Video-Assisted Thoracoscopic Surgery for Primary Spontaneous Pneumothorax: Effects and Mechanisms of Additional Minocycline Pleurodesis
Date Issued
2004
Date
2004
Author(s)
DOI
zh-TW
Abstract
Primary spontaneous pneumothorax most commonly occurs in young, tall, lean males. The most common cause of primary spontaneous pneumothorax is the rupture of an apical subpleural bleb. The estimated recurrence rate is 23-50% after the first episode and increases to 60-80% after the second pneumothorax. Optimal management of this benign disease has been a matter of debate. Traditionally, open thoracotomy has been considered the definite treatment for patients with recurrence. With this surgical approach, the offending bleb is found and removed, then, pleurodesis or pleurectomy is performed to encourage adhesion formation. While open thoracotomy provides the definite treatment in patients with recurrence, physicians are reluctant to refer patients for this treatment because of a long postoperative recovery, pain, and a high rate of complications. The advancement in video-assisted thoracic surgery (VATS) has enabled bullectomy and pleural abrasion through thoracoscopy to become a viable alternative in the treatment of primary spontaneous pneumothorax. However, problems associated with thoracoscopic management of primary spontaneous pneumothorax remained unsolved. First, the postoperative chest pain has not been completely alleviated and the surgical wounds of VATS have not been cosmetically perfect. Second, the recurrence rate of this procedure ranges between 4 % and 10% in most series and is generally higher than open thoracotomy. In this study, novel approaches were attempted to solve these problems.
Part I: Using Modified Needlescopic VATS in Primary Spontaneous Pneumothorax Recently, the development of technology in the videoscopic field has produced 2-mm and 3-mm needlescopic equipments and instruments for thoracic procedures. Sympathectomy for hyperhidrosis and preoperative diagnostic work-up in general thoracic surgery fields using the needlescopic VATS technique has shown clinically excellent results with less postoperative pain and scarring. The initial reports also suggest that needlescopic VATS is a feasible technique in treating primary spontaneous pneumothorax. While needlescopic surgery may reduce the trauma inflicted on the chest wall, there are still some limitations to its use due to narrow field of vision, lower resolution, and difficulty in handling bulky tissue when compared with conventional VATS. Furthermore, no comparative or prospective studies have been conducted to prove that needlescopic VATS is less painful, equally effective, or more cosmetic. In addition, the patient number was small in these studies and the long-term safety and efficacy of this new technique is unknown. In this study, we used a modified method and port strategy of needlescopic VATS technique to treat primary spontaneous pneumothorax. We compared the feasibility, complications, and short-term outcomes of this procedure with those of conventional VATS procedures. The safety and efficacy of the needlescopic VATS approach for treating primary spontaneous pneumothorax were also evaluated. 1. Needlescopic VATS is technically feasible and provides superior pain control and cosmetic results From April 2001 to April 2002, a total of 63 consecutive patients requiring VATS due to recurrent, persistent, or contralateral spontaneous pneumothorax were enrolled in this study. Patients chose to undergo conventional VATS or needlescopic VATS by his or her own choice after the attending surgeon explained the differences between the two procedures. The cost of needlescopic VATS is higher than that of conventional VATS because the national health insurance program in this country will cover only a part of the disposable equipment. The median age of the patients was 22 years (range: 14 to 48 years; 51 males, 12 females). Of these patients, 15 (23.8%) were smokers. The indications for operation were ipsilateral recurrence in 24 (38.1%), continuous air leaks in 33 (52.4%), and contralateral recurrence in 6 (9.5%). Blebs or bullae were identified in 57 (90.5%) patients. Among these patients, multiple blebs (>3 blebs) were visualized in 20 cases (35.1%), and the most common site for blebs was the upper lobe (86 %). Thirty-four patients chose conventional VATS and 29 chose needlescopic VATS. However, one patient in the needlescopic VATS group was converted to conventional VATS because air leaks could not be found. In the needlescopic VATS group, the initial 9 patients were managed with 2-mm instruments. The 3-mm instruments were used in the remaining 19 patients because one patient had early recurrence caused by a missed bleb. In addition, manipulation of the lung tissue with 2-mm instruments was inconvenient. The two groups did not differ in age, sex, weight, body surface area, smoking status, side involvement, surgical indications, and operative findings. Time of