


Table 6. Studies comparing the utility of pulmonary sealants in preventing prolonged air leak.

#### **3.6 Minimizing post-resectional spaces**

Minimizing the potential space left behind after pulmonary resection allows for a more complete apposition of the lung surface with the parietal pleura to encourage the resolution of any post-operative air leak. Usually this can be accomplished with straightforward means such as the proper placement of chest tubes, division of the inferior pulmonary ligament and lysis of all adhesions at the conclusion of surgery or the use of adequate analgesia, chest physiotherapy or bronchoscopy to clear the airways of mucus and blood post-operatively to promote maximal re-expansion of the residual lung (7). In the event that the above mentioned methods are insufficient, several techniques have been described, including the creation of a pleural tent, creation of a pneumoperitoneum or deliberate diaphragmatic paralysis.

Again, interpretation of the results of studies on these methods to reduce post-resectional spaces is complicated by the heterogenous inclusion criteria and method of reporting outcomes in these studies. Furthermore, almost none have looked specifically at patients with emphysema, thus making it difficult to simply extrapolate the results of these studies to patients with emphysema.

Nonetheless, amongst the methods mentioned previously, pleural tenting has been the most widely studied technique for preventing prolonged air leak by minimizing post-resectional spaces. This involves stripping the parietal pleural over the apex, which is then resutured over the chest wall to produce an extrapleural space(7, 77). It has been used as a means for

prolonged air

>7 days 3.3% vs

>7 days 4.5% vs

>7 days 18% vs

Table 6. Studies comparing the utility of pulmonary sealants in preventing prolonged air leak.

Minimizing the potential space left behind after pulmonary resection allows for a more complete apposition of the lung surface with the parietal pleura to encourage the resolution of any post-operative air leak. Usually this can be accomplished with straightforward means such as the proper placement of chest tubes, division of the inferior pulmonary ligament and lysis of all adhesions at the conclusion of surgery or the use of adequate analgesia, chest physiotherapy or bronchoscopy to clear the airways of mucus and blood post-operatively to promote maximal re-expansion of the residual lung (7). In the event that the above mentioned methods are insufficient, several techniques have been described, including the creation of a pleural tent, creation of a pneumoperitoneum or deliberate diaphragmatic

Again, interpretation of the results of studies on these methods to reduce post-resectional spaces is complicated by the heterogenous inclusion criteria and method of reporting outcomes in these studies. Furthermore, almost none have looked specifically at patients with emphysema, thus making it difficult to simply extrapolate the results of these studies

Nonetheless, amongst the methods mentioned previously, pleural tenting has been the most widely studied technique for preventing prolonged air leak by minimizing post-resectional spaces. This involves stripping the parietal pleural over the apex, which is then resutured over the chest wall to produce an extrapleural space(7, 77). It has been used as a means for

Incidence of prolonged air leak

26.7%, p=0.029

31.8%, p=0.031

N/A N/A 4 vs 5 days,

23%, p=0.627 Time to chest tube removal (mean)

3.53 vs 5.9 days, p=0.002

2.83 vs 5.88 days, p<0.001

p=0.012 (median)

5 vs 5 days, p=0.473

Length of stay (mean)

5.87 vs 7.5 days, p=0.01

N/A

6 vs 7 days, p=0.004 (median)

8 vs 7 days, p=0.382

leak

Patient population Definition of

60 patients with

undergoing open lobectomy or segmentectomy

25 patients with emphysema undergoing bilateral VATS

COPD

LVRS

52 patients undergoing open lobectomy, segmentectomy or other resection

102 patients undergoing open bilobectomy, lobectomy, segmentectomy, or other resection

Author Surgical

Rena et al.(73) Coated

Moser et al.(62)

Tansley et al.(76)

Belcher et al. (75)

paralysis.

to patients with emphysema.

sealant

collagen patch vs none

Fibrin glue vs none

Bovine based surgical adhesive vs none

Bovine based surgical adhesive vs fibrin glue

**3.6 Minimizing post-resectional spaces** 

controlling the size of the potential space post-pulmonary resection in the upper thoracic cavity, and thus has been predominantly studied in patients undergoing upper lobectomy.

In a retrospective review on risk factors for prolonged post-operative air leak, Brunelli and associates(16) noted that patients with upper lobectomies who underwent a pleural tent had a significantly decreased duration of air leak compared to those who did not undergo a similar adjunctive procedure. Nevertheless, he later published a retrospective case matched analysis comparing patients with prolonged air leak after pulmonary resection and those without, which did not demonstrate that pleural tenting conferred any protective effect(9). DeCamp et al.(12) in reviewing the factors influencing air leak post-lung volume reduction surgery in patients from the National Emphysema Treatment Trial also did not find a significant decrease in incidence or duration of air leak in patients who underwent tenting compared to those who did not undergo tenting.

In addition, a number of randomized prospective studies have also been performed to assess its efficacy, and in general, the studies conducted on pleural tenting have shown an overall beneficial effect in terms of decreasing incidence of air leak, time to chest tube removal and length of stay. However, this procedure adds to operative time and may cause bleeding(35) though these were not shown to be significantly increased compared to controls in the studies below.

Author Patient population Definition of prolonged air leak Incidence of prolonged air leak Time to chest tube removal (mean) Length of stay (mean) Brunelli et al.(77) 200 patients undergoing open upper lobectomy or bilobectomy (100 with tenting vs 100 without) >7 days 14% vs 32% p=0.003 7 vs 11.2 days, p<0.0001 8.2 vs 11.6 days, p<0.0001 Allama et al.(78) 48 patients undergoing open upper lobectomy (23 with tenting vs 25 without) >5 days 9% vs 40%, p=0.02 4.6 vs 5.6 days, p=0.11 4.96 vs 5.7 days, p=0.05 Okur et al.(79) 40 patients undergoing open upper lobectomy or bilobectomy (20 with tenting vs 20 without) >5 days 0 vs 30% 4.3 vs 7.4 days, p<0.0001 7.6 vs 9.35 days, p=0.024

The table below summarizes the results of the randomized prospective studies performed to evaluate this technique.

