LVR in Severe Emphysema Using Bronchoscopic Autologous Blood Instillation in Combination With Intra-bronchial Valves (BLOOD-VALVES)

Chronic obstructive pulmonary disease (COPD) is an umbrella term encompassing two entities causing progressive and ultimately disabling breathlessness. Emphysema is a process destructive of the airspaces distal to the terminal bronchioles, with loss of gas exchange tissue, of elastic recoil and of circumferential tethering of the small airways leading to their collapse on forced expiration. Chronic bronchitis is a disorder of the bronchi causing excess production and impaired mobilisation of mucus. Increased parasympathetic tone and progressive remodelling of airways impairs response to bronchodilators. Static and dynamic hyperinflation with a persistently expanded chest and flattened diaphragms despite increasing use of accessory respiratory muscles results in a disadvantaged respiratory pump.

Patients with severe emphysema and hyperinflation may benefit from lung volume reduction techniques designed to reduce gas trapping and to improve airflow, chest wall and lung mechanics. The best evidence exists for lung volume reduction surgery (LVRS), which however is not without risk and there is increasing interest in the development of bronchoscopic lung volume reduction (BLVR) techniques including emplacement of intra-bronchial valves and bronchoscopic instillation of blood products, which have been shown individually to improve lung function, exercise capacity, and quality of life.

Most of the experience in bronchoscopic lung volume reduction has been with endobronchial valves which were introduced in 2001. One-way valves are inserted into segmental airways to deflate the most emphysematous lobes of the lung, allowing compromised lesser diseased tissue to expand and regain its function. Reduction of hyperinflation and improved lung function, exercise capacity, and quality of life, have been observed using the intra-bronchial valve (IBV Valve System) by Olympus in patients with upper lobe-predominant emphysema. These improvements are most pronounced in those with radiologically intact lobar fissures, a surrogate observation thought to indicate an absence of collateral ventilation, which can be confirmed using the Chartis balloon catheter system. A combined approach of CT fissure analysis and Chartis measurement is suggested to ensure the appropriate selection of patients.

Bronchoscopic instillation of biological agents such as fibrinogen, thrombin or autologous blood into the sub-segmental airways induces lung volume reduction initially by airway obstruction and resorption atelectasis followed by a localised inflammatory reaction leading to tissue remodelling at the alveolar level, with fibrosis and contraction of the target lobe. Unlike the intra-bronchial valve, collateral ventilation is not an issue, seeming not to influence the outcome. The cost compares favourably with that of prosthetic implants. Preliminary data from phase 1 and 2 trials using fibrinogen and thrombin in patients with upper lobe-predominant emphysema demonstrated improvements in lung function, exercise capacity, and quality of life scores up to 6 months with a trend towards better outcomes in those receiving 20mls (versus 10mls) to each of eight sub-segmental sites (four per upper lobe). Most patients experienced a self-limiting inflammatory reaction characterised by fever, malaise, shortness of breath, pleuritic chest pain and/or leucocytosis within 24 hours. 11 of 50 patients (22%) in phase 2 experienced a procedure-related COPD exacerbation comparable to other forms of endoscopic lung volume reduction. Similar physiological and symptomatic outcomes were observed in patients with homogeneous emphysema with 20mls (versus 10mls) per sub-segment instillation. Bakeer et al compared bronchoscopic lung volume reduction in patients with heterogeneous emphysema using autologous blood (n=7) with fibrin glue (n=8). At 12 weeks, statistically significant improvements in hyperinflation, lung function, exercise capacity (6MWT), and quality of life scores were observed in both groups. COPD exacerbations were fewer compared to earlier studies, which the authors suggest may be due to the use of a triple lumen balloon catheter protecting surrounding sub-segments from overspill and unintended inflammatory responses.

The prospect of broadening the eligibility for intra-bronchial valve implantation to include those with collateral ventilation treated with autologous blood is attractive and not yet studied.

Furthermore, the mechanisms of actions of intra-bronchial valves and of autologous blood instillation are not fully understood and may extend beyond lung volume reduction. In valve procedures where volume reduction has not been achieved, clinically meaningful improvements in quality of life independent of lung function have been described. Recruitment of compressed lung, restoration of elastic recoil and redirection of airflow are some of the postulated effects that are likely to involve the small airways. This may be investigated, for example, with multiple breath nitrogen washout (MBNW) which is a sensitive marker of small airways disease and can measure ventilation inhomogeneity, functional residual capacity and estimate trapped gas volumes. Impulse oscillometry (IOS) yields information on airway resistance and reactance (a measure of compliance) and distinguishes between large and small airway resistance.