operation, postoperative pain, request of opioid analgesics, and results of treatment were also comparable in each groups. No operative deaths and no major complications were reported in either of the two groups. Three patients (4.8%) had air leaks lasting longer than five days; these patients were managed conservatively. Pleural detachment was noted in one patient after removal of the chest drainage. Subcutaneous hematoma was noted in one patient in the conventional VATS group. Patients underwent followe-up for a duration of 2 to 14 months, with a mean follow-up of 8 months. Only one patient in the conventional VATS group was lost to follow-up. Ipsilateral recurrence of pneumothorax occurred in one patient 3 weeks after the 2-mm needlescopic VATS. He underwent a subsequent conventional VATS and a missed bleb was noted at the lower edge of the right middle lobe of the lung. After surgery, patients returned to work or school very early in the course of this study, with a mean interval of 10.0±2.7 days in the conventional VATS group and 9.9±2.4 days in the needlescopic VATS group. When the groups were compared for residual neuralgia, occasional or persistent pain on the operated side presented in 53% of patients in the conventional VATS group and only in 25% of patients in the needlescopic VATS group (p =0.021). In addition, more patients were very satisfied or satisfied with their scars in the needlescopic VATS group than in the conventional VATS group (86% vs. 75%, p =0.043). 2. Needlescopic VATS is a safe and valid alternative for the treatment of unilateral primary spontaneous pneumothorax From April 2001 to October 2003, 110 patients with primary spontaneous pneumothorax who had undergone a needlescopic VATS procedure were identified. The median age was 21 years (range: 15 to 48 years; 93 males, 17 females), 28 (25.5%) were smokers. The indications for operation were ipsilateral recurrence in 69 (62.7%), continuous air leaks in 18 (16.4%), contralateral recurrence in 13 (11.8 %), bilateral pneumothorax in 4 (3.6%), associated hemothorax in 3 (2.7%), and uncomplicated first episode in 3 (2.7%). The needlescopic VATS procedure was unilateral in 102 patients. Eight patients had a bilateral procedure owing to bilateral pneumothorax (4 patients) or unilateral pneumothorax with obvious blebs or bullae on the contralateral lung by computed tomographic scanning (4 patients). Among the 118 procedures, blebs or bullae were identified in 111 (94.1%) cases, in which multiple blebs (>3 blebs) were visualized in 51 cases (43.2%). The most common site for blebs was the upper lobe (77.1 %). In three cases, the procedure was converted to conventional VATS because air leaks could not be found. The mean operation time was 75.7 + 23.3 minutes. After surgery, additional minocycline pleurodesis was undertaken in 65 cases (55.1%). After the operation, the median visual analog scale rating decreased steadily during the first three postoperative days. Meperidine was requested by 71.2 % of the patients, mainly on the first postoperative day. The mean accumulated dosage of injection was 1.4 + 1.4 ampules. No operative deaths and no major complications were noted. Six patients (5.1%) had air leaks lasting longer than 5 days; these patients were managed conservatively. Pleural detachment was noted in two patients after removal of the chest drainage. One patient was treated with needle aspiration and the other was treated by tube thoracostomy. The mean postoperative hospital stay was 4.2 + 2.4 days. Patients underwent follow-up for a duration between 3 and 32 months, with a mean follow-up of 16 months. Six patients (5.5%) were lost to follow-up. After the operation, patients returned to work or school very early, with a median interval of 7 days. In terms of postoperative residual neuralgia, only 16.3% of patients experienced occasional pain on the operated side. In addition, most patients (73%) were very satisfied or satisfied with their scars. Ipsilateral recurrence of pneumothorax occurred in 8 of the 118 procedures. Among them, 5 recurrences developed within 6 months after the operation. The recurrent pneumothoraces were managed in several ways. Three patients underwent conventional VATS procedures with pleural abrasion. Two patients were treated with a chest tube. The remaining 3 patients had a small pneumothorax (< 15%) and were managed by observation. To identify the risk factors associated with ipsilateral recurrence after needlescopic VATS, we entered 10 perioperative variables, including age, gender, smoking history, operative indications, number of blebs, site of blebs, unilateral or bilateral procedure, use of additional minocycline pleurodesis, dose of requested meperidine, and the presence of complications, into univariate analyses using the Cox proportional hazards regression model. Three variables were significant predictors of recurrence (p < 0.05): the number of identified blebs, unilateral or bilateral procedures, and use of additional minocycline