Version May 2024
INTRODUCTION — Emphysema is a structural lung lesion that occurs in patients with chronic obstructive pulmonary disease (COPD). It is defined pathologically by abnormal and permanent enlargement of the airspaces distal to the terminal bronchioles and is associated with destruction of the alveolar walls. Progressive emphysema leads to early airway closure in exhalation, lung hyperinflation, air-trapping, and loss of gas-exchanging surface area, all of which contribute to refractory dyspnea.
In carefully selected patients with severe COPD, lung volume reduction may be an option to improve their lung function, quality of life, and exercise capacity by decreasing lung hyperinflation.
Lung volume reduction surgery (LVRS; also called reduction pneumoplasty or bilateral pneumectomy) is a surgical treatment for patients with advanced emphysema whose dyspnea is poorly controlled with other standard therapies (eg, short- and long-acting bronchodilators, inhaled glucocorticoids, supplemental oxygen, and pulmonary rehabilitation) [1]. LVRS entails reducing the lung volume by wedge excisions of emphysematous tissue. However, surgical morbidity is significant and nonpulmonary comorbidities preclude surgical approaches in many patients.
Bronchoscopic lung volume reduction (bLVR) refers to techniques developed to treat hyperinflation due to emphysema using endoscopic approaches. Several options for bLVR exist, but treatment using one-way endobronchial valves is the most studied and has regulatory approval worldwide. Additional bronchoscopic techniques include coils, sealants, and vapor ablation.
The devices and techniques for bLVR will be reviewed here. The general management of COPD, an overview of flexible bronchoscopy, and the roles of LVRS, bullectomy, and lung transplantation in the management of advanced COPD are discussed separately.
●(See "Management of refractory chronic obstructive pulmonary disease".)
●(See "Flexible bronchoscopy in adults: Overview".)
●(See "Lung volume reduction surgery in COPD".)
●(See "Lung transplantation: General guidelines for recipient selection".)
RATIONALE AND PATIENT SELECTION
Rationale — Emphysematous destruction of alveolar walls causes loss of elastic recoil, early airway closure during exhalation, and air trapping in the distal air spaces. Air trapping and subsequent hyperinflation press the diaphragm into a flat configuration, rather than its normal domed shape, and place all the muscles of respiration at a mechanical overstretch disadvantage. Furthermore, loss of alveolar walls and formation of emphysematous blebs and bullae results in loss of gas-exchanging surface. Lung volume reduction counteracts some, but not all, of these adverse physiologic effects.
Although the dominant mechanisms through which lung volume reduction provides benefit are not known with certainty, the following salutary effects have been investigated:
●Reduction in size-mismatch between the (previously hyperinflated) lungs and the chest cavity, thereby restoring the outward circumferential pull on the bronchioles (ie, increasing elastic recoil) and improving expiratory airflow [2-8]. With improved expiratory airflow, the amount of dynamic hyperinflation associated with exercise decreases and consequently reduces exercise-related dyspnea. (See "Dynamic hyperinflation in patients with COPD", section on 'Pathophysiology'.)
●Improvement in the mechanical function of the diaphragm and intercostal muscles by decreasing the functional residual capacity (FRC; the amount of air left in the lungs after exhalation of a tidal volume breath) and returning the diaphragm to a more normal domed configuration [9,10].
●Reduction in the inhomogeneity of regional ventilation and perfusion, resulting in improved ventilation-perfusion matching, alveolar gas exchange, and ventilatory effectiveness [11]. (See "Measures of oxygenation and mechanisms of hypoxemia".)
●Improvement in biventricular filling, end-diastolic dimensions, and cardiac output due to decreased intrathoracic pressure and reduced air trapping [12,13].
●Improvement in endothelial function, inflammatory cytokines, and antiprotease activity, which may arise from the more favorable cardiopulmonary physiology [14,15].
This physiologic rationale mirrors that for lung volume reduction surgery (LVRS), which is discussed separately. (See "Lung volume reduction surgery in COPD", section on 'Rationale of LVRS'.)
Among selected patients with advanced upper lobe predominant emphysema, LVRS improved exercise capacity and, in some patients, reduced mortality at two years. However, the morbidity of LVRS is substantial. (See "Lung volume reduction surgery in COPD", section on 'Primary endpoints' and "Lung volume reduction surgery in COPD", section on 'Complications' and "Lung volume reduction surgery in COPD", section on 'Long-term outcomes'.)
Bronchoscopic lung volume reduction (bLVR) uses endoscopic methods (eg, valves, sealants, thermal ablation) to collapse areas of overinflated emphysematous lung, which ideally should have a beneficial physiologic effect similar to resecting these areas during LVRS but without the morbidity of surgery. Thus, patients who are not good surgical candidates might be able to undergo bLVR instead. Several bLVR techniques are reversible, which may contribute to increased safety of the procedure.
Patient selection — bLVR is indicated in patients with refractory dyspnea due to chronic obstructive pulmonary disease (COPD) despite optimization of inhaled therapies, evaluation for other causes of dyspnea, and a trial of pulmonary rehabilitation. The management of these patients is discussed in detail elsewhere. (See "Management of refractory chronic obstructive pulmonary disease".)
Typical evaluation and inclusion/exclusion criteria have been established for endobronchial valves (table 1). Most experimental device trials use similar criteria except for the absence of collateral circulation, which is not necessary for several other techniques. (See 'Choice of technique' below.)
A key step in evaluation of potential patients is high-resolution computed tomography (HRCT) to measure lobar volumes, determine the amount of emphysematous destruction of each lobe, and to assess for lack of collateral circulation (high-to-complete fissure integrity) [16]. The computed tomography (CT) is also important to rule out other important diseases like bronchiectasis and assess nodules or other findings that may require additional evaluation.
