REVIEW URRENT C OPINION
Intrapleural minocycline pleurodesis for the treatment of primary spontaneous pneumothorax Jin-Shing Chen a, Wing-Kai Chan b, and Pan-Chyr Yang c
Purpose of review The role of chemical pleurodesis in the treatment of primary spontaneous pneumothorax remains unclear. According to current practice guidelines, chemical pleurodesis is reserved for patients who are unable or unwilling to have surgery. Some recent studies showed that intrapleural minocycline pleurodesis could decrease the rate of pneumothorax recurrence, when used either as the initial treatment for simple pneumothorax after successful aspiration and drainage or as an adjuvant treatment for complicated or recurrent pneumothorax following thoracoscopic surgery. The purpose of this review is to discuss the current available evidence on intrapleural minocycline pleurodesis for the treatment of primary spontaneous pneumothorax. Recent findings In a recently published prospective, randomized controlled trial, additional minocycline pleurodesis following simple aspiration and drainage was a well tolerated and more effective initial treatment for a first episode of primary spontaneous pneumothorax than simple aspiration and drainage alone. Other prospective, randomized controlled trials showed that additional minocycline pleurodesis after thoracoscopic treatment was a well tolerated and convenient procedure which can reduce the rate of ipsilateral recurrence of primary spontaneous pneumothorax. Summary Intrapleural minocycline pleurodesis can be considered an adjunct to standard treatment of primary spontaneous pneumothorax, after either simple aspiration and drainage or after thoracoscopic surgery. Video abstract http://links.lww.com/COPM/A12 Keywords aspiration, drainage, minocycline pleurodesis, pneumothorax treatment, thoracoscopy
INTRODUCTION Primary spontaneous pneumothorax most commonly occurs in young, lean males [1–3]. The recurrence rate of primary spontaneous pneumothorax varies between 16 and 52% after the first episode and increases to 60–80% after the second pneumothorax [1,4–7]. This high recurrence rate and variable clinical presentations have stimulated the development of different therapeutic approaches, such as observation, simple aspiration, chest tube drainage, chemical pleurodesis, thoracoscopic surgery, open thoracotomy, or combinations of the above methods [1–3]. Optimal management of this benign disease has been a matter of debate. In addition to evacuating air from the pleural space by simple aspiration or chest tube drainage, the management of primary
spontaneous pneumothorax has also focused on stopping the air leakage and preventing recurrences by surgical intervention or chemical pleurodesis. Intrapleural instillation of a chemical irritant (chemical pleurodesis) is an effective way to shorten
a Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, bDepartment of Medical Research, National Taiwan University Hospital and cDepartment of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
Correspondence to Dr Pan-Chyr Yang, National Taiwan University College of Medicine, No. 1, Section 1, Ren-Ai Road, Taipei 100, Taiwan. Tel: +886 2 23562185; fax: +886 2 23224793; e-mail: pcyang@ntu. edu.tw Curr Opin Pulm Med 2014, 20:371–376 DOI:10.1097/MCP.0000000000000067
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KEY POINTS A high-quality randomized controlled trial confirmed that intrapleural minocycline pleurodesis following simple aspiration and drainage is a well tolerated and more effective treatment for primary spontaneous pneumothorax than simple aspiration and drainage alone. A randomized controlled trial showed that minocycline pleurodesis can reduce the rate of ipsilateral recurrence after thoracoscopic treatment for primary spontaneous pneumothorax. A randomized controlled trial showed that pleural abrasion with minocycline pleurodesis is as effective as apical pleurectomy, and either technique is appropriate for treating patients with a high risk of recurrence of primary spontaneous pneumothorax. Narcotic analgesics should be given before minocycline pleurodesis to prevent immediate chest pain.
The selection of the approach depends on the size of the pneumothorax, the degree of clinical compromise, and whether the pneumothorax is the first episode or a recurrence. Generally, observation is suggested for a first, small pneumothorax, which is defined as the presence of a visible rim of less than 2 cm between the lung margin and the chest wall (at the level of the hilum) [2]. Simple aspiration or chest tube drainage is used for the first episode of a large pneumothorax or when the patient is breathless. Simple aspiration is recommended as the initial treatment because the procedure seems as effective as chest tube drainage, but is associated with fewer admissions and shorter hospital stays [23,24]. Surgical intervention is reserved for patients with recurrent or complicated spontaneous pneumothorax. However, the role of and indications for chemical pleurodesis, as well as the selection of sclerosing agents in primary spontaneous pneumothorax, are rarely investigated.