pleurodesis. When 1 or 2 blebs were identified, the recurrence rate was 1.7% (1/60). When no bleb or multiple blebs (> 3) were noted, the recurrence rate was 12.0% (7/58) (p = 0.03). Bilateral procedures had a significantly higher rate of recurrence (31.3%, 5/16) compared to unilateral procedures (2.9%, 3/102) (p < 0.01). Recurrence occurred in 3.1% (2/65) of patients who had additional minocycline pleurodesis and in 11.3% (6/53) of those in whom minocycline was not used (p = 0.02). The multivariate analyses by the Cox proportional hazards regression model revealed that a bilateral procedure and no minocycline pleurodesis were significant and independent predictors of ipsilateral recurrence after needlescopic VATS (p < 0.001 and p = 0.019, respectively). The estimated rates of recurrence after the needlescopic VATS procedures were also significantly different between the unilateral and bilateral procedures. Part II: Effects of Additional Minocycline Pleurodesis after Thoracoscopic Procedures for Primary Spontaneous Pneumothorax Intrapleural instillation of a chemical irritant (chemical pleurodesis) is an effective way to shorten the duration of air leaks and prevent the recurrence of spontaneous pneumothorax in non-surgical patients. Tetracycline, which was the most commonly used irritant, is no longer available. Minocycline, a derivative of tetracycline, is as effective as tetracycline in inducing pleural fibrosis in rabbits. However, published studies with its use in human subjects are limited, with studies of small cohorts of patients focusing on the effect of diminishing air leaks. The safety and long-term efficacy on preventing recurrence of pneumothorax have never been addressed. In the present study, we evaluate the effects of additional minocycline pleurodesis in treating primary spontaneous pneumothorax patients after thoracoscopic procedures by a retrospective study and a prospective randomized clinical trial. We also used animal studies to unveil the underlying mechanisms of minocycline pleurodesis. In addition, we tried to identify markers to predict the degrees of pleurodesis. 1. Minocycline pleurodesis: improved outcome and lower rate of recurrence after thoracoscopic treatment for primary spontaneous pneumothorax Between January 1992 and April 2001, 364 consecutive patients with spontaneous pneumothorax were referred to our thoracic surgical division for VATS surgery. Before April 1994, nothing was administered to the pleural cavity after operation (control group). Since April 1994, additional minocycline pleurodesis was performed for the purpose of decreasing the incidence of prolonged air leaks and ipsilateral recurrence of pneumothorax after operation (minocycline group). The minocycline group consisted of 313 patients; the control group consisted of 51 patients. Their average age of the patients was 25 years (ranging = 13 to 59). Blebs or bullae were identified in 346 (95.1%) patients, and the most common site for blebs was the upper lobe (87 %). The operation duration was 90.3±31.8 minutes (ranging from 40 to 250 minutes). The two groups did not differ in age, sex, weight, smoking status, side involvement, surgical indications, surgical approaches, operative findings, and time of operation. The results of treatment showed that there was no hypersensitivity or adverse reactions for minocycline instillation. Chest pain was a common complaint after minocycline instillation and severe pain that required immediate meperidine injection occurred in 63 patients (20.1%). However, the total amount of meperidine was not significantly different between the two groups. Patients treated with minocycline had significantly shorter periods of chest drainage and postoperative hospital stay. No deaths occurred and no full thoracotomy was needed during and after the treatment. Thirty-one patients (8.5%) had air leaks lasting longer than 5 days. The rate of prolonged air leaks was significantly lower in the minocycline group. Pleural detachment was noted in 6 patients after removal of chest drainage. Hemothorax developed in 2 patients of the minocycline group. In one patient, massive bleeding occurred before instillation of minocycline and mini-thoracotomy was required to stop bleeding. The other patient had hemothorax 10 days after minocycline instillation. He was managed by tube thoracostomy. Wound infection was noted in 2 patients. No patient had pleural empyema in this study. During the postoperative follow-up, recurrent ipsilateral pneumothorax was noted in 14 of the 364 patients, with a significant lower rate in patients with minocycline instillation (2.9% vs. 9.8%, p = 0.033). Using the Kaplan-Meier method, it appears that patients in the minocycline group had a lower rate of recurrence and that the recurrences took place at a later time (p = 0.036 by log-rank test). However, minocycline did not completely prevent recurrence. The median recurrence time was 4.0 (mean = 6.4) months in the control group and 13.3 months (mean = 17.7) in the minocycline group, with a recurrence rate within 6 months of 7.8% and 0.3% respectively (p = 0.002). To determine whether the difference of recurrence was associated with the learning curve of thoracoscopic technique, we stratified the recurrent patients in the minocycline group according to the first, second, and third groups of 100 patients. We found no obvious temporal trends of decreasing recurrence rate during different operation periods. 