Indications — The indications for bLVR are still being defined for some investigational techniques but are generally similar to the consensus criteria for endobronchial valves (table 1), which include:
●Severe dyspnea (modified Medical Research Council [mMRC] dyspnea scale ≥2; (table 2)) despite optimal medical therapy and maximal pulmonary rehabilitation
●Longer than four months of smoking cessation
●Marked airflow obstruction on spirometry (forced expiratory volume in one second [FEV1] less than 45 percent predicted), consistent with the diagnosis of advanced COPD
●Lung volume measurements showing air trapping (eg, residual volume [RV] greater than 175 percent predicted, total lung capacity [TLC] greater than 100 percent predicted, and an increased RV/TLC ratio). An increased RV/TLC ratio correlates with improved forced vital capacity (FVC) following LVRS [3,17-19]. Meaningful clinical outcomes have also been reported in patients with RVs between 150 and 175 percent predicted as long a clear target for treatment was identified [20].
●CT findings of hyperinflation and emphysema, ideally including areas with more preserved lung tissue
●Postrehabilitation, a six-minute walk distance greater than 100 meters, but less than 500 meters
●Ability to tolerate procedural sedation
●For endobronchial valves only, patients require intact lobar fissures (minimal collateral ventilation) in targetable lung regions highly affected by emphysema
Contraindications — As with indications, contraindications to some procedures are evolving as techniques are under investigation. Prior major thoracic surgeries, active pulmonary infections, continued tobacco use, severe resting pulmonary physiologic derangements, and active myocardial ischemia or systolic heart failure are contraindications to bLVR therapies. Contraindications for endobronchial valve therapies have been better established (table 1), and include:
●Cigarette smoking within the prior four months
●Comorbid cardiac illness that would increase surgical mortality (eg, significant coronary heart disease, heart failure with a left ventricular ejection fraction less than 40 percent)
●Severe obesity (≥35 kg/m2)
●Inability to complete a 6- to 10-week program of pulmonary rehabilitation
●Prior cardiothoracic surgery in the pleural space, including lung transplant, LVRS, or lobectomy
●End-stage pulmonary disease as defined by severe resting hypoxemia (arterial partial pressure of oxygen [PaO2] <45 mmHg), hypercapnia (arterial partial pressure of carbon dioxide (PaCO2) >60 mmHg), FEV1 <15 percent predicted, six-minute walk distance <100 m
●Active pulmonary infection
Radiologic evaluation — CT scan plays an important role in bLVR techniques. An HRCT with acquisition of images in inspiration and expiration is typically required. Determination of fissure integrity, severity, and distribution of emphysema are all critical to determine if the patient is appropriate for therapy and to select appropriate target lobes for treatment. The exact protocol for each technology may differ somewhat and it is best to consult the individual companies prior to establishing a local protocol. CT analysis includes the following:
●Fissure integrity – Determination of potential collateral ventilation is essential to establish candidacy for placement of endobronchial valves. Intact lobar fissures prevent collateral ventilation and can be assessed by analyzing HRCT images. In general, if the fissure completeness score is low (<80 percent on the left and <90 percent on right) then success is unlikely for valve placement. Other modalities including surgery may then be considered. (See 'Disadvantages (collateral ventilation)' below.)
●Emphysema severity – Degree of emphysematous damage can also be calculated from scan images. The destruction score is a term used to give an estimate for how much emphysema is present. Multiple thresholds have been studied, but most agree that a destruction score of at least 30 percent at -950 HU is a minimum requirement for bLVR.
●Emphysema distribution – Analysis of the CT scan can demonstrate which lobes contain the most emphysematous lung as well as which lobes occupy the most volume [21-23]. The combination of these measures, along with fissural integrity, guides lobar selection, with the guiding principle being maximal volume reduction of ineffective lung.
●Other findings – Other potential important findings include the presence of pulmonary nodules, interstitial lung disease (ILD), blebs, and others that may have an impact on the decision process. This population almost always has a significantly increased risk of malignancy, so the presence of nodules can be critical to future management. A therapy for volume reduction should not be done in a manner to obscure a suspicious nodule.
If multiple lobes are eligible for treatment based on CT findings but no single lobe can be identified as the most appropriate target, many practitioners evaluate perfusion using perfusion scintigraphy or single photon emission CT (SPECT). The area with the lowest perfusion is selected as the target lobe [24,25].
TECHNIQUES — Over the past 20 years, multiple bronchoscopic lung volume reduction (bLVR) techniques have been introduced with the goal of reducing hyperinflation and subsequently improving exercise capacity and quality of life. Of these techniques, endobronchial valves (EBVs) are the most thoroughly studied. They are the only devices with widespread regulatory approval or inclusion in the Global Initiative for Chronic Obstructive Lung Disease recommendations [26,27] due to demonstrated physiologic improvements and likely survival benefit in selected patients [28-32]. Other investigational bronchoscopic options include airway bypass stents, endobronchial coils, thermal vapor ablation, and polymeric sealants.
Choice of technique — Each of the bronchoscopic options have an inherently different mechanism of action, so the phenotype of each patient must be kept in mind while making the decision on which technique is most appropriate [33]. Ideally, the procedural approach should be made in the setting of a multidisciplinary team including pulmonologists, thoracic surgeons, and radiologists. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Choice of procedure'.)
In general, most candidates for lung volume reduction who meet criteria for EBV placement (table 1) should receive either a Zephyr or Spiration EBV, as these techniques are the most rigorously tested and widely available. Patients who do not meet these criteria due to collateral ventilation (lack of intact lobar fissures) are often good candidates for clinical trials of other device types. Other criteria for investigational techniques vary by individual trial. (See 'Investigational procedures' below and 'Clinical trial sites' below.)