CHEMICAL PLEURODESIS the duration of air leaks and prevent the recurrence of primary spontaneous pneumothorax [8–12]. In current practice guidelines, chemical pleurodesis is reserved for patients unable or unwilling to receive surgery [2]. Tetracycline, which was formerly the most commonly used irritant, is no longer available [8,12]. Minocycline, a derivative of tetracycline, is as effective as tetracycline in inducing pleural fibrosis in animal studies [13,14]. Recently, researchers have found that intrapleural minocycline pleurodesis is also well tolerated and effective in preventing pneumothorax recurrence in patients with primary spontaneous pneumothorax with a first episode of spontaneous pneumothorax or after thoracoscopic surgery [9,10,15 ,16–18,19 ,20–22]. The aim of this review is to discuss key studies analyzing the effects of intrapleural minocycline pleurodesis for the treatment of primary spontaneous pneumothorax. &&
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TREATMENT OPTIONS FOR PRIMARY SPONTANEOUS PNEUMOTHORAX The management of primary spontaneous pneumothorax focuses on evacuating air from the pleural space, stopping the air leakage and preventing recurrences. Available therapeutic options include observation, simple aspiration, intercostal drainage with a pigtail catheter or chest tube, intercostal drainage with chemical pleurodesis, medical thoracoscopy with chemical pleurodesis, or surgical intervention (video-assisted thoracoscopic surgery or thoracotomy) with/without chemical pleurodesis [1–4,7]. 372
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Pleurodesis is a procedure to achieve symphysis between the two layers of the pleura to prevent recurrent pleural effusion or recurrent pneumothorax. It can be achieved either by instilling a chemical irritant (chemical pleurodesis) or performing a pleural abrasion or pleurectomy (mechanical pleurodesis) during surgery [1–4,21]. Chemical pleurodesis can control difficult or recurrent pneumothoraces, but, since surgical options are more effective, it is recommended only if a patient is either unwilling or unable to undergo surgery [2]. Chemical pleurodesis can be applied through an intercostal drainage tube, medical thoracoscopy, or during an operation. However, there are no clear guidelines directing physicians in their use. In clinical practice, a variety of sclerosants have been used, including tetracycline and its derivatives (doxycycline or minocycline), talc, bleomycin, autologous blood patch, iodopovidone, OK-432 [picibanil; a lyophilized mixture of group A Streptococcus pyogenes with antineoplastic (Chugai Pharmaceutical Co., Tokyo, Japan)], silver nitrate, and quinacrine [25–30]. Tetracycline had been recommended as the first-line sclerosant therapy for both primary and secondary pneumothoraces as it proved to be the most effective sclerosant in animal models [13,31]. Recently, it has become difficult to obtain parenteral tetracycline for pleurodesis. Minocycline and doxycycline have also been shown to be reasonable alternative sclerosing agents in animal models [13,14,32]. Chemical pleurodesis using graded talc is an effective alternative to tetracycline pleurodesis [33], but there have been no controlled trials Volume 20 Number 4 July 2014
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Minocycline pleurodesis for spontaneous pneumothorax Chen et al.
comparing these agents in the treatment of pneumothorax. In a survey from five English-speaking countries (United States, United Kingdom, Canada, Australia, and New Zealand), the most commonly used agent was talc followed by tetracycline derivatives such as minocycline [30]. The role of chemical pleurodesis for primary spontaneous pneumothorax has been controversial because pleurodesis-induced pleural adhesions may interfere with subsequent surgery, the most definite and effective treatment modality for recurrent primary spontaneous pneumothorax.