Table 7. Studies comparing the utility of pleural tenting in preventing prolonged air leak.

Conversely, the creation a pneumoperitoneum has been utilized to minimize the postresectional space in the lower thoracic cavity. This has been described as both an intraoperative adjunct to prevent prolonged air leak(80) as well as a post-operative technique(81- 83) to treat it. It can be accomplished through instillation of air into the peritoneal cavity by

leak(98).

Author Patient

Travaline et al.(98)

Gillespie et al.(99)

prolonged air leak.

patients with no other therapeutic options.

Duration of air leak prior to valve placement (median)

Number of patients with improvement

population

40 patients with underlying lung disease (30% COPD) that had persistent air leaks (17.5% postoperative)

7 patients with underlying lung disease (71% COPD) that had persistent air leaks (71% postoperative)

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 117

stents) succeeded in treating only 30% of them. Overall mortality was 40%, with many patients requiring multiple bronchoscopic procedures or additional surgical drainage.

In addition, the placement of endobronchial valves is a new technique that has emerged recently for the treatment of persistent air leak in patients with underlying lung disease such as emphysema that are not candidates for more extensive procedures such as surgery(96, 97). Endobronchial one-wave valves inserted via bronchoscopy were initially developed as an investigational technique to treat emphysema by promoting atelectasis of emphysematous lungs distal to the valve, which would allow air to exit via the valve but not re-enter. They have now been used in selected patients with persistent air leaks, in hope that they accelerate closure of the leak by minimizing flow of air through the

The procedure can be performed either under sedation or general anesthesia, using either a flexible or rigid bronchoscope. A balloon tipped catheter is used to provide selective bronchial occlusion to determine the segmental or subsegmental airway that results in the greatest decrease in air leak. The endobronchial valve is then inserted in these airways (98, 99). The results of the two largest series on endobronchial valve placement are summarized below, and the overall conclusion is it is a promising mode of therapy particularly for

> Duration of chest tube drainage after valve placement (median)

20 days 37 (92.5%) 7.5 days 11 days 6 (valve

28 days 7 (100%) 16 days 3 days Nil

Table 8. Studies reporting the efficacy of endobronchial valve placement in the treatment of

Duration of hospitalization after valve placement (median)

Complications

expectoration, malpositioning of the valve requiring redeployment, pneumonia, oxygen

desaturation and

MRSA colonization)

a variety of means, including under direct vision through a transdiaphragmatic opening made in the diaphragm during surgery(80), via insertion of a peritoneal dialysis catheter under local anesthesia(81), or with the aid of a Veres needle under local anesthesia(82, 83) .

A small randomized prospective trial by Cerfolio and colleagues(80) studied 16 patients undergoing right middle and lower bilobectomy, dividing them into a group who underwent intra-operative pneumoperitoneum creation and a group who did not undergo this procedure. 0/8 patients with an intra-operative pneumoperitoneum had air leak by POD3, compared to 4/8 patients who did not have an intra-operative pneumoperitoneum (p<0.001). Moreover, patients in the former group had a median hospitalization stay of 4 days compared to 6 days for patients in the latter group (p<0.001). Thus, this is an interesting technique, but conclusions on its efficacy are difficult to draw based on the limited data available. The results of postoperative pneumoperitoneum creation will be discussed later in the section on post-operative strategies for management of prolonged air leak.

Deliberate diaphragmatic paralysis is an alternative method used to decrease the potential space in the lower thoracic cavity to allow for more rapid resolution of air leak. Several means are available to achieve this, including infiltration of the phrenic nerve with local anesthetic, phrenic nerve crush or sectioning. The main drawback of diaphragmatic paralysis is the compromise in ventilatory function and cough mechanism. Thus, the use of para-phrenic local anesthetic has the advantage over phrenic nerve crush or sectioning, in that it only resulting in temporary paralysis, so that diaphragmatic function may recover after the effect of the local anesthetic wears off. A recent case report by Clavero and associates(84) explains how an epidural catheter can be placed in close proximity of the phrenic nerve through video-assisted thoracoscopic surgery or thoracotomy, so that the managing physician can dictate the exact duration of diaphragmatic paralysis required to resolve the air leak before reversing the effect of the local anesthetic infusion. However, no large studies specifically describing the use of diaphragmatic paralysis for preventing prolonged air leaks are available.

#### **4. Post-operative strategies for management of prolonged air leak**

#### **4.1 Bronchoscopy and endobronchial techniques**

Bronchoscopy plays an important role in the post-operative management of prolonged air leak. It can be used to clear the airways of mucus and blood to aid maximal re-expansion of the lung to promote resolution of air leaks. Furthermore, it should be performed in all patients with persistent air leak to exclude stump dehiscence, as its presence will often necessitate surgery to treat the problem. Should surgery be contraindicated for whatever reason, a large number of endobronchial approaches have been studied as an alternative therapeutic option for bronchopleural fistulas, including the use of glue(85, 86), polidocanol(87), tetracycline(88), coils(89), surgicel(90), gelfoam(91), tracheobronchial stents(92), atrial septal defect closure devices(93) and even lasers(94). Unfortunately, experience with these techniques have been limited to mostly case reports and case series, with no controlled studies comparing the different methods or comparing them against surgical therapy. A recent systematic review of several of the larger case series by West et al. (95) showed that among 85 patients with post-pneumonectomy bronchopleural fistulas, endobronchial therapy (40 fibrin glue, 15 cyanoacrylate glue, 19 polidocanol, 6 lasers, 5

a variety of means, including under direct vision through a transdiaphragmatic opening made in the diaphragm during surgery(80), via insertion of a peritoneal dialysis catheter under local anesthesia(81), or with the aid of a Veres needle under local anesthesia(82, 83) . A small randomized prospective trial by Cerfolio and colleagues(80) studied 16 patients undergoing right middle and lower bilobectomy, dividing them into a group who underwent intra-operative pneumoperitoneum creation and a group who did not undergo this procedure. 0/8 patients with an intra-operative pneumoperitoneum had air leak by POD3, compared to 4/8 patients who did not have an intra-operative pneumoperitoneum (p<0.001). Moreover, patients in the former group had a median hospitalization stay of 4 days compared to 6 days for patients in the latter group (p<0.001). Thus, this is an interesting technique, but conclusions on its efficacy are difficult to draw based on the limited data available. The results of postoperative pneumoperitoneum creation will be discussed later in the section on post-operative