Endobronchial valves — One-way EBVs have been designed for bronchoscopic placement based on the hypothesis that they will allow air and mucus to exit the treated area, but not allow air to re-enter. The goal of this treatment is to facilitate atelectasis of the emphysematous, hyperinflated lung distal to the valve. This atelectasis leads to effective volume reduction akin to surgical lung volume reduction. EBVs have demonstrated physiologic improvement and likely survival benefit in selected patients with advanced COPD.
Two different valve designs are available for bLVR. The Zephyr valve is a duckbill-shaped valve housed within a silicone coated nitinol frame. Once deployed it is held in place in the bronchus by the radial forces of the frame. (picture 1A-B). The Spiration valve is an umbrella-shaped valve with a nitinol frame and thin membrane. It uses small anchors that affix into the airway wall to prevent migration (picture 2). Both valves come in a variety of sizes to allow for a best individual fit.
Advantages — EBVs may have some technical advantages over other bLVR techniques and are also the only bLVR therapy to demonstrate an improvement in patient survival.
EBVs can be removed if the patient has no response or develops a complication. Removal is generally straightforward using standard biopsy forceps and a flexible bronchoscope. It can be done under general anesthesia or conscious sedation. The longer a valve is in place, the more likely it is to be challenging to remove due to formation of granulation tissue around the insertion site. Valve removal was successfully performed (less than six months after insertion) in several of the initial randomized controlled trials with minimal difficulty or complications [28-31]. Valve removal can still be done more than six months from implantation but is associated with a more difficult removal and higher rate of failure or complications, though still with an acceptable safety profile [34]. Valve placement can also be combined with other endobronchial techniques for bLVR.
Initial trial data demonstrated that EBV therapy can improve lung function, quality of life, and exercise tolerance similar to lung volume reduction surgery (LVRS). (See 'Zephyr duckbill valve' below and 'Spiration umbrella valve' below.)
Subsequent long-term follow-up of recipients has suggested a modest survival benefit as well. For example, observational follow-up of 353 EBV recipients and 988 evaluated but not treated patients showed the median survival for patients treated with EBV was significantly longer (3133 versus 2503 days, hazard ratio [HR] 1.4, 95% CI 1.1-1.7) [32]. In a post-hoc analysis of a randomized trial of EBV placement, patients who received EBV were much more likely to have a meaningful (≥1 point) improvement in the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index (calculator 1), a well-known predictor of chronic obstructive pulmonary disease (COPD) survival, at six months, compared with the untreated arm (74 versus 21 percent) [35]. Additionally, several cohorts have shown that patients who successfully achieve atelectasis after valve placement have improved survival compared with those who do not, suggesting that successful lung volume reduction is the mechanism of benefit [36-38].
Disadvantages (collateral ventilation) — The primary barrier to achieving lung volume reduction using EBVs is the need for minimal collateral ventilation of the targeted lobe(s) [39-41].
Collateral ventilation and fissure integrity have been found to be critical to successful volume reduction via EBVs [33,36-38]. Each valve type has a recommended proprietary software algorithm (Zephyr – StratX™; Spiration – SeleCT™) that uses high-resolution CT (HRCT) images to assess fissural completeness and the probability of collateral circulation.
The Zephyr valve system also allows bronchoscopic assessment of collateral circulation using the Chartis™ Pulmonary Assessment System [42-44]. This system uses a specialized balloon catheter with a central lumen. The balloon is inflated, occluding the lobe(s) to be tested. The central lumen can then detect whether air flow is still present downstream of the occlusion. If there is no flow, there is no significant collateral ventilation and valve placement can proceed. If air flow is detected, no valve placement should occur.
This bronchoscopic verification at the time of placement allows providers to use a lower threshold of predicted fissure completeness using the CT algorithm for Zephyr valves than they can when using the Spiration system. However, retrospective studies have shown a fairly good agreement between bronchoscopic evaluation of collateral ventilation and CT-based evaluation of fissural integrity [45].
Endobronchial valve selection — Zephyr and Spiration valves have not been compared directly, and the choice frequently depends on negotiations between hospital systems and individual vendors.
Clinically, Zephyr and Spiration valves perform similarly, with each leading to modest increases in lung function (average forced expiratory volume in one second [FEV1] improvement of 100 to 200 mL) and quality of life (average Saint George's Respiratory Questionnaire (SGRQ) improvement of seven to ten points) accompanied by a 20 to 30 percent risk of pneumothorax [28,46-49]. Both valve types are removable in the setting of complications. Some bronchoscopists may prefer the Zephyr system because it allows physiologic verification of minimal collateral ventilation. (See 'Disadvantages (collateral ventilation)' above.)
Zephyr duckbill valve — The Zephyr EBV is a one-way, removable silicone duckbill valve (picture 1A-B). This valve is available in several sizes, which vary in diameter as well as length. Typically, more than one valve is needed to achieve lung volume reduction. This type of valve should only be used in patients with severe dyspnea and hyperinflation associated with emphysema who have little to no collateral circulation in the target lobe(s) [26,50].
A key step in evaluation of potential patients is HRCT to measure lobar volumes, determine the amount of emphysematous destruction of each lobe, and assess for high-to-complete fissure integrity [16]. The CT is also important to rule out other important diseases like bronchiectasis and assess nodules or other incidental findings that may require additional evaluation.
●Zephyr valve placement – A specialized catheter to measure localized pressure and flow, known as the Chartis™ System, is used for bronchoscopic assessment of collateral ventilation during placement of the Zephyr valve. The absence of collateral ventilation improves the likelihood of resorption atelectasis following EBV placement [39-44,51]. (See 'Disadvantages (collateral ventilation)' above.)