MINOCYCLINE PLEURODESIS FOLLOWING ASPIRATION AND DRAINAGE IN THE INITIAL TREATMENT OF PNEUMOTHORAX Simple aspiration and chest tube drainage are the most frequently used methods in the initial treatment of primary spontaneous pneumothorax. However, the 1-year recurrence rate for simple aspiration and drainage is roughly 30% (16–52%) [1,4–7]. Thus, the standard treatment for primary spontaneous pneumothorax can be improved upon. Several prospective randomized trials have investigated the ability of chemical pleurodesis following chest drainage to decrease the recurrence rate after initial treatment of primary or secondary spontaneous pneumothorax [8,11,12,15 ]. All studies showed a significant reduction in recurrence with chemical pleurodesis and chest-tube drainage compared with chest-tube drainage alone. In a recently published prospective, randomized controlled clinical trial, Chen et al. [15 ] investigated 214 patients, 15–40 years old, with a first episode of primary spontaneous pneumothorax with an air rim greater than 2 cm on chest radiographs. Patients were randomly assigned to simple aspiration via a pigtail catheter (control group, n ¼ 108) or catheter drainage followed by pleurodesis with minocycline 300 mg (minocycline group, n ¼ 106). Minocycline pleurodesis was performed immediately after radiographic confirmation of complete lung expansion and cessation of the air leak. Patients were followed up for at least 12 months and assessed for postprocedural pain and spirometry at 6 months. More patients in the minocycline group (72 of 106, 67.9%) than the control group (21 of 108, 19.4%) had pain and requested intramuscular pethidine injections. At 1 year, the pneumothorax recurrence rate was significantly lower in the minocycline group (31 patients, 29.2%) than in the control group (53 patients, 49.1%) using an intention-to-treat analysis by including all patients after randomization (Fig. 1a) [15 ]. During subsequent thoracoscopic surgery, pleural adhesions were more common in the minocycline &&
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group than in the control group. Spirometry results at 6 months did not show restrictive ventilator defects in either group. Because the rate of hospital admission was only 28.3% in the minocycline group, Chen et al. [15 ] claimed that intrapleural minocycline pleurodesis following aspiration and drainage could be done as an outpatient procedure and could be an adjunct to the standard initial treatment for primary spontaneous pneumothorax. Concerns have been raised regarding the high pneumothorax recurrence rate of 29% in the minocycline group [34,35], which was comparable to the efficacy of simple aspiration alone in prospective randomized studies [23,24]. This could be because previous trials excluded patients with early treatment failure after aspiration or chest-tube drainage [23,24]. There were high recurrence rates in the minocycline and control groups because this trial included all randomized cases for recurrence analyses [15 ]. If patients with early treatment failures were excluded, such as those with persistent air leaks for more than 7 days after catheter removal, the 1-year pneumothorax recurrence rate would have been 18.5% (17 of 92) in the minocycline group versus 37.5% (33 of 88) in the control group (Fig. 1b) [16]. The data also confirm the conclusion that simple aspiration and drainage and minocycline pleurodesis is more effective than simple aspiration and drainage for treatment of primary spontaneous pneumothorax. &&
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MINOCYCLINE PLEURODESIS FOLLOWING THORACOSCOPIC TREATMENT OF PNEUMOTHORAX Although surgical treatment is the most effective way to treat spontaneous pneumothorax, pneumothorax recurs in 5–12% of patients after thoracoscopic surgery with or without mechanical pleurodesis, which is a significantly higher rate compared with open thoracotomy (0–1%) [36–40]. It is suggested that there is a higher chance of missed leaking blebs and that a less intense pleural inflammatory reaction is induced with the thoracoscopic procedure compared with a thoracotomy [41,42]. As a result, the efficacy of thoracoscopic surgery has been questioned and more aggressive procedures, such as a limited thoracotomy with pleurectomy, are sometimes performed to enhance the effects of pleural symphysis [39,42]. Some studies showed that minocycline pleurodesis following thoracoscopic surgical procedures is effective in preventing pneumothorax recurrence. Alayouty et al. [22] randomized 84 patients to receive pleural abrasion (42 patients) or minocycline pleurodesis (42 patients) after thoracoscopic bullectomy
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(a)
Pneumothorax recurrence (%)
70 60
Control group (n = 108)
50
Reduction at 1-year: 40.4% Overall: 41.6%
40 30
Minocycline group (n = 106)
20 10 P = 0.004 (log rank test)
0 0
12
24
36
48
60
72
3 2
0 0
Time (months) No. at risk Control group 108 Minocycline group 106
55 75
33 48
15 23
7 9
(b)
Pneumothorax recurrence (%)
70 60 50 Control group (n = 88)
40
Reduction at 1-year: 50.7% Overall: 51.1%
30 20
Minocycline group (n = 92)
10 P = 0.004 (log rank test)
0 0
12
24
36
48
60
72
3 2
0 0
Time (months) No. at risk Control group Minocycline group
88 92
55 75
33 48
15 23
7 9
FIGURE 1. Kaplan–Meier curves of pneumothorax recurrence in the minocycline versus control group including all patients after randomization (a) or excluding patients with early treatment failures (b). The reduction in the relative risk at 1-year and overall (65 months) pneumothorax recurrence rates were estimated by the Kaplan–Meier method. Reproduced with permission [15 ,16]. &&