Deliberate diaphragmatic paralysis is an alternative method used to decrease the potential space in the lower thoracic cavity to allow for more rapid resolution of air leak. Several means are available to achieve this, including infiltration of the phrenic nerve with local anesthetic, phrenic nerve crush or sectioning. The main drawback of diaphragmatic paralysis is the compromise in ventilatory function and cough mechanism. Thus, the use of para-phrenic local anesthetic has the advantage over phrenic nerve crush or sectioning, in that it only resulting in temporary paralysis, so that diaphragmatic function may recover after the effect of the local anesthetic wears off. A recent case report by Clavero and associates(84) explains how an epidural catheter can be placed in close proximity of the phrenic nerve through video-assisted thoracoscopic surgery or thoracotomy, so that the managing physician can dictate the exact duration of diaphragmatic paralysis required to resolve the air leak before reversing the effect of the local anesthetic infusion. However, no large studies specifically describing the use of diaphragmatic paralysis for preventing

**4. Post-operative strategies for management of prolonged air leak** 

Bronchoscopy plays an important role in the post-operative management of prolonged air leak. It can be used to clear the airways of mucus and blood to aid maximal re-expansion of the lung to promote resolution of air leaks. Furthermore, it should be performed in all patients with persistent air leak to exclude stump dehiscence, as its presence will often necessitate surgery to treat the problem. Should surgery be contraindicated for whatever reason, a large number of endobronchial approaches have been studied as an alternative therapeutic option for bronchopleural fistulas, including the use of glue(85, 86), polidocanol(87), tetracycline(88), coils(89), surgicel(90), gelfoam(91), tracheobronchial stents(92), atrial septal defect closure devices(93) and even lasers(94). Unfortunately, experience with these techniques have been limited to mostly case reports and case series, with no controlled studies comparing the different methods or comparing them against surgical therapy. A recent systematic review of several of the larger case series by West et al. (95) showed that among 85 patients with post-pneumonectomy bronchopleural fistulas, endobronchial therapy (40 fibrin glue, 15 cyanoacrylate glue, 19 polidocanol, 6 lasers, 5

strategies for management of prolonged air leak.

prolonged air leaks are available.

**4.1 Bronchoscopy and endobronchial techniques** 

stents) succeeded in treating only 30% of them. Overall mortality was 40%, with many patients requiring multiple bronchoscopic procedures or additional surgical drainage.

In addition, the placement of endobronchial valves is a new technique that has emerged recently for the treatment of persistent air leak in patients with underlying lung disease such as emphysema that are not candidates for more extensive procedures such as surgery(96, 97). Endobronchial one-wave valves inserted via bronchoscopy were initially developed as an investigational technique to treat emphysema by promoting atelectasis of emphysematous lungs distal to the valve, which would allow air to exit via the valve but not re-enter. They have now been used in selected patients with persistent air leaks, in hope that they accelerate closure of the leak by minimizing flow of air through the leak(98).

The procedure can be performed either under sedation or general anesthesia, using either a flexible or rigid bronchoscope. A balloon tipped catheter is used to provide selective bronchial occlusion to determine the segmental or subsegmental airway that results in the greatest decrease in air leak. The endobronchial valve is then inserted in these airways (98, 99). The results of the two largest series on endobronchial valve placement are summarized below, and the overall conclusion is it is a promising mode of therapy particularly for patients with no other therapeutic options.


Table 8. Studies reporting the efficacy of endobronchial valve placement in the treatment of prolonged air leak.

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 119

dialysis catheter under local anesthesia(81), or with the aid of a Veres needle under local anesthesia(82, 83). The creation of a pneumoperitoneum is often combined with a form of pleural sclerosis, such as talc(81, 82) or autologous blood(83), to aid the resolution of air leak. Several potential disadvantages of this technique include the risk of insertion of peritoneal dialysis catheter / Veres needle (eg bleeding, injury to intra-abdominal viscera)

Not many studies have been performed to evaluate this modality of therapy, except for a few isolated case reports, so the technique has shown promise in treatment of some patients but has not been evaluated on a large scale basis. Handy and associates(81) reported the successful use of this technique to resolve a persistent air leak of more than 3 weeks duration in a patient with emphysema who underwent lung volume reduction surgery. De Giacomo and colleagues(82) described the use of post-operative pneumoperitoneum to manage persistent air leak (>5 days) in 14 patients who underwent pulmonary resection for lung cancer, with resolution of the air leak occurring within 4-12 (mean 8) days after the procedure. The most recent paper assessing this technique by Korasidis et al.(83) demonstrated that combined post-operative pneumoperitoneum and autologous blood patch was able to control prolonged air leak (>3 days) present in 39 patients who underwent pulmonary resection for lung cancer within 144 hours of therapy. No major complications

and possible respiratory compromise from the creation of the pneumoperitoneum.