During flexible bronchoscopy, the lobe with the greatest degree of emphysematous destruction is assessed for collateral ventilation with the Chartis™ system. If none is found, an EBV is deployed into that bronchus. The Zephyr EBV is deployed with the Endobronchial Delivery Catheter (EDC). The EDC can be inserted through the working channel of a bronchoscope under direct vision. The EDC also acts as a sizing mechanism, enabling the bronchoscopist to select the size valve that will best fit that bronchus. There are two sets of sizing "wings" on the EDC. These allow for the appropriately sized valve to be chosen for each individual airway. Four sizes of valve are commonly available (4.0 low-profile, 4.0, 5.5 low-profile, and 5.5, corresponding to the minimum width of the subsegment to be treated). The standard or "low-profile" option is chosen based on the length of airway making up the landing zone.
Additional EBVs are placed in other segments to achieve complete occlusion of the target lobe; on average, four valves (range two to eight) are implanted per patient [28,46]. The valves are readily removable using a flexible bronchoscope and standard forceps should the need arise.
●Zephyr valve efficacy – Several trials and a multicenter registry have reported modest improvements in symptoms and lung function after placement of Zephyr EBVs, but with a risk of pneumothorax of 25 to 30 percent [28-30,46,52-59]. The two largest trials are discussed below:
•In one trial (LIBERATE), 190 patients with severe heterogeneous emphysema and little or no collateral ventilation in the target lung (based on Chartis™ assessment) were assigned to Zephyr EBV placement or standard of care (SoC) [46]. At 12 months, 48 percent of participants receiving EBVs and 17 percent of those receiving SoC had a relative improvement in FEV1 ≥15 percent. Between group differences in FEV1 (+100 mL; 95% CI 50-170 mL), residual volume (RV; -520 mL; 95% CI -770 to -270 mL), six-minute walk distance (6MWD; +40 m; 95% CI 15-64 m), dyspnea (modified Medical Research Council [mMRC], -0.8 points; 95% CI -1.1 to -0.4) and quality of life (SGRQ, -7 points; 95% CI -12 to -2) were all modestly improved. Pneumothoraces developed in 26 percent of the EBV group; four deaths occurred in the first three months in the EBV group compared with none in the SoC group.
•A separate multicenter trial (TRANSFORM) assigned 97 patients with severe heterogeneous emphysema without collateral ventilation in the target lobe (by Chartis™) to receive Zephyr EBV or SoC (2:1 ratio) [28]. Almost 90 percent of participants in the EBV group had a target lobe volume reduction ≥350 mL (mean 110±60 mL), and 55 percent had an improvement in FEV1 ≥12 percent. At six months, the between group difference in FEV1 was 230 mL, RV was -670 mL, 6MWD was +78.7 m, SGRQ was -6.5 points, and mMRC dyspnea score was -0.6 points. Once again, the most common adverse event was pneumothorax in 29 percent of EBV patients; there was one death due to pneumothorax complications.
Spiration umbrella valve — The Spiration Intrabronchial Valve System (SVS) uses an umbrella-shaped nitinol-framed prosthesis with a polyurethane cover (picture 2) [47]. The flexible frame struts allow for the valve to maintain contact with the airway wall and prevent air from passing inwards while allowing for mucus and air to escape. The five anchors secure the valve in place. This creates a one-way valve effect with the intent of redirecting airflow to more normal areas and/or inducing atelectasis of the emphysematous area blocked by the valve. SVS should be deployed in patients with hyperinflation and shortness of breath due to severe emphysema in lung regions that have evidence of low collateral ventilation [60].
Patient selection for the SVS includes using a HRCT by identifying those with ≥40 percent emphysema and greater than 90 percent intact or nearly intact fissures in the target lobe. The HRCT images are uploaded into the SeleCT™ QCT Analysis; this work-flow integrated cloud platform will analyze fissure integrity and degree of emphysema and produce a report for the clinician to evaluate and decide on treatment. (See 'Disadvantages (collateral ventilation)' above.)
●Spiration valve placement – Target lobes are identified by CT assessment of emphysema severity and the presence of intact fissures. The valve can be deployed under direct vision via a deployment catheter through the working channel of a flexible bronchoscope with a minimum working channel of 2.6 mm. The SVS utilizes an airway sizing balloon to ensure proper fit of the valve in an airway. The sizing balloon is calibrated and then used to measure the size of the airways the valves will be inserted into. Four sizes of valves can be used. Once the appropriate sizes have been determined, the valves are loaded into a deployment catheter. Then, under direct vision, the valve deployment device is passed through the working channel of the bronchoscope and the valve is deployed. If the valve needs to be repositioned or removed, standard biopsy forceps are used to grab the central rod; when the rod is pulled, the umbrella collapses and can be removed. Several small modifications have been made on this valve, but the basic design has changed little (picture 2). The treatment algorithm calls for complete occlusion of a lobe, achieved by placement of one or more valves in appropriate segments (ie, lobar, segmental, and/or subsegmental). As with the Zephyr valve, four to eight valves are generally required to target a given lobe for collapse. The valves can readily be removed with forceps if needed.
●Spiration valve efficacy – Based on data from randomized trials and a systematic review, bronchoscopic treatment with the Spiration EBV provides meaningful improvement in several parameters, including pulmonary function and quality of life (mMRC dyspnea scale, SGRQ), but impact on exercise capacity appears limited [47,48,61-63]. The largest studies are summarized below:
•A systematic review and meta-analysis of four trials (629 participants) found improvement in FEV1 (120 mL; 95% CI 90-150 mL), SGRQ quality of life (-12 points; 95% CI -16 to -9), and the mMRC dyspnea scale (-0.5; 95% CI -0.7 to -0.3) among participants with intact fissures (collateral ventilation unlikely) [49]. No improvement was noted in the 6MWD.
•A multicenter, open-label trial (EMPROVE) randomly assigned 172 participants with severe, heterogeneous emphysema and intact fissures by HRCT to placement of Spiration EBVs or medical management [47]. At 6 and 12 months, the EBV group had a relative improvement in FEV1 of 100 mL. Quality of life, based on the SGRQ and mMRC, improved, but 6MWD did not. Serious adverse events were more common in the EBV group due to prolonged pneumothoraces (air leak >7 days) in 12 percent of these patients.