in a prospective clinical trial. The results showed that pleurodesis with minocycline 7 mg/kg was associated with a trend towards a decreased rate of prolonged air leaks (2 versus 5%; P ¼ 0.100) and was more effective in preventing recurrence (0 versus 5%; P < 0.05) than pleural abrasion for patients with primary spontaneous pneumothorax [22]. In another prospective, randomized trial by Chen et al. [10], 202 patients with primary spontaneous pneumothorax were treated by thoracoscopic surgery. The procedures included resection of the blebs and mechanical pleurodesis by scrubbing the parietal pleura. After the operation, 374
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patients were randomly assigned to additional minocycline pleurodesis (103 patients) or to observation (99 patients). Patients in the minocycline group demonstrated a trend of a decreased rate of prolonged air leaks (1.9 versus 6.1%; P ¼ 0.100). After a mean follow-up of 29 months (12–47 months), recurrent ipsilateral pneumothorax was noted in two patients (1.9%) in the minocycline group and eight patients (8.1%) in the observation group (P ¼ 0.044 by the Kaplan–Meier method and log-rank test). The only concern about additional minocycline pleurodesis following thoracoscopic surgery is that Volume 20 Number 4 July 2014
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patients in the minocycline group had a higher intensity of chest pain and required a larger accumulated dose of meperidine compared with the control group. Chen et al. [19 ] also compared the safety and efficacy between apical pleurectomy and pleural abrasion with minocycline after thoracoscopic bullectomy in patients with primary spontaneous pneumothorax with a high recurrence risk in a prospective, randomized trial. After stapled bullectomy, 160 patients with no identifiable bleb or multiple blebs (three or more) were randomly assigned to apical pleurectomy (pleurectomy group, 80 patients) or pleural abrasion with minocycline (abrasion/minocycline group, 80 patients). Patients in the pleurectomy group had a longer duration of surgery, a greater amount of operative bleeding, and a greater amount of postoperative chest drainage. Patients in the abrasion/minocycline group had a higher intensity of chest pain and required more frequent meperidine injections. Hemothorax occurred in three patients (3.8%) in the pleurectomy group, but none in the abrasion/minocycline group. After a mean follow-up of 26.1 months, pneumothorax recurred in three patients (3.8%) in each group. The authors therefore concluded that pleural abrasion with minocycline pleurodesis is as effective as apical pleurectomy, and either technique is appropriate for treating patients with a high risk of recurrence of primary spontaneous pneumothorax.
low patient numbers, the effect of minocycline pleurodesis for postoperative air leaks after surgery for primary spontaneous pneumothorax remains unclear.
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MINOCYCLINE PLEURODESIS FOR PERSISTENT AIR LEAK FOLLOWING TREATMENT OF PNEUMOTHORAX Persistent air leak is the most common complication following chest tube drainage or thoracoscopic surgery for primary spontaneous pneumothorax. Thoracic surgical intervention is usually recommended if an air leak persists for more than 3–5 days after chest tube drainage [2,43]. Air leaks may persist or develop following surgery, with a rate ranging from 7 to 14%, and the optimal management is rarely mentioned [20,44,45]. A retrospective study by Chen et al. [9] showed that additional minocycline pleurodesis is associated with a decreased rate of postoperative persistent air leaks in patients with primary spontaneous pneumothorax compared with surgery alone. Recently, How et al. [20,21] reported that chemical pleurodesis using OK-432 or minocycline was effective in stopping air leaks in patients with primary spontaneous pneumothorax with prolonged air leaks after thoracoscopic surgery. Because the two studies were retrospective with
CONCERNS ABOUT MINOCYCLINE PLEURODESIS Immediate chest pain is the most common complaint associated with minocycline pleurodesis [9,10,15 ,19 ]. Even with the use of 300–400 mg intrapleural lidocaine before pleurodesis, most patients had immediate intense chest pain which required pethidine injections. Chen et al. [10,15 ] therefore suggested that pethidine or other narcotic analgesics be given before minocycline pleurodesis procedures to prevent immediate chest pain. The other concern is that minocycline-induced pleural adhesions can cause restrictive pulmonary dysfunction or interfere with subsequent surgery. Chen et al. [15 ] showed that minocycline pleurodesis did not significantly interfere with forced vital capacity or forced expiratory volume in 1 s. In addition, minocycline pleurodesis induced scant, loose adhesions in patients with recurrent pneumothorax which did not affect subsequent surgical procedures or outcomes [15 ,18]. &&
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CONCLUSION Although there are a variety of options in the treatment of primary spontaneous pneumothorax, minocycline pleurodesis should play a more important role in this benign disease. Several prospective, randomized trials have confirmed the safety and efficacy of intrapleural minocycline pleurodesis in preventing pneumothorax recurrence. It can be considered an adjunct to standard treatment, after either simple aspiration and drainage or thoracoscopic surgery. Because minocycline pleurodesis is painful and the recurrence rate following aspiration/ drainage and minocycline pleurodesis is not low, future studies should focus on the identification of patients at high risk of recurrence as well as compare the efficacy of different sclerosing agents in specific clinical settings of primary spontaneous pneumothorax. Acknowledgements The study was supported by a research grant from National Science Council, Taiwan (NSC 102-2325-B002-077). Conflicts of interest There are no conflicts of interest.