2. Prospective, randomized trial shows minocycline pleurodesis reduces recurrence rate after thoracoscopic treatment for primary spontaneous pneumothorax Between June 2001 and February 2004, 202 patients with spontaneous pneumothorax were enrolled for this trial. Needlescopic VATS was performed in 142 patients (70%) and conventional VATS in 60 patients (30%). The operation procedures consisted of bullectomy and abrasion of the upper half of the parietal pleura. After the operation, patients were randomized to receive additional minocycline pleurodesis (7mg/kg, minocycline group) or not (control group). The minocycline group consisted of 102 patients, and the control group consisted of 99 patients. Their average age was 25 years (ranging from 15 to 50 years). Of these patients, 57 (28%) were smokers. Blebs or bullae were identified in 190 (94%) patients. Among them, 75 patients (37%) had multiple blebs (> 3 blebs). The mean operation duration was 79 minutes (ranging from 40 to 180 minutes). The two groups did not differ in age, sex, weight, smoking status, side involvement, surgical indications, surgical approaches, operative findings, number of endoscopic stapler cartridge, and time of operation. The results of treatment showed that there was no hypersensitivity or adverse reactions for minocycline instillation. Chest pain was a common complaint after minocycline instillation and around 70% of the patients required meperidine injection. The mean dose of meperidine injection was 2.3 ampules in the minocycline group and 1.4 ampules in the control group (p = 0.002). Patients treated with minocycline had comparable chest drainage duration, postoperative hospital stay, and complication rates as the control group. No deaths occurred and no mini-thoracotomy was needed during and after the treatment. Eight patients (8.5%) had air leaks lasting longer than 5 days. Patients in the minocycline group have trends of a decreased rate of prolonged air leaks (2% vs. 6%, p = 0.1). The patients underwent follow-up for a mean of 15 months (range = 1-32). After discharge from the hospital, patients in each group had a similar duration to return to work or school (with a mean of 8.3 days in the minocycline group vs. 8.2 days in the control group). Postoperative residual neuralgia and pulmonary function were also comparable in both groups. Patients’ pulmonary function test was performed at least 6 month after the operation and showed that the two groups had comparable forced vital capacity (FVC) and forced expiratory volume in one second (FEV1.0). During the postoperative follow-up, recurrent ipsilateral pneumothorax was noted in 2 patients in the minocycline group and 8 patients in the control group (2 % vs. 8%, p = 0.055). When these patients were stratified into low-risk (bleb number = 1 or 2) and high-risk groups (bleb number = 0 or > 3), minocycline pleurodesis decreased the rate of recurrence from 16% to 2 % in the high-risk group (p = 0.03), but had no obvious effects in the low risk group (2% vs. 2%). The results were similar when the Kaplan-Meier method was used to estimate the rate of recurrence after VATS. Part III: Effects and Mechanisms of Additional Minocycline Pleurodesis 1. Combined pleural abrasion and minocycline instillation for best pleurodesis Clinically we have shown that additional minocycline pleurodesis decreases the rate of ipsilateral pneumothorax recurrence in high-risk patients. In addition, minocycline pleurodesis may decrease the rate of prolonged air leaks after thoracoscopic treatment for primary spontaneous pneumothorax. However, the underlying mechanisms remain unknown. We hypothesize that additional minocycline pleurodesis produces better effects of pleurodesis than mechanical pleural abrasion alone, and animal studies were used to test this hypothesis. Thirty six New Zealand white male rabbits weighing between 2.5 and 4.0 kg were randomized into four groups: 1, thoracoscopic parietal pleural abrasion (abrasion group = 10 rabbits), 2, thoracoscopic instillation of minocycline, 7mg/kg (minocycline group = 10 rabbits), 3, a combination of both methods (combination group =10 rabbits), or 4, thoracoscopic examination alone (controlled group = 6 rabbits). After the operation, a soft silastic catheter was inserted into the pleural space. The pleural effusions were collected at 24, 48, and 72 hours, and then the chest tube was removed. The total volume of pleural fluid aspirated was recorded. Pleural fluid analyses included RBC count, WBC count and classification, and IL-6, IL-8, and TGF-
