Authors: Zhu Jing, Yin Wen, Xiao Yang, Yuan Mingli, Ni Fang, Hu Yi
Affiliation: Department of Respiratory and Critical Care Medicine, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Clinical Research Center for Interventional Diagnosis and Treatment of Respiratory Diseases
Cite this article: Zhu Jing, Yin Wen, Xiao Yang, et al. Research progress of interventional respiratory techniques in the treatment of pulmonary bullae [J] . Chinese Journal of Tuberculosis and Respiration, 2024, 47(3) : 259-264. DOI: 10.3760/cma.j.cn112147-20230902-00129.
summary
Bullae are a common complication of chronic obstructive pulmonary disease, which can cause the deterioration of lung function, lead to worsening dyspnea, and seriously affect the quality of life of patients. Surgical thoracoscopic surgery is often used to remove bullae in the traditional way, but there are still many postoperative complications and the possibility of recurrence, and some patients often cannot tolerate surgery due to poor lung function or other diseases, and new methods are urgently needed to replace surgical treatment of bullae. In recent years, many scholars at home and abroad have tried to use interventional respiratory medicine technology to treat bullae and achieved certain good results. Therefore, this article will introduce the relevant clinical research progress of interventional respiratory technology in the treatment of pulmonary bullae. Bullae are thin-walled air-containing cavities with a diameter of > 1 cm formed by the destruction of the alveolar septum by increased intraalveolar pressure, and most of them are associated with chronic obstructive pulmonary disease. Although the incidence of GEB has been reported to be rare by foreign scholars, only 0.21 per 100,000 per year [2], and the incidence of pulmonary bullae in mainland China is unknown, it is speculated that COPD combined with pulmonary bullae may have a high incidence due to the nearly 100 million patients with chronic obstructive pulmonary disease in mainland China. Because medical treatment for GEB is often ineffective, surgical removal of the bullae is routinely recommended. After surgical resection, the lung function and quality of life of patients can be continuously improved for about 3~4 years[3]. Although the early mortality rate after bullectomy is low (0~2.5%), it is not without surgical risks, and there are still many complications after surgery, including the occurrence of persistent air leak time >7 days (53%), atrial fibrillation (12%), postoperative mechanical ventilation (9%), and pneumonia (5%) [4]. Nakahara et al. [5] also noted that postoperative functional recovery is unsatisfactory even after bullectomy in patients with preoperative FEV1 of % <35% predicted, severely reduced diffusion function, hypoxemia, and hypercapnia. Therefore, there is an urgent need for less invasive alternatives to surgical treatment of bullae. In recent years, interventional respiratory techniques such as endoscopic implantation of endobronchial valves (EBV) or injection of autologous blood, and medical thoracoscopic therapy for the treatment of pulmonary bullae have also made some progress.
1. Pathophysiological mechanism of bullae
GEB was proposed by Burke to describe radiographic changes that result in a large loss of lung markings on chest x-ray because bullae occupy more than one-third of the unilateral chest cavity and are also referred to as vanishing lung syndrome [6]. GEB is classified into four types based on its imaging findings: type I, a bullae protruding from the pleural surface and a narrow neck bullae, predominantly in the upper lobes of the lungs, type II, a broad-basilar superficial bullae prone to spontaneous pneumothorax, type III a broad-basal bullae with deep hilar orientation, and type IV with bilateral bullae and pneumothorax [7, 8]. Normal alveoli are communicated through tiny pores in the alveolar wall, and when intraalveolar pressures are formed due to any acute but more common chronic cause, these pressures are sufficient to stretch and eventually destroy the alveolar wall to form bullae [9]. Smoking, alpha-1 antitrypsin deficiency, intravenous drug use, marijuana and cocaine use, sarcoidosis, autoimmune diseases, and coronavirus pneumonia are common causes of bullae [10, 11, 12]. The origin and mechanism of formation of bullae remain unclear. Traditionally, it has been believed that due to repeated lung tissue infections, bronchospasm, and destruction of the pulmonary septum, the destruction of the lung parenchyma is localized, resulting in the formation of a valve occlusion effect, which only allows air to enter but cannot expel the cystic space, and gas retention leads to the gradual expansion, rupture, and fusion of the bullae to form GEB, however, no evidence of this valve mechanism has been found [13]. Another view is that bullae communicate with the bronchial tree, and because the bullae are more compliant than the surrounding lung tissue, they are preferentially filled during inspiration, and intermittent pressure changes stretch the lung tissue in the weak area, resulting in collapse of the adjacent normal lung parenchyma [14]. Hirata et al. [15] found that the formation of bullae may be secondary to bronchiolitis obliterans or a non-return valve mechanism due to obstructive air leakage due to fistula formation.