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Intrapleural minocycline pleurodesis for the treatment of primary spontaneous pneumothorax Jin-Shing Chen a, Wing-Kai Chan b, and Pan-Chyr Yang c
Purpose of review The role of chemical pleurodesis in the treatment of primary spontaneous pneumothorax remains unclear. According to current practice guidelines, chemical pleurodesis is reserved for patients who are unable or unwilling to have surgery. Some recent studies showed that intrapleural minocycline pleurodesis could decrease the rate of pneumothorax recurrence, when used either as the initial treatment for simple pneumothorax after successful aspiration and drainage or as an adjuvant treatment for complicated or recurrent pneumothorax following thoracoscopic surgery. The purpose of this review is to discuss the current available evidence on intrapleural minocycline pleurodesis for the treatment of primary spontaneous pneumothorax. Recent findings In a recently published prospective, randomized controlled trial, additional minocycline pleurodesis following simple aspiration and drainage was a well tolerated and more effective initial treatment for a first episode of primary spontaneous pneumothorax than simple aspiration and drainage alone. Other prospective, randomized controlled trials showed that additional minocycline pleurodesis after thoracoscopic treatment was a well tolerated and convenient procedure which can reduce the rate of ipsilateral recurrence of primary spontaneous pneumothorax. Summary Intrapleural minocycline pleurodesis can be considered an adjunct to standard treatment of primary spontaneous pneumothorax, after either simple aspiration and drainage or after thoracoscopic surgery. Video abstract http://links.lww.com/COPM/A12 Keywords aspiration, drainage, minocycline pleurodesis, pneumothorax treatment, thoracoscopy
INTRODUCTION Primary spontaneous pneumothorax most commonly occurs in young, lean males [1–3]. The recurrence rate of primary spontaneous pneumothorax varies between 16 and 52% after the first episode and increases to 60–80% after the second pneumothorax [1,4–7]. This high recurrence rate and variable clinical presentations have stimulated the development of different therapeutic approaches, such as observation, simple aspiration, chest tube drainage, chemical pleurodesis, thoracoscopic surgery, open thoracotomy, or combinations of the above methods [1–3]. Optimal management of this benign disease has been a matter of debate. In addition to evacuating air from the pleural space by simple aspiration or chest tube drainage, the management of primary
spontaneous pneumothorax has also focused on stopping the air leakage and preventing recurrences by surgical intervention or chemical pleurodesis. Intrapleural instillation of a chemical irritant (chemical pleurodesis) is an effective way to shorten
a Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, bDepartment of Medical Research, National Taiwan University Hospital and cDepartment of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
Correspondence to Dr Pan-Chyr Yang, National Taiwan University College of Medicine, No. 1, Section 1, Ren-Ai Road, Taipei 100, Taiwan. Tel: +886 2 23562185; fax: +886 2 23224793; e-mail: pcyang@ntu. edu.tw Curr Opin Pulm Med 2014, 20:371–376 DOI:10.1097/MCP.0000000000000067
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KEY POINTS A high-quality randomized controlled trial confirmed that intrapleural minocycline pleurodesis following simple aspiration and drainage is a well tolerated and more effective treatment for primary spontaneous pneumothorax than simple aspiration and drainage alone. A randomized controlled trial showed that minocycline pleurodesis can reduce the rate of ipsilateral recurrence after thoracoscopic treatment for primary spontaneous pneumothorax. A randomized controlled trial showed that pleural abrasion with minocycline pleurodesis is as effective as apical pleurectomy, and either technique is appropriate for treating patients with a high risk of recurrence of primary spontaneous pneumothorax. Narcotic analgesics should be given before minocycline pleurodesis to prevent immediate chest pain.
The selection of the approach depends on the size of the pneumothorax, the degree of clinical compromise, and whether the pneumothorax is the first episode or a recurrence. Generally, observation is suggested for a first, small pneumothorax, which is defined as the presence of a visible rim of less than 2 cm between the lung margin and the chest wall (at the level of the hilum) [2]. Simple aspiration or chest tube drainage is used for the first episode of a large pneumothorax or when the patient is breathless. Simple aspiration is recommended as the initial treatment because the procedure seems as effective as chest tube drainage, but is associated with fewer admissions and shorter hospital stays [23,24]. Surgical intervention is reserved for patients with recurrent or complicated spontaneous pneumothorax. However, the role of and indications for chemical pleurodesis, as well as the selection of sclerosing agents in primary spontaneous pneumothorax, are rarely investigated.