•In a multicenter trial (REACH) of 107 participants with severe emphysema and intact interlobar fissures, placement of EBVs resulted in an increase in FEV1 compared with the control group (medical treatment) after three months (100±180 mL versus 3±150 mL) [48]. The 6MWD did not improve significantly, although it was relatively better than the control group at six months due to a decrease in exercise capacity in the control group. The SGRQ of EBV patients showed a significant improvement compared with controls, with between-group differences of approximately 11, 7, and 11 points at one, three, and six months, respectively. The most common serious adverse events seen in subjects were COPD exacerbations (20 percent) and pneumothorax (8 percent).
Complications of endobronchial valve placement — EBV therapy, even if performed well in appropriate patients, may still lead to a variety of complications. Long-term complications include granulation tissue formation, valve malfunction or migration, lobe torsion, and bacterial infection or colonization. Acutely, pneumothorax can be seen commonly and may require urgent or emergent management. Postprocedural COPD exacerbations are also common.
●Pneumothorax – The reported prevalence of pneumothorax is between 4 and 34 percent in those treated with valves, but it was seen in between 20 and 30 percent of patients in several of the larger clinical trials [64]. Most (86 percent) EBV-related pneumothoraces occur in the first three days after valve placement and are involved in most of the early procedural mortality [64,65]. Mortality is observed in approximately 0.75 percent of all EBV cases, but in 4.6 percent of patients who develop pneumothorax [65]. Management can be complicated and may require removal of one or more valves.
Most experts feel that pneumothorax after valve placement is due to the volume reduction in the treated lobe causing expansion in the nontreated ipsilateral lobe(s). Pleural adhesions, extension of emphysema, and location of the emphysema (paraseptal) may increase the likelihood of this [66]. The rapidity of atelectasis after valve placement may also increase the risk of shearing damage from ipsilateral lobe expansion. In one small multicenter cohort, use of minimal fraction of inspired oxygen (FIO2, mean FIO2 0.29) during EBV placement was associated with a large decrease in the incidence of postprocedural pneumothorax (14 of 45 patients using FIO2 0.9-1.0 compared with 2 out of 29 patients after initiating a low FIO2 protocol) [67]. There was also a large change in the timing of pneumothorax, with 9 of 14 pneumothoraces occurring in the first hour of postprocedural monitoring in the high FIO2 group compared with postoperative day two and six in the low FIO2 group. Although limited by small numbers and the before-after study design, these observations support the possibility that rapid atelectasis drives pneumothorax in patients receiving high levels of intraoperative oxygen (which is reabsorbed rapidly) and suggest a possible intraoperative strategy to reduce this complication.
Many factors may play a role in the management of a pneumothorax, from the stability of the patient to degree of air leak, length of leak, and more. Large (pneumothorax rim >2 cm from the chest wall) or symptomatic pneumothoraces require immediate drainage with a chest tube, but small pneumothoraces without accompanying pain and dyspnea can be observed with repeat imaging at 4 and 24 hours to confirm lack of enlargement and a trend towards resolution.
After chest tube placement, appropriate lung reexpansion and cessation of air leak facilitate chest tube removal, which occurs uneventfully in most patients. Failure of lung reexpansion for more than 72 to 96 hours despite adequate wall suction should prompt removal of one valve (generally the most proximal) to facilitate reexpansion; continued poor reexpansion over the ensuing 48 hours can necessitate removal of all the valves. Similarly, persistent air leak for more than seven to ten days prompts removal of a proximal valve and, if necessary, all valves to facilitate reexpansion and healing. Persistent air leak despite valve removal may require pleurodesis or surgical intervention at the site of injury.
If a single proximal valve needs removal for reexpansion or air leak, we will often replace the valve in 6 to 12 weeks if the patient is willing. We do not typically re-attempt valve placement in the affected lobe if all valves require removal.
●Hypoxemia – Although infection, bleeding, and new COPD exacerbation should also be investigated in this setting, early postprocedural hypoxemia often occurs due to temporary shunting of blood into the progressively atelectatic lobe that is no longer participating in ventilation. This hypoxemia is generally temporary due to adequate hypoxemic vasoconstriction and progressive atelectasis of the affected lung tissue. If the hypoxemia persists for more than 48 hours and no other cause is found, we first discontinue nonessential medications that may interfere with hypoxemic vasoconstriction (eg, calcium channel blockers) and make sure the patient is receiving minimum necessary supplemental oxygen (target O2 saturation 88 to 92 percent). Persistently worsened hypoxemia without other clinical benefit after treatment is an indication for valve removal.
●Central airway distortion – Successful lobar atelectasis may lead to positional shifts in the remaining lobes and central airways. This can occasionally result in distortion, narrowing, or even torsion of the remaining central airways. The most common clinical manifestation of the distorted airways is mucous retention with persistent cough, but in severe cases, ventilation to the affected lobe may be impaired. CT scans are often suggestive, and bronchoscopy can confirm the diagnosis. In many cases, enhanced expectoration techniques (chest physical therapy, flutter valves) can mitigate this problem in patients for whom the valves were otherwise effective, but in severe cases, the valves can be removed to restore the normal airway position.
●Hemoptysis – Minor hemoptysis for a few days after the procedure is common and generally self-limiting. Prolonged hemoptysis in follow up is less common (2 percent in one large series) and warrants bronchoscopic evaluation [68]. Minor granulation tissue-associated hemoptysis can sometimes be monitored or treated with local coagulation therapy; more significant hemoptysis or severe granulation tissue build-up can require removal of the affected valve. We do not replace the valve at the same site after removal, but if removal causes clinical worsening, a new valve can occasionally be placed distal to the prior site after appropriate healing (6 to 12 weeks). Additional treatment options for hemoptysis itself are described elsewhere. (See "Evaluation of nonlife-threatening hemoptysis in adults" and "Evaluation and management of life-threatening hemoptysis".)