2. Application of interventional respiratory technology in the treatment of pulmonary bullae
1. EBV in bullae: EBV is a new approach to bronchoscopic treatment that aims to achieve a more minimally invasive, reversible, and safer reduction of lung volume in patients with heterogeneous emphysema through the implantation of a unidirectional flap compared to traditional surgical lung volume reduction [16]. The GOLD guidelines also recommend EBV interventions for the treatment of severe COPD. Based on the principle of "unidirectional deflation" of lung volume reduction, the treatment of bullae can also allow patients with GEB to expel air and secretions from the distal lung segment during expiratory through a one-way flap, while preventing air from entering during inspiration, resulting in redistribution of airflow away from the blocked lung segment, a mechanism that favors the contraction of the bullae and the formation of atelectasis [17]. Noppen et al. [17] (2006) reported the first case of bronchoscopy in which four EBVs were placed in the left lower lobe bronchi of a patient to successfully treat symptomatic, dilated GEB in the left lower lobe. At 3 months after the follow-up, the lung function of the patients was significantly improved compared with that before operation (FEV1 increased from 0.91 L to 1.43 L; FEV1/FVC increased from 29% to 38%; TLC decreased from 8.68 L to 7.12 L, RV decreased from 5.55 L to 3.19 L), and chest CT confirmed that GEB was almost absent. A prospective, non-randomized, single-center study by Santini et al. [18] also found that endoscopic EBV implantation in patients with GEB who are not suitable for surgery had significant improvement in lung function and quality of life 24~48 h after surgery, and remained stable at 6 months of follow-up, suggesting that the strategy of EBV treatment for GEB has feasibility and potential efficacy. Subsequently, many scholars have published case reports of EBV's successful treatment of GEB, and it has been suggested that even if no bullae collapse is observed on imaging after surgery, EBV can redistribute airflow to the relatively healthy part of the lungs, thereby reducing physiological dead space and improving ventilation-perfusion dysbicity, thereby improving patients' symptoms, activity tolerance, and quality of life [19, 20, 21]. Because it is difficult to assess the lower limit of surgical tolerability in patients with severe emphysema and bullae, and no preoperative test can absolutely predict the risk of death after any type of lobectomy, EBV treatment for GEB can also reduce the length of hospital stay, postoperative care, and postoperative complications compared with surgery [18]. Therefore, endoscopic EBV is a good alternative treatment, and only a small proportion of patients may develop pneumothorax and hemoptysis, which are common complications. At present, the commonly used valve for EBV treatment is the Zephyr valve produced by Pulmonx in the United States. The key to the successful treatment of GEB with EBV is the precise selection of the bronchi that leads to the GEB target. High-resolution computed tomography (HRCT) can help obtain evidence that bullae supply the bronchial tubes [22]. Second, for GEBs distributed throughout the lobes of the lungs, EBV treatment requires attention to the integrity of the pulmonary fissure. The results of a study of EBV lung volume reduction by Koenigkam-Santos et al. [23] showed that atelectasis correlated with pulmonary fissure integrity, and when the fissure is incomplete, obstruction of the target bronchus may not be sufficient to obtain adequate bullous collapse, as air can still enter through adjacent untreated accessory channels. Tian et al. [24] also found that the right middle lobe bullae with intact right clefts can achieve satisfactory results with EBV treatment. In recent years, the Chartis system has been primarily used to assess and avoid the presence of bypass ventilation in GEB. The bypass ventilation status of GEB patients showed three patterns: (1) low gas flow in the bullous lobes and decreased flow in the adjacent lobes, indicating that the bypass ventilation of the corresponding bullous lobes was negative. (2) Low gas flow in the bullous lobes and continuous airflow in the adjacent lobes indicate positive bypass ventilation. (3) If the parenchyma of the surrounding lung tissue and adjacent lobes is severely disrupted by chronic inflammation, the bullae will communicate with the adjacent lobes; obviously, in this case, continuous airflow in both the lobes and adjacent lobes where the corresponding bullae are located also indicates a positive bypass ventilation. Tian et al. [25] further found that for patients with negative GEB with bypass ventilation, the pulmonary function FEV1 of patients with negative EBV treatment could be significantly improved 1 month after EBV treatment, but the FEV1 decreased after 6 months, while the bullae were located in the right middle lobe, and FEV1 continued to improve after 6 months of EBV treatment. In addition, in patients with severe COPD and bullae, the number of well-preserved lung parenchyma should be considered when performing bullous volume reduction surgery, as any improvement in lung function with any technique may be offset by the sacrifice of lung parenchyma [25]. Therefore, careful selection of the right patient prior to EBV implantation can ensure bullous clearance and satisfactory clinical outcomes. 