**4. Treatment of emphysema**

The treatment of pulmonary emphysema has not only puzzled surgeons but has also attracted their interest throughout history. Many operations have been proposed however, it was not until further understanding of the physiological impairment of the disease was understood that appropriate surgical treatment evolved. Surgical treatment for patients on maximal medical therapy but remain symptomatic carries both morbidity and mortality; however, the operations also carry with them the hope of relief from dyspnea. Three typical operations performed for emphysema are bullectomy, volume reduction, and lung transplantation.

### **4.1 Bullectomy**

36 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

Fig. 1a. Schematic of typical anteroposterior

Fig. 1b. Lateral chest radiograph findings of emphysema.

establish the presence of obstruction, with a ratio of less than 0.70 being significant for obstruction [33]. The inspiratory capacity is usually decreased with tachypnea due to dynamic hyperinflation and increased total lung capacity, functional residual capacity and residual volume. The measurement of carbon monoxide diffusing capacity can help to establish the presence of emphysema but is not used in the routine diagnosis of COPD. Arterial blood gases (ABG) is used to correlate symptoms with blood oxygenation levels but is not needed in mild to moderate airflow obstruction. ABG is optional in moderately severe Bullae are defined as emphysematous spaces larger than 1 cm in diameter in the inflated lung, usually demarcated from surrounding lung tissue and pathologically consists of enlarged airspaces covered by visceral pleural. Bullae have been characterized into three different types with Type I and II associated with diffuse emphysema, with type III representing complete loss of parenchymal architecture throughout lung fields [34]. Bullae in emphysematous disease is believed to arise *via* a ball-valve mechanism where air is allowed to enter the airspace but not allowed to escape with progressive enlargement of the airspace over time [35-36]. The enlarged space-occupying lesion leads to compression of the surrounding emphysematous lung tissue with preferential filling of the bullae, when exposed to the same negative intrapleural pressure results in continued enlargement [37-39]. The indication for a bullectomy is to permit expansion of the previously collapsed surrounding lung tissue to regain function as well as restore physiologic respiratory function [40]. Compression of surrounding lung tissue by bullae impairs overall gas exchange due to low ventilation to perfusion ratios in the compressed lung region. Furthermore, bullae can result in increased intra-thoracic pressures eventually resulting in hemodynamic dysfunction from compression of the pulmonary arterial system, decrease in systemic venous return, and increased expiratory airway resistance [40]. Large bullae my also restrict the function of the diaphragm and the thoracic chest wall muscles. Bullectomy would remove the space-occupying lesion, reduce expiratory airway resistance, and reduce dead-space ventilation that may result in overall improvement in respiratory function.

The benefit of a bullectomy must be determined based on careful selection of individuals based on the size of the bullae, the degree of compression and whether underlying condition of compressed lung parenchyma exists [42-45]. The highest predictor for benefit from a bullectomy is that young individuals with large localized unilateral bullae that are nonventilated, nonperfused, with significant compression of surrounding lung tissue that has good perfusion and early emphysema [43]. Although posteroanterior and lateral radiographs can identify bullae, CT has become the mainstay imaging technique in delineating the anatomy of bullae [46]. The operative approach for bullectomy is variable and is dependent on the anatomic details of the bullae and specific techniques deployed by the surgeon in question. Single large bullae with a small pedicle may be excised using either a muscle-sparing thoracotomy or a video-assisted thorascopic surgery (VATS), and resected

Chronic Obstructive Pulmonary Disease: Emphysema Revisited 39

with continued perfusion (ventilation-perfusion mismatch) nevertheless, resection of the diseased portions would result in improved ventilation to other functional regions. LVR also serves to re-establish normal chest wall dynamics and may result in improvement in hemodynamic function from the lowering of intra-thoracic pressure throughout the

Selection of candidates for LVR is dependent on the anatomic characteristics of the diseased portion of the lung with ideal candidates having heterogeneous upper-lobe involvement [53]. There is less dramatic improvement in candidates undergoing LVR with lower lobe involvement [54]. Patients being considered for LVR usually undergo scintigrams to identify potential targets for resection. The most important factor for success of LVR has been the meticulous selection of patients based on the National Emphysema Treatment Trial or NETT criteria [55]. Again CT has become the mainstay for characterization of possible resection margins. The mortality rate ranges from 0 to 7.5% with varying surgical approaches [52, 56- 58]. Multiple approaches have been used including median sternotomy, bilateral thoracotomies or VATS (*Figure 3)*. All have similar results with functional improvement disappearing over a period of 3 to 5 years, but LVR patients continue to have a clinical advantage over medical treatment for those 3-5 years with substantial gains in exercise tolerance, freedom with oxygen therapy, and overall improvement in quality of life. The most significant trial, NETT, reported the results which included 1218 patients randomized between LVRS and medical therapy between January 1998 and July 2002 [59]. This trial reported a 90-day surgical mortality of 7.9% without a significant difference in surgical approach. Patients with upper-lobe predominant emphysema had a greater survival benefit from surgery while those with lower-lobe predominant emphysema demonstrated survival benefits from medical therapy. Based on these promising results, LVR can be performed for