●Pneumonia and COPD exacerbation – Pneumonia and COPD exacerbation are common in the patient population undergoing EBV placement. The clinical trials generally show increased short-term (within 45 days of the procedure) risk for COPD exacerbation and pneumonia, but there is evidence for possible improvement in these outcomes longer term after valve placement [46]. Most trials show an approximately 5 percent one-year incidence of pneumonia, with half of the infections occurring in the treated lobe [46,47,58]. Some centers empirically treat with antibiotics or systemic glucocorticoids at the time of valve placement, although there is no evidence to suggest improvement in outcomes with this strategy. Pneumonia and COPD exacerbations are generally treated medically; however, pneumonia in the treated lobe that is not responsive to both an oral and subsequent intravenous (IV) broad spectrum antibiotic can necessitate temporary removal of valves.
●Granulation tissue – Granulation tissue formation is a medium- to long-term complication of valve placement and occurs idiosyncratically due to inflammatory response to a foreign body and to minor repetitive injury from the valve abutting the airway walls. Severe granulation tissue can result in valve malfunction or misplacement, postobstructive pneumonia, or hemoptysis that may require valve removal. For removal of valves associated with severe granulation tissue, we typically prescribe moderate doses of systemic glucocorticoids (eg, 20 to 40 mg of prednisone) for several days before and after removal to facilitate removal and airway healing. Additional airway treatment beyond removal of the valve is rarely necessary. For patients who had highly clinically effective initial valve placement, a valve can be replaced distal to the initial site after several weeks of healing (figure 1).
Long-term management — Despite appropriate patient selection, effective valve placement at the time of the procedure, and lack of perioperative complications, some patients will still not benefit from valve therapy. A standard protocolized follow-up may help in capturing those without benefit, identifying reversible tweaks, and appropriately removing valves in those who have not benefited from them [64].
Recommended follow-up practice includes a one-week check-in; this can be a telephone encounter, virtual visit, or a face-to-face visit. Additional testing, including chest CT, spirometry, lung volumes, and diffusing capacity, should be performed along with a face-to-face visit after six to eight weeks. Patients who clearly have had a positive response can be followed in six months and then yearly for at least five years.
Earlier follow-up and investigation are appropriate in patients who do not show benefit or if the benefit is transitory. Lack of or loss of benefit can arise for a variety of reasons, including valve migration or valve malfunction. For example, formation of granulation tissue is well described and can result in impaired valve performance. Initial evaluation includes an HRCT using a similar protocol to the one done preprocedurally; this may anatomically identify the culprit valve. The HRCT also may directly reveal valve migration, loss of atelectasis, or an obvious infection. Even in the absence of CT findings, a repeat bronchoscopy with inspection of the valves is reasonable, as direct visualization can often reveal otherwise occult causes of valve malfunction. Valve removal and repositioning may be all that is required to address the loss of benefit. Steroids and/or antibiotics may be added if there is significant mucus or culture positive specimen. Occasionally, the severity of infection or granulation tissue at a valve site requires removal of the valve, with later replacement after resolution of airway inflammation.
Investigational procedures — Nitinol coils, airway sealants, and thermal airway ablation are alternative bronchoscopic treatments that facilitate atelectasis of lung tissue regardless of the presence of collateral circulation. Unlike EBVs, these techniques are not reversible. Each of these treatments is under active clinical investigation.
Coil placement — This technique utilizes a Nitinol coil to create volume reduction without airway obstruction or absorption atelectasis.
●Patient selection – Ideal candidates are symptomatic with severe hyperinflation (preferably residual volume [RV] >200 percent pred, RV/total lung capacity [TLC] >0.58) and emphysema. Patients with bronchiectasis, small airway complications, or heightened risk of infectious complications are the best candidates. Individual trials will have additional criteria.
A potential advantage may be that collateral ventilation has no effect on this technique, as opposed to the valve techniques described above. (See 'Endobronchial valves' above.)
●Procedure – Typically the two lobes with the most disease are chosen for coil placement with a separate procedure performed for each lobe one to three months apart. Fluoroscopy is critical for positioning, and general anesthesia is preferred to facilitate placement of the 10 to 14 coils. Several sizes are available to the operator (100, 125, and 150 mm) [69]. The coils are deployed through the working channel of a flexible bronchoscope in a straightened configuration into subsegmental airways and out into the lung parenchyma. As they are released, they resume their coiled shape and thereby increase tension in the parenchyma in that area, leading to improved airway tethering (image 1). This theoretically leads to a reduction in lobar volume and RV [70].
●Efficacy – A few clinical trials have examined the effect of endobronchial coils in severe emphysema. They have found a variable degree of benefit:
•One multicenter trial randomly assigned 315 patients with predominantly homogeneous emphysema and severe hyperinflation to usual care alone or usual care plus bilateral placement of endobronchial coils [71]. For participants receiving coils, 10 to 14 coils were placed in one lung in the first procedure; four months later, the procedure was repeated, placing 10 to 14 coils in the other lung. After one year, the group receiving coils experienced a small increase in their 6MWD and a small increase in FEV1; both changes were below the level considered clinically significant. Major complications occurred in 35 percent of the coil group versus 19 percent of the usual care group.
•In contrast, in another trial of 100 patients with severe emphysema and hyperinflation, 36 percent of patients receiving bilateral coil placement experienced more than a 50 m improvement in the 6MWD compared with only 18 percent in the control group [72]. This was accompanied by a small improvement in FEV1 (90 mL). Pneumonia was the most frequent serious adverse event, occurring in 18 percent of the coil group and 4 percent of the control group.