**4.4 Optimal chest tube management and outpatient chest tube management** 

Appropriate chest tube management has also been shown to influence the duration of postoperative air leak. With respect to chest tube suction, it may be viewed in one of two ways. Firstly, chest tube suction may promote pleural apposition to decrease duration of air leaks, or alternatively, suction may cause tension on suture lines to prolong air leaks. The experience in lung volume reduction surgery had previously demonstrated that duration of prolonged air leak was decreased by avoiding routine chest tube suction in these

This was subsequently investigated in several randomized prospective studies to see if this also held true in patients undergoing other forms of thoracic operations. For patients undergoing apical pleurectomy following primary spontaneous pneumothorax, Ayed demonstrated that converting to water seal (no suction) after a period of initial active suction significantly decreased the risk of prolonged air leak and duration of chest tube drainage compared to active suction throughout(117). A similar benefit of converting to water seal after a period of initial active suction for patients undergoing pulmonary resection (lobectomy, segmentectomy or wedge resections) was demonstrated by two separate groups(118, 119). However, a comparable study by Brunelli and associates(120) showed that water seal had no advantage over active suction when limited to a population of patients undergoing lobectomy. A follow-up study demonstrated that in patients undergoing lobectomy, alternate suction (at night) and water seal (during the day) was

A different approach was evaluated by Alphonso and colleagues, who studied a mixed cohort of patients undergoing a variety of operations (VATS as well as open lobectomy, wedge resections, lung biopsies or pneumothorax operations) and found that adopting

with the technique were reported by any of the above studies.

patients(116).

better than water seal alone(121).

#### **4.2 Bedside pleurodesis**

Instillation of a sclerosing agent into the pleural space elicits an inflammatory reaction in the pleura that allows for the obliteration of the pleural space and resolution of an air leak. A variety of agents have been described for this purpose, including silver nitrate(100), quinacrine(101), minocycline(102), tetracycline(103), doxycycline(104), erythromycin(105), bleomycin(106), iodopovidone(107), talc powder(14) and autologous blood(108-111). Be that as it may, contemporary literature has mainly focused on autologous blood for treatment of persistent post-operative air leaks, so the utility of the other agents for this clinical context are not as well known. Also, these studies were not limited to patients with emphysema, so their results may not be directly applicable for these patients with persistent post-operative air leaks. However, based on available published data, bedside pleurodesis is a reasonably efficacious modality of treatment with few adverse effects, so it is often used as first line therapy for patients with prolonged air leak, even in our own institution.

Several small observational studies have demonstrated the efficacy and safety of autologous blood in treating post-operative prolonged air leak(108-110). In these studies, patients with prolonged air leak (>5-10 days) after undergoing a variety of operations (lobectomy, wedge resection, bullectomy, lung volume reduction or decortication) were treated with 1-2 injections of autologous blood pleurodesis with resolution of air leak in all patients within 48 hours of therapy. No major complications occurred except for fever, pneumonia or prolonged pleural effusion in a minority of patients.

In addition, Shackcloth et al.(111) performed a randomized prospective study on 20 postlobectomy patients with prolonged air leak (>5 days) to evaluate autologous blood pleurodesis compared to controls. They showed that there was a statistically significant (p<0.001) reduction in median time to chest tube removal (6.5 vs 12 days) and hospital discharge (8 vs 13.5 days) with autologous blood pleurodesis. One patient in the pleurodesis arm however developed an empyema.

As for the other forms of chemical pleurodesis, Liberman and associates(14) reported their experience with 41 patients who underwent chemical pleurodesis (30 talc, 7 doxycycline, 1 doxycycline+talc, 1 bleomycin, 1 bleomycin+talc) for prolonged air leak (>5 days) after undergoing lobectomy or bilobectomy. Sclerosis was successful in 40 patients (97.6%), with the remaining one patient having to undergo a pectoralis major flap for persistent air leak despite talc pleurodesis. Also, one patient developed empyema after talc pleurodesis.

As indicated above, complications of bedside pleurodesis include mainly consist of fever, pain and empyema. In addition, the most feared complication of talc pleurodesis is a systemic inflammatory response to talc that can result in acute respiratory distress syndrome(112, 113) particularly if the talc particle size is small(114). However, it has previously been found to be not associated with increased mortality in a meta-analysis of patients with malignant pleural effusion undergoing talc pleurodesis(115).

#### **4.3 Post-operative creation of pneumoperitoneum**

As mentioned previously, the creation of a pneumoperitoneum has been described as both an intra-operative as well as a post-operative method of controlling prolonged air leaks. This involves the instillation of air into the peritoneal cavity via insertion of a peritoneal

Instillation of a sclerosing agent into the pleural space elicits an inflammatory reaction in the pleura that allows for the obliteration of the pleural space and resolution of an air leak. A variety of agents have been described for this purpose, including silver nitrate(100), quinacrine(101), minocycline(102), tetracycline(103), doxycycline(104), erythromycin(105), bleomycin(106), iodopovidone(107), talc powder(14) and autologous blood(108-111). Be that as it may, contemporary literature has mainly focused on autologous blood for treatment of persistent post-operative air leaks, so the utility of the other agents for this clinical context are not as well known. Also, these studies were not limited to patients with emphysema, so their results may not be directly applicable for these patients with persistent post-operative air leaks. However, based on available published data, bedside pleurodesis is a reasonably efficacious modality of treatment with few adverse effects, so it is often used as first line

Several small observational studies have demonstrated the efficacy and safety of autologous blood in treating post-operative prolonged air leak(108-110). In these studies, patients with prolonged air leak (>5-10 days) after undergoing a variety of operations (lobectomy, wedge resection, bullectomy, lung volume reduction or decortication) were treated with 1-2 injections of autologous blood pleurodesis with resolution of air leak in all patients within 48 hours of therapy. No major complications occurred except for fever, pneumonia or

In addition, Shackcloth et al.(111) performed a randomized prospective study on 20 postlobectomy patients with prolonged air leak (>5 days) to evaluate autologous blood pleurodesis compared to controls. They showed that there was a statistically significant (p<0.001) reduction in median time to chest tube removal (6.5 vs 12 days) and hospital discharge (8 vs 13.5 days) with autologous blood pleurodesis. One patient in the pleurodesis

As for the other forms of chemical pleurodesis, Liberman and associates(14) reported their experience with 41 patients who underwent chemical pleurodesis (30 talc, 7 doxycycline, 1 doxycycline+talc, 1 bleomycin, 1 bleomycin+talc) for prolonged air leak (>5 days) after undergoing lobectomy or bilobectomy. Sclerosis was successful in 40 patients (97.6%), with the remaining one patient having to undergo a pectoralis major flap for persistent air leak despite talc pleurodesis. Also, one patient developed empyema after talc pleurodesis.