2. Application of autologous blood in pulmonary bullae: For patients with pulmonary bullae who are not suitable for other methods of treatment such as EBV or surgical treatment, the injection of autologous blood can be considered for the treatment of pulmonary bullae. This approach is a new, low-cost treatment based on the potential bioadhesion properties of blood (autologous "blood patches" have been used to treat pneumothorax) and that blood clots can cause bullous collapse through blockage and scarring [26, 27, 28]. The main procedure is as follows: first, thin-slice lung CT to determine the position of the bullae, then bronchoscopy reaches the target bronchi, the puncture needle is slowly inserted into the bullae and the air is aspirated (whether the gas is withdrawn or not is controversial), and finally the autologous blood, fibrinogen and thrombin are slowly injected into the bullae in batches through the catheter, so as to induce fibrotic atrophy of the bullous wall to prevent re-expansion and achieve the effect of lung volume reduction. Kanoh et al. [29] first reported in 2008 that the use of an endobronchial tube to deliver autologous blood followed by the injection of fibrinogen and thrombin solutions into the bullae resulted in a dramatic reduction in bullae (from 12 cm to 3 cm in diameter), and the patient's lung function and symptoms were relieved and remained effective 12 months after treatment. Subsequent studies have reported the successful use of autologous blood in bullae [30, 31]. Because this mechanism is based on triggering an inflammatory response, pneumonia with adverse events such as fever, hypoxemia, and tachycardia may occur early but can be relieved by antibiotics and steroids [32]. In order to find the target bronchi more accurately and reduce adverse reactions, Hetzel et al. [33] used three-dimensional navigation technology to determine the location and direction of the puncture, and then directed perfusion of autologous blood to bullous emphysema under fluoroscopic guidance under fluoroscopic guidance, which can also reduce lung volume and improve dyspnea. Our team also tried to guide the bronchoscopy to the bullae under fluoroscopy to inject autologous blood, and also achieved certain results. In addition, there have been attempts to convert bypass ventilation-positive target lobes into bypass-ventilation-negative target lobes by autologous blood or blood derivatives, however, this study was discontinued due to lack of adequate efficacy (Mind The Gap, NTR5007). In order to achieve the desired effect of scarring, there is currently no standard amount of blood perfused to the bullae, which may depend on the volume and size of the bullae, ranging from a single injection of 10 mL to a slow fraction of 150~240 mL, provided that phlebotomy does not cause volume depletion [30,34]. In addition to the conventional use of autologous blood alone, most methods are often mixed with fibrinogen and thrombin, and tranexamic acid and calcium chloride are recommended to promote blood clotting. The needle options are 21 G or 22 G COOK or BARD/Mill-Rose Labs aspiration needles and Olympus catheters [34]. Over time, blood products are absorbed or gradually degraded, and atelectasis from bullae may decrease. Various new lung biosealants such as methacrylate and AeriSeal have also been developed, but it is difficult to maintain histocompatibility and sustained action without degradation [35, 36]. It is worth noting that during transbronchial decompression, there is a clear risk of pneumothorax and bronchopleural fistula, which needs to be avoided by fluoroscopy during surgery. If bullous atrophy is not obvious, it is unclear whether repeated autologous blood perfusion is still effective after treatment, such as 3~6 months. Despite the impressive results reported in individual clinical cases, the current lack of standardized procedures and larger clinical trials may limit the widespread adoption of the technology. 