Fig. 3. VATS lung volume reduction surgery for upper-lobe predominant emphysema.

respiratory cycle.

patients who are not candidates for lung transplant.

with a stapler (*Figure 2)*. In some instances, large bullae may have completely destroyed an entire lobe requiring lobectomy.

Fig. 2. VATS stapled bullectomy.

Mortality rates of bullectomy should range from 1 to 5%. The mortality rate of approximately 2.3% in well-selected patients was established more than 30 years ago by Fitzgerald *et al* with similar results in modern studies [42, 47]. Similar rates have been seen in patients undergoing VATS compared to thoracotomy approaches. Delayed expansion of the remaining lung tissue, parenchymal air leaks and pulmonary infections are some known post-operative complications, with air leaks being the most frequently occurring. Persistent air-leaks can be managed with the use of a Heimlich valve [48]. Results from bullectomies are difficult to analyze given that there are no prospective randomized clinical trials comparing medical therapy with surgery, as all previous studies were retrospective case series. The most recent series by Schipper *et al* looking at intermediate- to long-term results showed improvement in functional status up to 3 years after resection of giant bullae [47].

#### **4.2 Lung volume reduction (LVR)**

Lung volume reduction (LVR) is similar to bullectomy, the difference being that LVR is an extension performed for diseases that affect the entire lung. LVR was pioneered by Otto Brantigan in the 1950s but was not adopted due to a high mortality rate of 18% [49]. Brantigan's initial hypothesis was that the diseased portions of the lung resulted in loss of elasticity and that removing the most diseased portions permitted and maintained patency of the remaining bronchioles to improve airflow [49]. It was not until several decades later that Delarue *et al* [50] and Dahan [51] *et al* re-introduced the concept in patients with endstage emphysema. However, the role of LVR would not become popular until 1994 when Cooper [52] adapted Brantigan's initial concept. The underlying pathology of end-stage emphysema is characterized by distended airspaces that are inadequately ventilated but

with a stapler (*Figure 2)*. In some instances, large bullae may have completely destroyed an

Mortality rates of bullectomy should range from 1 to 5%. The mortality rate of approximately 2.3% in well-selected patients was established more than 30 years ago by Fitzgerald *et al* with similar results in modern studies [42, 47]. Similar rates have been seen in patients undergoing VATS compared to thoracotomy approaches. Delayed expansion of the remaining lung tissue, parenchymal air leaks and pulmonary infections are some known post-operative complications, with air leaks being the most frequently occurring. Persistent air-leaks can be managed with the use of a Heimlich valve [48]. Results from bullectomies are difficult to analyze given that there are no prospective randomized clinical trials comparing medical therapy with surgery, as all previous studies were retrospective case series. The most recent series by Schipper *et al* looking at intermediate- to long-term results showed improvement in functional status up to 3 years after resection of giant bullae [47].

Lung volume reduction (LVR) is similar to bullectomy, the difference being that LVR is an extension performed for diseases that affect the entire lung. LVR was pioneered by Otto Brantigan in the 1950s but was not adopted due to a high mortality rate of 18% [49]. Brantigan's initial hypothesis was that the diseased portions of the lung resulted in loss of elasticity and that removing the most diseased portions permitted and maintained patency of the remaining bronchioles to improve airflow [49]. It was not until several decades later that Delarue *et al* [50] and Dahan [51] *et al* re-introduced the concept in patients with endstage emphysema. However, the role of LVR would not become popular until 1994 when Cooper [52] adapted Brantigan's initial concept. The underlying pathology of end-stage emphysema is characterized by distended airspaces that are inadequately ventilated but

entire lobe requiring lobectomy.

Fig. 2. VATS stapled bullectomy.