CHEMICAL PLEURODESIS the duration of air leaks and prevent the recurrence of primary spontaneous pneumothorax [8–12]. In current practice guidelines, chemical pleurodesis is reserved for patients unable or unwilling to receive surgery [2]. Tetracycline, which was formerly the most commonly used irritant, is no longer available [8,12]. Minocycline, a derivative of tetracycline, is as effective as tetracycline in inducing pleural fibrosis in animal studies [13,14]. Recently, researchers have found that intrapleural minocycline pleurodesis is also well tolerated and effective in preventing pneumothorax recurrence in patients with primary spontaneous pneumothorax with a first episode of spontaneous pneumothorax or after thoracoscopic surgery [9,10,15 ,16–18,19 ,20–22]. The aim of this review is to discuss key studies analyzing the effects of intrapleural minocycline pleurodesis for the treatment of primary spontaneous pneumothorax. &&
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TREATMENT OPTIONS FOR PRIMARY SPONTANEOUS PNEUMOTHORAX The management of primary spontaneous pneumothorax focuses on evacuating air from the pleural space, stopping the air leakage and preventing recurrences. Available therapeutic options include observation, simple aspiration, intercostal drainage with a pigtail catheter or chest tube, intercostal drainage with chemical pleurodesis, medical thoracoscopy with chemical pleurodesis, or surgical intervention (video-assisted thoracoscopic surgery or thoracotomy) with/without chemical pleurodesis [1–4,7]. 372
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Pleurodesis is a procedure to achieve symphysis between the two layers of the pleura to prevent recurrent pleural effusion or recurrent pneumothorax. It can be achieved either by instilling a chemical irritant (chemical pleurodesis) or performing a pleural abrasion or pleurectomy (mechanical pleurodesis) during surgery [1–4,21]. Chemical pleurodesis can control difficult or recurrent pneumothoraces, but, since surgical options are more effective, it is recommended only if a patient is either unwilling or unable to undergo surgery [2]. Chemical pleurodesis can be applied through an intercostal drainage tube, medical thoracoscopy, or during an operation. However, there are no clear guidelines directing physicians in their use. In clinical practice, a variety of sclerosants have been used, including tetracycline and its derivatives (doxycycline or minocycline), talc, bleomycin, autologous blood patch, iodopovidone, OK-432 [picibanil; a lyophilized mixture of group A Streptococcus pyogenes with antineoplastic (Chugai Pharmaceutical Co., Tokyo, Japan)], silver nitrate, and quinacrine [25–30]. Tetracycline had been recommended as the first-line sclerosant therapy for both primary and secondary pneumothoraces as it proved to be the most effective sclerosant in animal models [13,31]. Recently, it has become difficult to obtain parenteral tetracycline for pleurodesis. Minocycline and doxycycline have also been shown to be reasonable alternative sclerosing agents in animal models [13,14,32]. Chemical pleurodesis using graded talc is an effective alternative to tetracycline pleurodesis [33], but there have been no controlled trials Volume 20 Number 4 July 2014
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Minocycline pleurodesis for spontaneous pneumothorax Chen et al.
comparing these agents in the treatment of pneumothorax. In a survey from five English-speaking countries (United States, United Kingdom, Canada, Australia, and New Zealand), the most commonly used agent was talc followed by tetracycline derivatives such as minocycline [30]. The role of chemical pleurodesis for primary spontaneous pneumothorax has been controversial because pleurodesis-induced pleural adhesions may interfere with subsequent surgery, the most definite and effective treatment modality for recurrent primary spontaneous pneumothorax.