3. Application of internal medicine thoracoscopy in pulmonary bullae: The application of internal medicine thoracoscopy in pulmonary bullae mainly focuses on a series of clinical studies carried out by domestic scholars. In 2012, Zhang's team began experimenting with internal medicine thoracoscopic argon plasma coagulation (APC) for the treatment of subpleural bullae (SPB) [37]. The principle is as follows: through the APC thermal effect, the bullous tissue is dried, contracturized, and inactivated, and scarring is induced. A study found that 30 cases of pulmonary bullae (type II and III: diameter 2~5 cm, narrow pedicle, low tension) were cauterized and coagulated by internal medicine thoracoscopy, and about 70% of the patients could stop air leakage and recruitment 24 hours after surgery, and the effective rate could reach 89.3% 2 years after surgery. Complications include fever and chest pain, which can be improved with symptomatic management [37]. Liu Qinghua et al. [38] also included 23 cases of bullae complicated with refractory pneumothorax for medical thoracoscopic treatment to evaluate their efficacy and safety of thoracoscopy, and found that medical thoracoscopic APC treatment can provide safe and effective treatment measures for pulmonary bullae complicated with refractory pneumothorax, talcum powder pleural atresia has good efficacy, and some patients still continue to leak air, and it is recommended to combine autologous blood or erythromycin chest injection to improve the success rate of treatment after surgery. Other scholars have also achieved good results with internal medicine thoracoscopic APC+OB gel therapy [39]. Zhang's team refers to this technique as "one lens plus one needle", and believes that this technology can solve the problem of incomplete bullae management and increased risk of postoperative air leak in medical thoracoscopic APC [40]. In a study in recent years, 46 patients with SPB with multiple HRCT and some of them with a diameter of ≥4 cm were included, and 39 (84.78%) (84.78%) had SPB disappeared or were close to complete disappearance, 5 cases (10.87%) were reduced or reduced, and 2 cases (4.35%) had no change, of which 40 patients stopped air leakage within 1 week, 6 patients stopped air leakage after more than 1 week, and only 1 case recurred after follow-up. This study supports the safety and efficacy of medical thoracoscopic management of bullae [41]. The technical points of "one mirror plus one needle" include: (1) the ventilation of the affected lung and the basal gas source of SPB are completely blocked with the help of double-lumen endotracheal intubation during the operation, which makes it possible to completely and continuously collapse the SPB, which meets the necessary conditions for one-time rapid intravesicular volume reduction and facilitates the immediate and strong adhesion of medical adhesives; (2) the target SPB is mainly eliminated by puncture needle, with a high degree of minimally invasiveness; (3) the residual lung tissue is preserved to the greatest extent. The medical adhesive used in the operation is a new generation of medical adhesive, which has the characteristics of shorter curing time, good diffusion and sealing properties, good toughness of the polymeric film, and high adhesive strength [40]. 4. Application of percutaneous puncture technique in bullae: This method mainly determines the position of the bullae under the guidance of CT, the puncture needle is inserted into the target bullae percutaneously, and sealant or bioglue is injected through the catheter to promote bullae atrophy. The sealants currently reported for percutaneous treatment of bullae include porcine fibrin sealant, autologous blood, doxycycline, and medical glue [42, 43, 44, 45]. Secondary pneumothorax often caused by bullal puncture requires thoracostomy under continuous negative pressure [14~18 cmH2O (1 cmH2O=0.098 kPa)]. When the target bullae collapsed to a stable 72 h after radiographic examination, the drainage tube was clamped and removed after further confirmation for 24 hours. Li et al. [42] used percutaneous puncture technique to treat the bullae of 36 patients, and the pulmonary function and activity tolerance of the patients were significantly improved, among which 3 patients were almost unable to walk before surgery, and the walking test could reach 42, 72 and 528 m in 6 minutes after surgery, and in terms of complications, 22 cases developed ipsilateral pneumothorax, only 2 cases were tension pneumothorax, 6 cases developed subcutaneous emphysema, and there was no bronchopleural fistula and death, which has long-term efficacy. Other scholars in China have also published related articles, and the treatment of pulmonary bullae using the above methods (but the sealant is different) has also achieved good results [44, 45]. Another foreign scholar used EBV placement and then percutaneous catheter to drain a large amount of trapped air in the bullae to treat a patient with GEB in the right upper lobe and invaded the left hemithoracic through the anterior mediastinal connector, and the imaging examination showed a significant decrease in the extent of the bullae without any complications three days after surgery, and the patient recovered well and lung function was close to normal three months after surgery [46]. Other studies