•Similarly, evaluation of 91 patients (57 coils and 34 controls) from a prematurely terminated trial showed significant between-group differences in FEV1 (+70 mL, 95% CI +30 to +110 mL), RV (-460 mL, 95% CI -716 to -203 mL), and quality of life (SGRQ -10.6, 95% CI -15.9 to -5.4). Severe hyperinflation (RV percent predicted ≥225 percent), heterogeneous emphysema, and bilateral upper lobe treatment were associated with best results from subgroup analysis.
The future of coil therapy is unclear. More studies are likely needed to better define its place in bLVR.
●Complications – The most common complications of the coil procedure are development of coil-associated opacities (CAO) and pneumonia. These can be seen in up to 50 and 10 percent, respectively, and may be difficult to differentiate. Steroids and antibiotics are used to treat potential inflammation and/or infection. Hemoptysis and pneumothorax are also reported.
Sealants — The use of sealants, also sometimes referred to as biologic lung volume reduction, involves direct application of a sealant/remodelling system to collapse areas of emphysema.
●Types of sealants – The initial method applied fibrin-thrombin mixtures to selected endobronchial locations to collapse hyperinflated areas through resorptive atelectasis [73,74]. After the partial success of this method, a revised technique (called BioLVR) was developed that added chondroitin sulfate and poly-L-lysine to the fibrin mixture. A hydrogel is created when the fibrin and thrombin solutions mix, theoretically providing a scaffold for fibroblast attachment and collagen synthesis that promotes scarring and prevents future recanalization of the treated area. An alternative method uses a synthetic polymeric foam sealant called emphysematous lung sealant (ELS).
●Potential uses – One potential advantage of sealants may be direct blocking of interalveolar and bronchiolar-alveolar pores and channels, eradicating collateral ventilation [75]. This may allow the technique to be used in patients for whom EBV placement is not possible. It is hypothesized that instilling a limited amount of AeriSeal in an area with collateral ventilation could lead to closure of an incomplete fissure. This could allow for valve treatment in a population that was previously excluded due to lack of response. An ongoing clinical trial is evaluating this hypothesis.
●Procedure – The procedure is performed under conscious sedation via flexible bronchoscopy. The bronchoscope is introduced into an airway leading to emphysematous alveoli and moved into wedged position, completely occluding the segment or subsegment to be treated. Suction is applied through the bronchoscope to collapse the distal airways in that segment [75,76]. An enzymatic primer solution (eg, porcine trypsin) is instilled to promote detachment of epithelial cells from the target region. After two minutes, the primer is removed by suction and 10 mL of cell culture media is used to wash out residual primer. Next, a dual lumen catheter with the thrombin mixture in one lumen and the fibrin mixture in the other is placed through the wedged bronchoscope. The contents of the two lumens are instilled, followed by 60 mL of air to push the solutions distally. The solutions mix as they are simultaneously delivered to the distal airway and alveoli. The liquid component is thought to fill the alveoli prior to complete polymerization, thus blocking collateral ventilation. Each subsegmental application takes approximately 10 minutes and four to eight subsegments are treated during a single procedure.
●Efficacy
•BioLVR – In a preliminary human study of hydrogel-based lung volume reduction, 22 patients with upper lobe predominant emphysema were treated with 20 mL of hydrogel/subsegment and 28 patients with 10 mL/subsegment [77]. The six-month follow-up revealed a greater improvement in forced vital capacity (FVC), FEV1, and RV in the higher dose group compared with the low-dose group. No significant change in the six-minute walk test was seen in either group compared with baseline. Chest CT at six months revealed scarring and atelectasis in the previously hyperinflated area in the high-dose, but not the low-dose group (image 2). Similar findings were reported in a study of 25 patients with bilateral homogeneous emphysema in whom high- or low-dose hydrogel was administered to eight subsegments [78]. In a separate observational trial, targeting a single lobe led to a greater improvement in FEV1 at 12 weeks after the procedure than treating scattered subsegments in both upper lobes [79]. It is hypothesized that full treatment of one lobe prevented collateral ventilation, leading to sustained lobar collapse and a better functional result [76].
•ELS – In a randomized trial of polymer-based lung volume reduction, 57 patients were randomly assigned to ELS (two subsegments in each upper lobe) plus medical therapy or medical therapy alone and followed for six months. Significant improvements from baseline were noted in lung function, dyspnea, and quality of life at three months when compared with control, and the benefits persisted for six months [80]. However, clinically important adverse events requiring hospitalization occurred in 44 percent of the treatment group, in addition to two deaths. The study was terminated early due to financial problems. In the STAGE trial, patients underwent a staged, lower dose ELS administration protocol in an attempt to minimize the number of adverse events [81]. The modified protocol did not impact the overall safety profile. Lobar reduction was achieved, but there were not any clinically relevant changes; a larger dose may be needed to demonstrate efficacy.
●Complications – Over 90 percent of patients treated with sealants experience flu-like symptoms such as fever, dyspnea, pleuritic chest pain, nausea, headache, malaise, and leukocytosis within 24 hours of the procedure [76,82]. These symptoms resolve in 24 to 48 hours. Later inflammatory events including pneumonia, pleural effusions, and COPD exacerbations appear to occur more commonly in patients receiving sealants, particularly when higher doses are used [80]. As distinguishing between infection and inflammation can be difficult, typically both antibiotics and glucocorticoids are used.
Thermal airway ablation — The technique of thermal airway ablation involves using a specialized catheter via a flexible bronchoscope to administer steam vapor directly to segmental airways [83].
●Patient selection – Inclusion criteria are similar to those used for other bLVR modalities, with additional consideration of exacerbation history and immune status because these may increase the risk of complications. Selection of segments to be treated is based on a quantitative CT scan, much like that used for EBV placement. This CT is also used to calculate the volume of vapor needed [84].