Part I: Using Modified Needlescopic VATS in Primary Spontaneous Pneumothorax Recently, the development of technology in the videoscopic field has produced 2-mm and 3-mm needlescopic equipments and instruments for thoracic procedures. Sympathectomy for hyperhidrosis and preoperative diagnostic work-up in general thoracic surgery fields using the needlescopic VATS technique has shown clinically excellent results with less postoperative pain and scarring. The initial reports also suggest that needlescopic VATS is a feasible technique in treating primary spontaneous pneumothorax. While needlescopic surgery may reduce the trauma inflicted on the chest wall, there are still some limitations to its use due to narrow field of vision, lower resolution, and difficulty in handling bulky tissue when compared with conventional VATS. Furthermore, no comparative or prospective studies have been conducted to prove that needlescopic VATS is less painful, equally effective, or more cosmetic. In addition, the patient number was small in these studies and the long-term safety and efficacy of this new technique is unknown. In this study, we used a modified method and port strategy of needlescopic VATS technique to treat primary spontaneous pneumothorax. We compared the feasibility, complications, and short-term outcomes of this procedure with those of conventional VATS procedures. The safety and efficacy of the needlescopic VATS approach for treating primary spontaneous pneumothorax were also evaluated. 1. Needlescopic VATS is technically feasible and provides superior pain control and cosmetic results From April 2001 to April 2002, a total of 63 consecutive patients requiring VATS due to recurrent, persistent, or contralateral spontaneous pneumothorax were enrolled in this study. Patients chose to undergo conventional VATS or needlescopic VATS by his or her own choice after the attending surgeon explained the differences between the two procedures. The cost of needlescopic VATS is higher than that of conventional VATS because the national health insurance program in this country will cover only a part of the disposable equipment. The median age of the patients was 22 years (range: 14 to 48 years; 51 males, 12 females). Of these patients, 15 (23.8%) were smokers. The indications for operation were ipsilateral recurrence in 24 (38.1%), continuous air leaks in 33 (52.4%), and contralateral recurrence in 6 (9.5%). Blebs or bullae were identified in 57 (90.5%) patients. Among these patients, multiple blebs (>3 blebs) were visualized in 20 cases (35.1%), and the most common site for blebs was the upper lobe (86 %). Thirty-four patients chose conventional VATS and 29 chose needlescopic VATS. However, one patient in the needlescopic VATS group was converted to conventional VATS because air leaks could not be found. In the needlescopic VATS group, the initial 9 patients were managed with 2-mm instruments. The 3-mm instruments were used in the remaining 19 patients because one patient had early recurrence caused by a missed bleb. In addition, manipulation of the lung tissue with 2-mm instruments was inconvenient. The two groups did not differ in age, sex, weight, body surface area, smoking status, side involvement, surgical indications, and operative findings. Time of operation, postoperative pain, request of opioid analgesics, and results of treatment were also comparable in each groups. No operative deaths and no major complications were reported in either of the two groups. Three patients (4.8%) had air leaks lasting longer than five days; these patients were managed conservatively. Pleural detachment was noted in one patient after removal of the chest drainage. Subcutaneous hematoma was noted in one patient in the conventional VATS group. Patients underwent followe-up for a duration of 2 to 14 months, with a mean follow-up of 8 months. Only one patient in the conventional VATS group was lost to follow-up. Ipsilateral recurrence of pneumothorax occurred in one patient 3 weeks after the 2-mm needlescopic VATS. He underwent a subsequent conventional VATS and a missed bleb was noted at the lower edge of the right middle lobe of the lung. After surgery, patients returned to work or school very early in the course of this study, with a mean interval of 10.0±2.7 days in the conventional VATS group and 9.9±2.4 days in the needlescopic VATS group. When the groups were compared for residual neuralgia, occasional or persistent pain on the operated side presented in 53% of patients in the conventional VATS group and only in 25% of patients in the needlescopic VATS group (p =0.021). In addition, more patients were very satisfied or satisfied with their scars in the needlescopic VATS group than in the conventional VATS group (86% vs. 75%, p =0.043). 