**4.2 Lung volume reduction (LVR)** 

with continued perfusion (ventilation-perfusion mismatch) nevertheless, resection of the diseased portions would result in improved ventilation to other functional regions. LVR also serves to re-establish normal chest wall dynamics and may result in improvement in hemodynamic function from the lowering of intra-thoracic pressure throughout the respiratory cycle.

Selection of candidates for LVR is dependent on the anatomic characteristics of the diseased portion of the lung with ideal candidates having heterogeneous upper-lobe involvement [53]. There is less dramatic improvement in candidates undergoing LVR with lower lobe involvement [54]. Patients being considered for LVR usually undergo scintigrams to identify potential targets for resection. The most important factor for success of LVR has been the meticulous selection of patients based on the National Emphysema Treatment Trial or NETT criteria [55]. Again CT has become the mainstay for characterization of possible resection margins. The mortality rate ranges from 0 to 7.5% with varying surgical approaches [52, 56- 58]. Multiple approaches have been used including median sternotomy, bilateral thoracotomies or VATS (*Figure 3)*. All have similar results with functional improvement disappearing over a period of 3 to 5 years, but LVR patients continue to have a clinical advantage over medical treatment for those 3-5 years with substantial gains in exercise tolerance, freedom with oxygen therapy, and overall improvement in quality of life. The most significant trial, NETT, reported the results which included 1218 patients randomized between LVRS and medical therapy between January 1998 and July 2002 [59]. This trial reported a 90-day surgical mortality of 7.9% without a significant difference in surgical approach. Patients with upper-lobe predominant emphysema had a greater survival benefit from surgery while those with lower-lobe predominant emphysema demonstrated survival benefits from medical therapy. Based on these promising results, LVR can be performed for patients who are not candidates for lung transplant.

Fig. 3. VATS lung volume reduction surgery for upper-lobe predominant emphysema.

Chronic Obstructive Pulmonary Disease: Emphysema Revisited 41

Thermal ablation is the least developed and studied of the bronchoscopic LVR techniques. The use of heated vapor to induce an inflammatory response resulting in occlusion of a diseased portion of lung has only been tested in feasibility studies with further exploratory efforts required due to small sample sizes [68]. Although bronchoscpoic LVR is an emerging

Lung transplantation was originally thought to not be a feasible treatment for emphysema. It wasn't until after the seminal transplantation of single lungs demonstrating significant improvement in symptoms, that lung transplantation became a mainstay for the end-stage emphysema [69-71]. Currently, the most common indication for lung transplantation is idiopathic diffuse emphysema and AAT1 deficiency, two criteria that account for the majority of lung transplants [70]. Lung transplant patients are usually so critically ill that the risk of death from their lung disease enables the actual lung transplant operation to appear quite equitable. The advantages of a lung transplant result in complete replacement of the diseased lung with significant improvements in symptoms [72]. There are however, significant disadvantages to lung transplantation including higher mortality (5 to 15%), lifelong immunosuppression resulting in risks of serious infection and rejection with a

Emphysema can be a preventable and equally treatable pulmonary disease. With the advent of new diagnostic criteria such as the emergence of a key biomarker, circulating levels of EMP may lead to efficient diagnosis and preventative care. Patients with emphysema can present a varying array of symptoms and physical examination findings. While the majority of patients can be managed with medical therapy, those who continue to progress may require surgical intervention based on their diagnostic studies. The ideal surgical treatment of emphysema is dictated by a rigorous selection criteria for each of the possible interventions described and can dramatically improve the quality of life of individuals inflicted with this disease. New and innovative methods for treating crippling emphysemic patients who are not candidates for surgical treatments include bronchoscopic placement of one-way valves into diseased segments of lung tissue or airway bypass by means of inserting stents between bronchi and adjacent lung tissue [75-78], however, these emergent

[1] Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. *Eur Respir J* 2004;23:932–94. [2] World Health Organization. The GOLD global strategy for the management and prevention of COPD: Executive summary 2006 at http://www.goldcopd.org.

technique, further analyses as well as long-term follow-up studies are needed.

**4.3 Lung transplantation** 

**5. Summary** 

**6. References** 

cumulative survival rate of around 50% [73-74].

techniques necessitate further exploratory and long term studies.