MINOCYCLINE PLEURODESIS FOLLOWING ASPIRATION AND DRAINAGE IN THE INITIAL TREATMENT OF PNEUMOTHORAX Simple aspiration and chest tube drainage are the most frequently used methods in the initial treatment of primary spontaneous pneumothorax. However, the 1-year recurrence rate for simple aspiration and drainage is roughly 30% (16–52%) [1,4–7]. Thus, the standard treatment for primary spontaneous pneumothorax can be improved upon. Several prospective randomized trials have investigated the ability of chemical pleurodesis following chest drainage to decrease the recurrence rate after initial treatment of primary or secondary spontaneous pneumothorax [8,11,12,15 ]. All studies showed a significant reduction in recurrence with chemical pleurodesis and chest-tube drainage compared with chest-tube drainage alone. In a recently published prospective, randomized controlled clinical trial, Chen et al. [15 ] investigated 214 patients, 15–40 years old, with a first episode of primary spontaneous pneumothorax with an air rim greater than 2 cm on chest radiographs. Patients were randomly assigned to simple aspiration via a pigtail catheter (control group, n ¼ 108) or catheter drainage followed by pleurodesis with minocycline 300 mg (minocycline group, n ¼ 106). Minocycline pleurodesis was performed immediately after radiographic confirmation of complete lung expansion and cessation of the air leak. Patients were followed up for at least 12 months and assessed for postprocedural pain and spirometry at 6 months. More patients in the minocycline group (72 of 106, 67.9%) than the control group (21 of 108, 19.4%) had pain and requested intramuscular pethidine injections. At 1 year, the pneumothorax recurrence rate was significantly lower in the minocycline group (31 patients, 29.2%) than in the control group (53 patients, 49.1%) using an intention-to-treat analysis by including all patients after randomization (Fig. 1a) [15 ]. During subsequent thoracoscopic surgery, pleural adhesions were more common in the minocycline &&
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group than in the control group. Spirometry results at 6 months did not show restrictive ventilator defects in either group. Because the rate of hospital admission was only 28.3% in the minocycline group, Chen et al. [15 ] claimed that intrapleural minocycline pleurodesis following aspiration and drainage could be done as an outpatient procedure and could be an adjunct to the standard initial treatment for primary spontaneous pneumothorax. Concerns have been raised regarding the high pneumothorax recurrence rate of 29% in the minocycline group [34,35], which was comparable to the efficacy of simple aspiration alone in prospective randomized studies [23,24]. This could be because previous trials excluded patients with early treatment failure after aspiration or chest-tube drainage [23,24]. There were high recurrence rates in the minocycline and control groups because this trial included all randomized cases for recurrence analyses [15 ]. If patients with early treatment failures were excluded, such as those with persistent air leaks for more than 7 days after catheter removal, the 1-year pneumothorax recurrence rate would have been 18.5% (17 of 92) in the minocycline group versus 37.5% (33 of 88) in the control group (Fig. 1b) [16]. The data also confirm the conclusion that simple aspiration and drainage and minocycline pleurodesis is more effective than simple aspiration and drainage for treatment of primary spontaneous pneumothorax. &&
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MINOCYCLINE PLEURODESIS FOLLOWING THORACOSCOPIC TREATMENT OF PNEUMOTHORAX Although surgical treatment is the most effective way to treat spontaneous pneumothorax, pneumothorax recurs in 5–12% of patients after thoracoscopic surgery with or without mechanical pleurodesis, which is a significantly higher rate compared with open thoracotomy (0–1%) [36–40]. It is suggested that there is a higher chance of missed leaking blebs and that a less intense pleural inflammatory reaction is induced with the thoracoscopic procedure compared with a thoracotomy [41,42]. As a result, the efficacy of thoracoscopic surgery has been questioned and more aggressive procedures, such as a limited thoracotomy with pleurectomy, are sometimes performed to enhance the effects of pleural symphysis [39,42]. Some studies showed that minocycline pleurodesis following thoracoscopic surgical procedures is effective in preventing pneumothorax recurrence. Alayouty et al. [22] randomized 84 patients to receive pleural abrasion (42 patients) or minocycline pleurodesis (42 patients) after thoracoscopic bullectomy
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(a)
Pneumothorax recurrence (%)
70 60
Control group (n = 108)
50
Reduction at 1-year: 40.4% Overall: 41.6%
40 30
Minocycline group (n = 106)
20 10 P = 0.004 (log rank test)
0 0
12
24
36
48
60
72
3 2
0 0
Time (months) No. at risk Control group 108 Minocycline group 106
55 75
33 48
15 23
7 9
(b)
Pneumothorax recurrence (%)
70 60 50 Control group (n = 88)
40
Reduction at 1-year: 50.7% Overall: 51.1%
30 20
Minocycline group (n = 92)
10 P = 0.004 (log rank test)
0 0
12
24
36
48
60
72
3 2
0 0
Time (months) No. at risk Control group Minocycline group
88 92
55 75
33 48
15 23
7 9
FIGURE 1. Kaplan–Meier curves of pneumothorax recurrence in the minocycline versus control group including all patients after randomization (a) or excluding patients with early treatment failures (b). The reduction in the relative risk at 1-year and overall (65 months) pneumothorax recurrence rates were estimated by the Kaplan–Meier method. Reproduced with permission [15 ,16]. &&