As indicated above, complications of bedside pleurodesis include mainly consist of fever, pain and empyema. In addition, the most feared complication of talc pleurodesis is a systemic inflammatory response to talc that can result in acute respiratory distress syndrome(112, 113) particularly if the talc particle size is small(114). However, it has previously been found to be not associated with increased mortality in a meta-analysis of

As mentioned previously, the creation of a pneumoperitoneum has been described as both an intra-operative as well as a post-operative method of controlling prolonged air leaks. This involves the instillation of air into the peritoneal cavity via insertion of a peritoneal

patients with malignant pleural effusion undergoing talc pleurodesis(115).

**4.3 Post-operative creation of pneumoperitoneum** 

therapy for patients with prolonged air leak, even in our own institution.

prolonged pleural effusion in a minority of patients.

arm however developed an empyema.

**4.2 Bedside pleurodesis** 

dialysis catheter under local anesthesia(81), or with the aid of a Veres needle under local anesthesia(82, 83). The creation of a pneumoperitoneum is often combined with a form of pleural sclerosis, such as talc(81, 82) or autologous blood(83), to aid the resolution of air leak. Several potential disadvantages of this technique include the risk of insertion of peritoneal dialysis catheter / Veres needle (eg bleeding, injury to intra-abdominal viscera) and possible respiratory compromise from the creation of the pneumoperitoneum.

Not many studies have been performed to evaluate this modality of therapy, except for a few isolated case reports, so the technique has shown promise in treatment of some patients but has not been evaluated on a large scale basis. Handy and associates(81) reported the successful use of this technique to resolve a persistent air leak of more than 3 weeks duration in a patient with emphysema who underwent lung volume reduction surgery. De Giacomo and colleagues(82) described the use of post-operative pneumoperitoneum to manage persistent air leak (>5 days) in 14 patients who underwent pulmonary resection for lung cancer, with resolution of the air leak occurring within 4-12 (mean 8) days after the procedure. The most recent paper assessing this technique by Korasidis et al.(83) demonstrated that combined post-operative pneumoperitoneum and autologous blood patch was able to control prolonged air leak (>3 days) present in 39 patients who underwent pulmonary resection for lung cancer within 144 hours of therapy. No major complications with the technique were reported by any of the above studies.

#### **4.4 Optimal chest tube management and outpatient chest tube management**

Appropriate chest tube management has also been shown to influence the duration of postoperative air leak. With respect to chest tube suction, it may be viewed in one of two ways. Firstly, chest tube suction may promote pleural apposition to decrease duration of air leaks, or alternatively, suction may cause tension on suture lines to prolong air leaks. The experience in lung volume reduction surgery had previously demonstrated that duration of prolonged air leak was decreased by avoiding routine chest tube suction in these patients(116).

This was subsequently investigated in several randomized prospective studies to see if this also held true in patients undergoing other forms of thoracic operations. For patients undergoing apical pleurectomy following primary spontaneous pneumothorax, Ayed demonstrated that converting to water seal (no suction) after a period of initial active suction significantly decreased the risk of prolonged air leak and duration of chest tube drainage compared to active suction throughout(117). A similar benefit of converting to water seal after a period of initial active suction for patients undergoing pulmonary resection (lobectomy, segmentectomy or wedge resections) was demonstrated by two separate groups(118, 119). However, a comparable study by Brunelli and associates(120) showed that water seal had no advantage over active suction when limited to a population of patients undergoing lobectomy. A follow-up study demonstrated that in patients undergoing lobectomy, alternate suction (at night) and water seal (during the day) was better than water seal alone(121).

A different approach was evaluated by Alphonso and colleagues, who studied a mixed cohort of patients undergoing a variety of operations (VATS as well as open lobectomy, wedge resections, lung biopsies or pneumothorax operations) and found that adopting

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 121

An alternative strategy to prolonged air leaks is the use of Heimlich valves or portable chest drainage systems to allow for early discharge of patients who are otherwise ready to be discharged from hospital apart from their prolonged air leak. Heimlich valves are one way valves originally used for the outpatient management of a pneumothorax, and two studies have shown that they can be successfully used to discharge select patients with prolonged air leak early with relatively few complications(123, 124). Portable chest tube drainage systems have an additional advantage over Heimlich valves in that they are able to handle fluid drainage in addition to air leak and can also be connected to active suction when required(125). In conclusion, outpatient chest tube management appears to be an acceptable approach that is fairly safe for managing most patients with prolonged air leak if they are reliable enough to handle their Heimlich valve or portable chest tube system on

> chest tube management

Portable chest tube system with

Table 10. Studies reporting the use of Heimlich valves or portable chest tube systems in the

As to which patients with prolonged air leak are suitable for discharge without suction, Cerfolio and colleagues(126) reported that they successfully discharged 199 post-pulmonary resection patients with a suctionless portable device safely without complications as long as there was no development of a new or enlarging pneumothorax or subcutaneous emphysema after converting the original chest tube suction to water seal. More importantly, most of these patients had their air leak resolve by the end of 2 weeks of outpatient chest tube therapy, and for the remaining 57 who still had air leak, the chest tube was safely removed if these patients were asymptomatic, had no increase in pneumothorax or new subcutaneous emphysema on the outpatient device. There were no complications except for the development of empyema in 3 of these 57 patients (5.7%), but these 3 patients were

suction

Duration of outpatient chest tube management

Heimlich valve 7.5 days 1 pneumonia

11.2 days 1 cellulitis, 1

localized empyema, 1 recurrence of pneumothorax

Complications

(mean)

Heimlich valve 7.7 days Nil

their own at home.