[3] http://www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58\_19.pdf [4] http://www.cdc.gov/nchs/data/series/sr\_10/sr10\_249.pdf [5] http://www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58\_19.pdf

A new technique of lung volume reduction with less morbidity and mortality compared to surgical LVR is bronchoscopic lung volume reduction (LVR). Bronchoscopic LVR aims to achieve the same goals as LVRS: improve physiologic mechanics of the chest wall and diaphragm, restore ventilation-perfusion matching, and improve expiratory airflow. The method by which this is achieved is through the use of a bronchoscope to deploy one-way valves, administer sealants, or apply thermal ablation to exclude diseased portions of the lung [60-62]. It is important to note that these techniques have not been approved by the Food and Drug Administration (FDA) for the treatment of severe emphysema and are currently utilized on experimental basis only. The most developed and well-studied of the bronchoscopic techniques is the one-way valve. One-way valves allow air and mucus to escape from the excluded portion of lung yet concomitantly excluding that portion of the lung from normal physiological function. [61] Multiple valve designs have been tested, the largest on which was the Endobronchial Valve for Emphysema Palliation Trial (*Figure 4)*  (VENT) [63-64] There was significant improvement in dyspnea, exercise capacity, and quality of life but not as significant as that which is seen in LVRS. [64]. Possible explanations for the minor improvement seen compare to LVRS have been attributed to collateral ventilation through incomplete lobar fissures. There were more complications of pneumonia, hemoptysis, and pneumothorax in the treatment group, all of which would be expected from an invasive procedure. [64]. The administration of sealants is far less developed and studied when compared to that of one-way valves, and includes the use of fibrin-thrombin mixtures to create a scaffold for collagen deposition by fibrblasts [65]. Preliminary studies show minor improvements in pulmonary function tests but no significant clinical benefits [66-67].

Fig. 4. Endobronchial lung volume reduction with one-valve for lower-lobe predominant emphysema.

Thermal ablation is the least developed and studied of the bronchoscopic LVR techniques. The use of heated vapor to induce an inflammatory response resulting in occlusion of a diseased portion of lung has only been tested in feasibility studies with further exploratory efforts required due to small sample sizes [68]. Although bronchoscpoic LVR is an emerging technique, further analyses as well as long-term follow-up studies are needed.

### **4.3 Lung transplantation**

40 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

A new technique of lung volume reduction with less morbidity and mortality compared to surgical LVR is bronchoscopic lung volume reduction (LVR). Bronchoscopic LVR aims to achieve the same goals as LVRS: improve physiologic mechanics of the chest wall and diaphragm, restore ventilation-perfusion matching, and improve expiratory airflow. The method by which this is achieved is through the use of a bronchoscope to deploy one-way valves, administer sealants, or apply thermal ablation to exclude diseased portions of the lung [60-62]. It is important to note that these techniques have not been approved by the Food and Drug Administration (FDA) for the treatment of severe emphysema and are currently utilized on experimental basis only. The most developed and well-studied of the bronchoscopic techniques is the one-way valve. One-way valves allow air and mucus to escape from the excluded portion of lung yet concomitantly excluding that portion of the lung from normal physiological function. [61] Multiple valve designs have been tested, the largest on which was the Endobronchial Valve for Emphysema Palliation Trial (*Figure 4)*  (VENT) [63-64] There was significant improvement in dyspnea, exercise capacity, and quality of life but not as significant as that which is seen in LVRS. [64]. Possible explanations for the minor improvement seen compare to LVRS have been attributed to collateral ventilation through incomplete lobar fissures. There were more complications of pneumonia, hemoptysis, and pneumothorax in the treatment group, all of which would be expected from an invasive procedure. [64]. The administration of sealants is far less developed and studied when compared to that of one-way valves, and includes the use of fibrin-thrombin mixtures to create a scaffold for collagen deposition by fibrblasts [65]. Preliminary studies show minor improvements in pulmonary function tests but no significant clinical benefits [66-67].

Fig. 4. Endobronchial lung volume reduction with one-valve for lower-lobe predominant

emphysema.

Lung transplantation was originally thought to not be a feasible treatment for emphysema. It wasn't until after the seminal transplantation of single lungs demonstrating significant improvement in symptoms, that lung transplantation became a mainstay for the end-stage emphysema [69-71]. Currently, the most common indication for lung transplantation is idiopathic diffuse emphysema and AAT1 deficiency, two criteria that account for the majority of lung transplants [70]. Lung transplant patients are usually so critically ill that the risk of death from their lung disease enables the actual lung transplant operation to appear quite equitable. The advantages of a lung transplant result in complete replacement of the diseased lung with significant improvements in symptoms [72]. There are however, significant disadvantages to lung transplantation including higher mortality (5 to 15%), lifelong immunosuppression resulting in risks of serious infection and rejection with a cumulative survival rate of around 50% [73-74].