in a prospective clinical trial. The results showed that pleurodesis with minocycline 7 mg/kg was associated with a trend towards a decreased rate of prolonged air leaks (2 versus 5%; P ¼ 0.100) and was more effective in preventing recurrence (0 versus 5%; P < 0.05) than pleural abrasion for patients with primary spontaneous pneumothorax [22]. In another prospective, randomized trial by Chen et al. [10], 202 patients with primary spontaneous pneumothorax were treated by thoracoscopic surgery. The procedures included resection of the blebs and mechanical pleurodesis by scrubbing the parietal pleura. After the operation, 374
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patients were randomly assigned to additional minocycline pleurodesis (103 patients) or to observation (99 patients). Patients in the minocycline group demonstrated a trend of a decreased rate of prolonged air leaks (1.9 versus 6.1%; P ¼ 0.100). After a mean follow-up of 29 months (12–47 months), recurrent ipsilateral pneumothorax was noted in two patients (1.9%) in the minocycline group and eight patients (8.1%) in the observation group (P ¼ 0.044 by the Kaplan–Meier method and log-rank test). The only concern about additional minocycline pleurodesis following thoracoscopic surgery is that Volume 20 Number 4 July 2014
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patients in the minocycline group had a higher intensity of chest pain and required a larger accumulated dose of meperidine compared with the control group. Chen et al. [19 ] also compared the safety and efficacy between apical pleurectomy and pleural abrasion with minocycline after thoracoscopic bullectomy in patients with primary spontaneous pneumothorax with a high recurrence risk in a prospective, randomized trial. After stapled bullectomy, 160 patients with no identifiable bleb or multiple blebs (three or more) were randomly assigned to apical pleurectomy (pleurectomy group, 80 patients) or pleural abrasion with minocycline (abrasion/minocycline group, 80 patients). Patients in the pleurectomy group had a longer duration of surgery, a greater amount of operative bleeding, and a greater amount of postoperative chest drainage. Patients in the abrasion/minocycline group had a higher intensity of chest pain and required more frequent meperidine injections. Hemothorax occurred in three patients (3.8%) in the pleurectomy group, but none in the abrasion/minocycline group. After a mean follow-up of 26.1 months, pneumothorax recurred in three patients (3.8%) in each group. The authors therefore concluded that pleural abrasion with minocycline pleurodesis is as effective as apical pleurectomy, and either technique is appropriate for treating patients with a high risk of recurrence of primary spontaneous pneumothorax.
low patient numbers, the effect of minocycline pleurodesis for postoperative air leaks after surgery for primary spontaneous pneumothorax remains unclear.
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MINOCYCLINE PLEURODESIS FOR PERSISTENT AIR LEAK FOLLOWING TREATMENT OF PNEUMOTHORAX Persistent air leak is the most common complication following chest tube drainage or thoracoscopic surgery for primary spontaneous pneumothorax. Thoracic surgical intervention is usually recommended if an air leak persists for more than 3–5 days after chest tube drainage [2,43]. Air leaks may persist or develop following surgery, with a rate ranging from 7 to 14%, and the optimal management is rarely mentioned [20,44,45]. A retrospective study by Chen et al. [9] showed that additional minocycline pleurodesis is associated with a decreased rate of postoperative persistent air leaks in patients with primary spontaneous pneumothorax compared with surgery alone. Recently, How et al. [20,21] reported that chemical pleurodesis using OK-432 or minocycline was effective in stopping air leaks in patients with primary spontaneous pneumothorax with prolonged air leaks after thoracoscopic surgery. Because the two studies were retrospective with
CONCERNS ABOUT MINOCYCLINE PLEURODESIS Immediate chest pain is the most common complaint associated with minocycline pleurodesis [9,10,15 ,19 ]. Even with the use of 300–400 mg intrapleural lidocaine before pleurodesis, most patients had immediate intense chest pain which required pethidine injections. Chen et al. [10,15 ] therefore suggested that pethidine or other narcotic analgesics be given before minocycline pleurodesis procedures to prevent immediate chest pain. The other concern is that minocycline-induced pleural adhesions can cause restrictive pulmonary dysfunction or interfere with subsequent surgery. Chen et al. [15 ] showed that minocycline pleurodesis did not significantly interfere with forced vital capacity or forced expiratory volume in 1 s. In addition, minocycline pleurodesis induced scant, loose adhesions in patients with recurrent pneumothorax which did not affect subsequent surgical procedures or outcomes [15 ,18]. &&
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CONCLUSION Although there are a variety of options in the treatment of primary spontaneous pneumothorax, minocycline pleurodesis should play a more important role in this benign disease. Several prospective, randomized trials have confirmed the safety and efficacy of intrapleural minocycline pleurodesis in preventing pneumothorax recurrence. It can be considered an adjunct to standard treatment, after either simple aspiration and drainage or thoracoscopic surgery. Because minocycline pleurodesis is painful and the recurrence rate following aspiration/ drainage and minocycline pleurodesis is not low, future studies should focus on the identification of patients at high risk of recurrence as well as compare the efficacy of different sclerosing agents in specific clinical settings of primary spontaneous pneumothorax. Acknowledgements The study was supported by a research grant from National Science Council, Taiwan (NSC 102-2325-B002-077). Conflicts of interest There are no conflicts of interest.
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