●Procedure – The procedure utilizes a reusable vapor generator with a disposable bronchoscopic catheter that delivers heated water vapor to the targeted airways. During the procedure, a vapor occlusion balloon is inflated to protect other airways from the heated vapor. The goal is to induce an inflammatory response that will result in occlusion and atelectasis of that segment. Ideally, the complication rate will be lower than with bronchial valve techniques as no foreign body is left in place. The procedure is typically performed under general anesthesia.
●Efficacy – Preliminary data of targeted thermal ablation show promise in improving respiratory physiology and quality of life in selected patients.
•In a multicenter trial from 13 European and 3 Australian sites, 69 patients were randomly assigned to targeted thermal ablation (n = 45) or standard medical management (n = 24) [85]. At six months post-treatment, patients receiving targeted thermal vapor ablation of more diseased segments with preservation of less diseased segments demonstrated improvement in FEV1 (+130 mL compared with standard management, 95% CI 65-200 mL) and quality of life (Saint George's Respiratory Questionnaire for COPD patients [SGRQ-C] -9·7 points [95% CI -15·7 to -3·7]). The most frequent complication was COPD exacerbation (24 versus 4 percent). One patient died 84 days after treatment.
•In a multicenter observational study, 44 patients with upper lobe predominant emphysema underwent unilateral bronchoscopic thermal airway ablation or sham bronchoscopy [86]. At six months, FEV1 was improved by 140±30 mL over baseline. Exercise tolerance (6MWD, +47 m), and quality of life (mMRC dyspnea scale, +0.9; SGRQ, +14) also improved, with 73 percent of patients demonstrating clinically meaningful improvements. Adverse events included exacerbations of COPD, pneumonia, lower respiratory tract infection, and hemoptysis. One patient died during an exacerbation of COPD two months after the procedure.
●Complications – Like other bLVR techniques, pneumonia, pneumonitis, and COPD exacerbations are common; infrequently hemoptysis and pneumothorax can also occur. As with polymer sealants, identifying the difference between pneumonitis and pneumonia can be a challenge; after thermal ablation, these are treated similarly with both antibiotics and glucocorticoids [84,87].
CLINICAL TRIAL SITES — A listing of active clinical trials in this area may be found at www.clinicaltrials.gov using the search terms "bronchoscopy" and "emphysema."
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)
SUMMARY AND RECOMMENDATIONS
●Rationale – By removing emphysematous, hyperinflated areas of lung, lung volume reduction surgery (LVRS) decreases hyperinflation, improves diaphragm and chest wall mechanics, and decreases work of breathing. Bronchoscopic lung volume reduction (bLVR) was developed to collapse areas of emphysematous lung in hopes of having the same effect on respiratory function as LVRS but without the morbidity and mortality of surgery. (See 'Rationale and patient selection' above.)
●Patient population – Based on the inclusion criteria for the pivotal clinical trials, candidates for endobronchial valve (EBV) placement should have emphysema, a modified Medical Research Council (mMRC) dyspnea score ≥2 (table 2) despite optimized medical therapy, postbronchodilator forced expiratory volume in one second (FEV1) between 15 and 45 percent predicted, total lung capacity (TLC) ≥100 percent predicted, residual volume (RV) ≥175 percent predicted, and a six-minute walk distance (6MWD) between 100 and 500 m following supervised pulmonary rehabilitation (table 1). Criteria for investigational techniques may vary slightly but have been largely similar in most trials. (See 'Patient selection' above.)
●Contraindications – Common relative contraindications include prior major cardiothoracic surgeries in the pleural space, active pulmonary infections, continued tobacco use, severe resting pulmonary physiologic derangements (arterial partial pressure of oxygen [PaO2] <45 mmHg, arterial partial pressure of carbon dioxide [PaCO2] >60 mmHg, FEV1 <15 percent predicted), and active myocardial ischemia or systolic heart failure. (See 'Contraindications' above.)
●Techniques – Proposed techniques for bLVR include endobronchial placement of one-way EBVs, plugs, and coils; biologic sealants; and thermal ablation. EBV placement is the most available and well-studied treatment for patients with refractory dyspnea and emphysema who have a high degree of fissure integrity based on high-resolution computed tomography (HRCT) or other testing. The use of plugs, blockers, and stents has been abandoned due to adverse effects. The other options remain investigational. (See 'Techniques' above.)
•Endobronchial valves – Two types of EBV are available for bLVR. The Zephyr EBV uses a duckbill mechanism (picture 1A and picture 1B), while the Spiration EBV is umbrella-shaped and expands on inhalation and contracts on exhalation (picture 2). Both EBVs prevent air from entering the bronchus during inhalation but allow air and secretions to pass around or through the device during exhalation, thus leading to atelectasis of the lobe.
EBV placement leads to modest improvements in lung function, quality of life, and possibly mortality but carries a significant short-term risk of pneumothorax. Placement of EBVs requires specialized training and equipment. (See 'Endobronchial valves' above and "Management of refractory chronic obstructive pulmonary disease", section on 'Bronchoscopic lung volume reduction'.)
Follow-up assessment by CT imaging verifies expected target-lobe volume loss – failure of initial atelectasis or reexpansion after initial atelectasis should prompt CT and bronchoscopic reevaluation. (See 'Complications of endobronchial valve placement' above and 'Long-term management' above.)
•Investigational procedures – Nitinol coils, airway sealants, and thermal airway ablation are alternative bronchoscopic treatments that facilitate atelectasis of lung tissue regardless of the presence of collateral circulation. Unlike EBVs, these techniques are not reversible. These treatments are under clinical investigation. (See 'Investigational procedures' above.)
●Current clinical trials – A listing of active clinical trials for bLVR may be found at www.clinicaltrials.gov using the search terms "bronchoscopy" and "emphysema."
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