McKenna et al.(124)

Rieger et al.(125)

Author Patient population Type of outpatient

25 patients post-lung volume reduction surgery with prolonged air leak (>

lobectomy, wedge resection or bullectomy with prolonged air leak

(not defined)

outpatient treatment of prolonged air leak.

36 patients postlobectomy,

segmentectomy, wedge resection, pleurodesis, pericardial window, mediastinal dissection or esophagogastrectomy with prolonged air leak or excessive drainage

immunocompromised and were on chronic steroid therapy.

5 days)

Ponn et al.(123) 45 patients post

water seal immediately after surgery showed no difference in air leak duration compared to active suction(122).

Whether these approaches are applicable to patients with underlying emphysema undergoing pulmonary resection or pleurodesis has yet to be conclusively demonstrated, but a strategy of minimizing duration of chest tube suction or alternating it with water seal would be prudent based on evidence available so far. In addition, it should be noted that patients on water seal, particularly those with large air leaks, should be monitored for evidence of increasing subcutaneous emphysema or enlarging pneumothorax, as these patients will need to be placed back on active suction to prevent clinical deterioration(118).


Table 9. Studies comparing the utility of chest tube management strategies in preventing prolonged air leak.

water seal immediately after surgery showed no difference in air leak duration compared to

Whether these approaches are applicable to patients with underlying emphysema undergoing pulmonary resection or pleurodesis has yet to be conclusively demonstrated, but a strategy of minimizing duration of chest tube suction or alternating it with water seal would be prudent based on evidence available so far. In addition, it should be noted that patients on water seal, particularly those with large air leaks, should be monitored for evidence of increasing subcutaneous emphysema or enlarging pneumothorax, as these patients will need to be placed back on active suction to prevent clinical deterioration(118).

> Definition of prolonged air

Incidence of prolonged air Time to chest tube removal (mean)

2.7 vs 3.8 days (p=0.004)

days (p=0.06)

11.5 vs 10.3 (p=0.2)

8.6 vs 5.2 days (p=0.002)

NA

leak

NA NA NA

>7 days 27.8% vs 30.1% (p=0.8)

>7 days 19% vs 4%

>6 days 10.1% vs 7.8%

(p=0.02)

(p=0.62)

NA NA 3.33 vs 5.47

(p=0.03)

>5 days 2% vs 14%

leak

management

Initial chest tube suction, then water seal vs active suction throughout

Initial chest tube suction, then water seal vs active suction throughout

Initial chest tube suction, then water seal vs active suction throughout

Initial chest tube suction, then water seal vs active suction throughout

Initial chest tube suction, then water seal vs alternating suction (at night) and water seal (during the day)

Immediate water seal vs active suction throughout

Table 9. Studies comparing the utility of chest tube management strategies in preventing

active suction(122).

Author Patient population Chest tube

undergoing VATS pleurodesis for primary spontaneous pneumothorax

33 patients undergoing bilobectomy, lobectomy, segmentectomy or wedge resection

68 patients undergoing lobectomy, segmentectomy or wedge resection

145 patients undergoing bilobectomy or lobectomy

94 patients undergoing bilobectomy or lobectomy

239 patients undergoing lobectomy, segmentectomy, wedge resection or pneumothorax operations

Ayed(117) 100 patients

Cerfolio et al.(118)

Marshall et al.(119)

Brunelli et al.(120)

Brunelli et al.(121)

Alphonso et al.(122)

prolonged air leak.

An alternative strategy to prolonged air leaks is the use of Heimlich valves or portable chest drainage systems to allow for early discharge of patients who are otherwise ready to be discharged from hospital apart from their prolonged air leak. Heimlich valves are one way valves originally used for the outpatient management of a pneumothorax, and two studies have shown that they can be successfully used to discharge select patients with prolonged air leak early with relatively few complications(123, 124). Portable chest tube drainage systems have an additional advantage over Heimlich valves in that they are able to handle fluid drainage in addition to air leak and can also be connected to active suction when required(125). In conclusion, outpatient chest tube management appears to be an acceptable approach that is fairly safe for managing most patients with prolonged air leak if they are reliable enough to handle their Heimlich valve or portable chest tube system on their own at home.


Table 10. Studies reporting the use of Heimlich valves or portable chest tube systems in the outpatient treatment of prolonged air leak.

As to which patients with prolonged air leak are suitable for discharge without suction, Cerfolio and colleagues(126) reported that they successfully discharged 199 post-pulmonary resection patients with a suctionless portable device safely without complications as long as there was no development of a new or enlarging pneumothorax or subcutaneous emphysema after converting the original chest tube suction to water seal. More importantly, most of these patients had their air leak resolve by the end of 2 weeks of outpatient chest tube therapy, and for the remaining 57 who still had air leak, the chest tube was safely removed if these patients were asymptomatic, had no increase in pneumothorax or new subcutaneous emphysema on the outpatient device. There were no complications except for the development of empyema in 3 of these 57 patients (5.7%), but these 3 patients were immunocompromised and were on chronic steroid therapy.

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 123

Fig. 2. (b) Latissimus dorsi and serratus anterior reflected to demonstrate the axillary window. The latissimus dorsi flap is then passed though the axillary window and laid over

Fig. 2. (c) Serratus anterior flap is rotated anteriorly over the latissimus dorsi flap to close the

At our institution, our indications for surgical air leak repair with flap reconstruction are (1) severe air leaks (high leak rate or continuous leak despite application of chest tube suction), (2) persistent air leak exceeding 4 weeks despite conservative management (or beyond 1 week for patients with underlying lung disease such as COPD), and (3) significant pleural dead space defined radiologically by absence of pleural-pleural contact despite maximal re-

The operation is performed via a muscle sparing posterolateral thoracotomy with a lazy-S incision extending from the axilla to the lumbar region. Then, the latissimus dorsi and the serratus anterior muscle flaps are raised, with care taken to ensure that the serratus anterior

axillary window. Primary closure of the incision was then performed.

expansion efforts(16, 36, 130).

the lung to obliterate the pleural space and seal the air leak.