have reported similarly that the combination of EBV and implanted drains may be superior in preserving the remaining lung parenchyma. Drainage tube insertion, followed by bronchial isolation to prevent gas leakage, allows the valve to be placed into the precise lung segment involved [47]. However, it is also necessary to carefully review the candidate patient, focusing on the patient's other comorbidities, as well as the size and location of the bullae, which may affect the potential benefits and risks of two consecutive interventions. There are no guidelines for GEB due to other causes, such as tuberculosis infection, but Jeongwon reported that the combination of antituberculosis therapy and ultrasound-guided chest tube implantation into the bullae for continuous drainage, and multiple injections of talcum powder into the bullae, ultimately succeeded in treating the bullae through postural changes, but the presence of bullae-bronchial fistula needs to be ruled out and the spread of sclerotherapy to the contralateral lung is prevented before sclerotherapy is perfused. <5 mL) without any symptoms or signs of inhalation [48]. In the early years, it has also been reported that percutaneous antibiotic injection through a chest tube can be used to treat infectious giant fluidous bullae to avoid surgical trauma [49]. At present, these studies are case reports, and a large number of cases are still needed to conduct cohort studies to summarize the experience. 5. Other techniques: such as bronchoscopic implantation of silicone plugs. Silicone stoppers have the advantages of good tissue compatibility, pruning and shaping, and low cost. Lin et al. [50] reported that 4 cases were preoperatively planned using HRCT and a virtual bronchoscopic navigation system, and then a customized silicone plug was placed in the target bronchi through bronchoscopy to completely occlude the bronchi, and the lung CT showed that the GEB was significantly reduced and the lung function and quality of life were significantly improved compared with the previous ones 3 months after surgery.
3. Difficulties and prospects in the treatment of pulmonary bullae
Since the mechanism of bullae formation is still unclear, there are currently two schools of thought that the existence of bullae exists: (1) bullae have channels to communicate with the bronchial tree, and (2) bullae do not communicate with the bronchial tree and can exist in isolation. The former appears to be an option for transbronchoscopic intervention, while the latter may not be able to pinpoint the target bronchi. To sum up, the author believes that there are several difficulties in the respiratory intervention treatment of bullae: (1) the determination of the main channel for the bullae to enter the bronchi, due to the compression of GEB, the ventilated bronchial tree may be distorted and deformed, and its opening may be transposed to different positions, which increases the difficulty of finding the ventilated bronchial tube leading to the bullae. The accuracy can be increased by the Chartis system, virtual navigation or electromagnetic navigation technology, and the bronchi of the target area may change its position on the still image with respiration due to the persistence of respiration, so it is necessary to improve the positioning accuracy of the target area by breathing gating technology or cone beam CT (CBCT). (2) The lack of better identification of pleural adhesions and simpler and more effective management of pleural adhesions are important factors in the successful management of bullae and the reduction of adverse events by respiratory intervention. (3) Most of the reported cases of successful treatment are individual cases or retrospective studies, and no subgroup analysis has been conducted, and there is a lack of multicenter, large-scale, and prospective cohort studies, so the rational selection of patients is particularly important, and it is urgent to formulate unified standards and procedures for respiratory interventional therapy. (4) The size of various materials used for intraoperative implantation and the volume of perfusion required cannot be accurately calculated, and there are still histocompatibility problems. In the future, with the development of imaging technology, such as ventilatory scintigraphy or artificial intelligence technology, it can better assist in identifying ventilated bronchial and pleural adhesions of pulmonary bullae, with the help of CBCT technology, various navigation technologies, intelligent endoscopic surgical robots and other positioning tools to help find ventilated bronchial tubes more accurately, as well as the advancement of biomedical materials engineering technology and the update of related interventional equipment, interventional respiratory medicine technology can be a safer and more effective alternative to surgical treatment of pulmonary bullae.
References (abbreviated)