#### **4.5 Re-operation**

If all else fails, in cases of persistent air leak that is refractory to methods described above, re-operation can be considered to look for the source of air leak and perform therapeutic maneuvers. Often this can be accomplished with video assisted thoracoscopy, such as described by Suter and associates(127), who managed to identify the source of air leak thoracoscopically in 3 patients who had prolonged air leak after pulmonary resection. The air leaks were subsequently sealed with direct application of fibrin glue or pleurodesis with silver nitrate.

However, patients with massive, severe prolonged air leaks, particularly those with a concomitant large pleural space problem, usually require a more extensive operation such as a thoracoplasty or muscle flap transposition via an open thoracotomy. Thoracoplasty, the reduction of thoracic cavity by removal of ribs, is rarely done as it results in thoracic deformity, restriction in shoulder mobility and decreased respiratory function(7, 128). As such, muscular flap transpositions have become the preferred technique, and we have developed the combined latissimus dorsi-serratus anterior transposition flap for this purpose. We have previously described 5 patients who underwent this technique (two COPD patients with pneumothorax refractory to conservative management, one COPD patient with prolonged air leak post lung volume reduction surgery, two patients with bronchopleural fistula/empyemas), with resolution of air leak that allows the chest tubes to be removed within 5 days after surgery and no recurrence of air leak noted at 1 year followup(129).

Fig. 2. (a) The latissimus dorsi and proximal slips of the serratus anterior are raised as pedicled flaps via a lazy S incision from mid-axillary line to the inferior limit of the latissimus dorsi. An axillary window is then created by resecting the 2nd and 3rd ribs superior to the serratus anterior.

If all else fails, in cases of persistent air leak that is refractory to methods described above, re-operation can be considered to look for the source of air leak and perform therapeutic maneuvers. Often this can be accomplished with video assisted thoracoscopy, such as described by Suter and associates(127), who managed to identify the source of air leak thoracoscopically in 3 patients who had prolonged air leak after pulmonary resection. The air leaks were subsequently sealed with direct application of fibrin glue or pleurodesis with

However, patients with massive, severe prolonged air leaks, particularly those with a concomitant large pleural space problem, usually require a more extensive operation such as a thoracoplasty or muscle flap transposition via an open thoracotomy. Thoracoplasty, the reduction of thoracic cavity by removal of ribs, is rarely done as it results in thoracic deformity, restriction in shoulder mobility and decreased respiratory function(7, 128). As such, muscular flap transpositions have become the preferred technique, and we have developed the combined latissimus dorsi-serratus anterior transposition flap for this purpose. We have previously described 5 patients who underwent this technique (two COPD patients with pneumothorax refractory to conservative management, one COPD patient with prolonged air leak post lung volume reduction surgery, two patients with bronchopleural fistula/empyemas), with resolution of air leak that allows the chest tubes to be removed within 5 days after surgery and no recurrence of air leak noted at 1 year follow-

Fig. 2. (a) The latissimus dorsi and proximal slips of the serratus anterior are raised as pedicled flaps via a lazy S incision from mid-axillary line to the inferior limit of the latissimus dorsi. An axillary window is then created by resecting the 2nd and 3rd ribs

**4.5 Re-operation** 

silver nitrate.

up(129).

superior to the serratus anterior.

Fig. 2. (b) Latissimus dorsi and serratus anterior reflected to demonstrate the axillary window. The latissimus dorsi flap is then passed though the axillary window and laid over the lung to obliterate the pleural space and seal the air leak.

Fig. 2. (c) Serratus anterior flap is rotated anteriorly over the latissimus dorsi flap to close the axillary window. Primary closure of the incision was then performed.

At our institution, our indications for surgical air leak repair with flap reconstruction are (1) severe air leaks (high leak rate or continuous leak despite application of chest tube suction), (2) persistent air leak exceeding 4 weeks despite conservative management (or beyond 1 week for patients with underlying lung disease such as COPD), and (3) significant pleural dead space defined radiologically by absence of pleural-pleural contact despite maximal reexpansion efforts(16, 36, 130).

The operation is performed via a muscle sparing posterolateral thoracotomy with a lazy-S incision extending from the axilla to the lumbar region. Then, the latissimus dorsi and the serratus anterior muscle flaps are raised, with care taken to ensure that the serratus anterior

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 125

pneumoperitoneum), or reduces the patient's functional lung reserve (phrenic nerve

Other muscular flaps that have been described in contemporary literature to eliminate potential pleural spaces (though these have been traditionally ascribed for managing empyema spaces rather than persistent air leaks) include isolated pectoralis major (14, 131), latissimus dorsi (131, 132), serratus anterior (131), rectus abdominis(131, 133) and the trapezius flaps (131, 134). However, we have found in our own experience that these flaps either lack the reach or necessary bulk in order to properly treat the large pleural space problems that we have encountered. Thus, we feel that this combination muscle flap technique is an important and useful tool in the thoracic surgeon's armamentarium in dealing with recalcitrant post-operative air leaks in a variety of situations, particularly in patients with a background of impaired respiratory function such as severe emphysema.

Fig. 4. Two months after the initial operation, this patient has good recovery of shoulder

In summary, prolonged air leak is a common problem for patients with emphysema undergoing thoracic surgery that is associated with significant morbidity. Clinicians involved in the surgical care of this group of patients should be aware of the various factors which can further increase the risk of this complication occurring and need to know the various measures that should be employed to prevent this problem, as well as the treatment options available should prolonged air leak occur even if preventive measures are taken. Based on the review of best available evidence as discussed previously, we propose a suggested algorithm for the management of prolonged air leaks in patients with emphysema with gradual progression of therapy similar to what has been proposed by others(2-4) but that also takes into account criteria for surgical intervention as we have

paralysis, thoracoplasty).

function.

**5. Summary** 

mentioned earlier.

flap is sufficient to cover the intended axillary window (usually by raising muscle slips from the 2nd to 4th ribs) but sparing the lower slips of muscle that insert into the scapula to avoid scapular winging. Creation of the axillary window involves resection of the second to fourth ribs centered over the mid-axillary line which allows good exposure of the underlying lung for surgical treatment (eg suture repair of parenchymal tears, decortication) and allows the latissimus dorsi to the passed through without compressing its vascular pedicle. The latissimus dorsi is loosely anchored over the lung and a chest tube is inserted after a final check for air leak. The axillary window is then closed with the serratus anterior muscle flap and the skin incision is closed over a subcutaneous drain.

Fig. 3. Pre-operative chest x-ray (left) showing a large potential pleural space with resulting persistent air leak in this patient who had underwent bilateral lung volume reduction surgery, and post-operative chest x-ray (right) showing effective re-expansion of the right lung after the placement of the latissimus dorsi flap.

We believe our technique has several distinct advantages, as firstly it offers direct visualization for repair of diseased lung parenchyma via an open thoracotomy. Secondly, the latissimus dorsi flap provides a large, well vascularised surface for the lung to adhere to for healing. Moreover, the large mass of the muscle eliminates any pleural dead space and facilitates subsequent controlled re-expansion of the lung with time. Finally, the serratus anterior flap compartmentalizes the pleural cavity from the large subcutaneous space created by the latissimus dorsi harvest to prevent seroma formation or spread of infection between compartments. Minimal functional disability occurs after these muscle harvests, and scapular winging is prevented by sparing the lower slips of the serratus anterior muscle and the long thoracic nerve. This is in contrast to other methods for reducing pleural dead space which may only be sufficient to deal with a small volume of space (pleural tenting, pneumoperitoneum), or reduces the patient's functional lung reserve (phrenic nerve paralysis, thoracoplasty).

Other muscular flaps that have been described in contemporary literature to eliminate potential pleural spaces (though these have been traditionally ascribed for managing empyema spaces rather than persistent air leaks) include isolated pectoralis major (14, 131), latissimus dorsi (131, 132), serratus anterior (131), rectus abdominis(131, 133) and the trapezius flaps (131, 134). However, we have found in our own experience that these flaps either lack the reach or necessary bulk in order to properly treat the large pleural space problems that we have encountered. Thus, we feel that this combination muscle flap technique is an important and useful tool in the thoracic surgeon's armamentarium in dealing with recalcitrant post-operative air leaks in a variety of situations, particularly in patients with a background of impaired respiratory function such as severe emphysema.

Fig. 4. Two months after the initial operation, this patient has good recovery of shoulder function.

#### **5. Summary**

124 Emphysema

flap is sufficient to cover the intended axillary window (usually by raising muscle slips from the 2nd to 4th ribs) but sparing the lower slips of muscle that insert into the scapula to avoid scapular winging. Creation of the axillary window involves resection of the second to fourth ribs centered over the mid-axillary line which allows good exposure of the underlying lung for surgical treatment (eg suture repair of parenchymal tears, decortication) and allows the latissimus dorsi to the passed through without compressing its vascular pedicle. The latissimus dorsi is loosely anchored over the lung and a chest tube is inserted after a final check for air leak. The axillary window is then closed with the serratus anterior muscle flap

Fig. 3. Pre-operative chest x-ray (left) showing a large potential pleural space with resulting persistent air leak in this patient who had underwent bilateral lung volume reduction surgery, and post-operative chest x-ray (right) showing effective re-expansion of the right

We believe our technique has several distinct advantages, as firstly it offers direct visualization for repair of diseased lung parenchyma via an open thoracotomy. Secondly, the latissimus dorsi flap provides a large, well vascularised surface for the lung to adhere to for healing. Moreover, the large mass of the muscle eliminates any pleural dead space and facilitates subsequent controlled re-expansion of the lung with time. Finally, the serratus anterior flap compartmentalizes the pleural cavity from the large subcutaneous space created by the latissimus dorsi harvest to prevent seroma formation or spread of infection between compartments. Minimal functional disability occurs after these muscle harvests, and scapular winging is prevented by sparing the lower slips of the serratus anterior muscle and the long thoracic nerve. This is in contrast to other methods for reducing pleural dead space which may only be sufficient to deal with a small volume of space (pleural tenting,

and the skin incision is closed over a subcutaneous drain.

lung after the placement of the latissimus dorsi flap.

In summary, prolonged air leak is a common problem for patients with emphysema undergoing thoracic surgery that is associated with significant morbidity. Clinicians involved in the surgical care of this group of patients should be aware of the various factors which can further increase the risk of this complication occurring and need to know the various measures that should be employed to prevent this problem, as well as the treatment options available should prolonged air leak occur even if preventive measures are taken. Based on the review of best available evidence as discussed previously, we propose a suggested algorithm for the management of prolonged air leaks in patients with emphysema with gradual progression of therapy similar to what has been proposed by others(2-4) but that also takes into account criteria for surgical intervention as we have mentioned earlier.

Surgical Management of Prolonged Air Leak in Patients with Underlying Emphysema 127

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### *Edited by Ravi Mahadeva*

Chronic Obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality world-wide. The most common cause is chronic cigarette smoke inhalation which results in a chronic progressive debilitating lung disease with systemic involvement. COPD poses considerable challenges to health care resources, both in the chronic phase and as a result of acute exacerbations which can often require hospital admission. At the current time it is vital that scientific resources are channeled towards understanding the pathogenesis and natural history of the disease, to direct new treatment strategies for rigorous evaluation. This book encompasses some emerging concepts and new treatment modalities which hopefully will lead to better outcomes for this devastating disease.

Emphysema

Emphysema

*Edited by Ravi Mahadeva*

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