2. Needlescopic VATS is a safe and valid alternative for the treatment of unilateral primary spontaneous pneumothorax From April 2001 to October 2003, 110 patients with primary spontaneous pneumothorax who had undergone a needlescopic VATS procedure were identified. The median age was 21 years (range: 15 to 48 years; 93 males, 17 females), 28 (25.5%) were smokers. The indications for operation were ipsilateral recurrence in 69 (62.7%), continuous air leaks in 18 (16.4%), contralateral recurrence in 13 (11.8 %), bilateral pneumothorax in 4 (3.6%), associated hemothorax in 3 (2.7%), and uncomplicated first episode in 3 (2.7%). The needlescopic VATS procedure was unilateral in 102 patients. Eight patients had a bilateral procedure owing to bilateral pneumothorax (4 patients) or unilateral pneumothorax with obvious blebs or bullae on the contralateral lung by computed tomographic scanning (4 patients). Among the 118 procedures, blebs or bullae were identified in 111 (94.1%) cases, in which multiple blebs (>3 blebs) were visualized in 51 cases (43.2%). The most common site for blebs was the upper lobe (77.1 %). In three cases, the procedure was converted to conventional VATS because air leaks could not be found. The mean operation time was 75.7 + 23.3 minutes. After surgery, additional minocycline pleurodesis was undertaken in 65 cases (55.1%). After the operation, the median visual analog scale rating decreased steadily during the first three postoperative days. Meperidine was requested by 71.2 % of the patients, mainly on the first postoperative day. The mean accumulated dosage of injection was 1.4 + 1.4 ampules. No operative deaths and no major complications were noted. Six patients (5.1%) had air leaks lasting longer than 5 days; these patients were managed conservatively. Pleural detachment was noted in two patients after removal of the chest drainage. One patient was treated with needle aspiration and the other was treated by tube thoracostomy. The mean postoperative hospital stay was 4.2 + 2.4 days. Patients underwent follow-up for a duration between 3 and 32 months, with a mean follow-up of 16 months. Six patients (5.5%) were lost to follow-up. After the operation, patients returned to work or school very early, with a median interval of 7 days. In terms of postoperative residual neuralgia, only 16.3% of patients experienced occasional pain on the operated side. In addition, most patients (73%) were very satisfied or satisfied with their scars. Ipsilateral recurrence of pneumothorax occurred in 8 of the 118 procedures. Among them, 5 recurrences developed within 6 months after the operation. The recurrent pneumothoraces were managed in several ways. Three patients underwent conventional VATS procedures with pleural abrasion. Two patients were treated with a chest tube. The remaining 3 patients had a small pneumothorax (< 15%) and were managed by observation. To identify the risk factors associated with ipsilateral recurrence after needlescopic VATS, we entered 10 perioperative variables, including age, gender, smoking history, operative indications, number of blebs, site of blebs, unilateral or bilateral procedure, use of additional minocycline pleurodesis, dose of requested meperidine, and the presence of complications, into univariate analyses using the Cox proportional hazards regression model. Three variables were significant predictors of recurrence (p < 0.05): the number of identified blebs, unilateral or bilateral procedures, and use of additional minocycline pleurodesis. When 1 or 2 blebs were identified, the recurrence rate was 1.7% (1/60). When no bleb or multiple blebs (> 3) were noted, the recurrence rate was 12.0% (7/58) (p = 0.03). Bilateral procedures had a significantly higher rate of recurrence (31.3%, 5/16) compared to unilateral procedures (2.9%, 3/102) (p < 0.01). Recurrence occurred in 3.1% (2/65) of patients who had additional minocycline pleurodesis and in 11.3% (6/53) of those in whom minocycline was not used (p = 0.02). The multivariate analyses by the Cox proportional hazards regression model revealed that a bilateral procedure and no minocycline pleurodesis were significant and independent predictors of ipsilateral recurrence after needlescopic VATS (p < 0.001 and p = 0.019, respectively). The estimated rates of recurrence after the needlescopic VATS procedures were also significantly different between the unilateral and bilateral procedures. Part II: Effects of Additional Minocycline Pleurodesis after Thoracoscopic Procedures for Primary Spontaneous Pneumothorax Intrapleural instillation of a chemical irritant (chemical pleurodesis) is an effective way to shorten the duration of air leaks and prevent the recurrence of spontaneous pneumothorax in non-surgical patients. Tetracycline, which was the most commonly used irritant, is no longer available. Minocycline, a derivative of tetracycline, is as effective as tetracycline in inducing pleural fibrosis in rabbits. However, published studies with its use in human subjects are limited, with studies of small cohorts of patients focusing on the effect of diminishing air leaks. The safety and long-term efficacy on preventing recurrence of pneumothorax have never been addressed. In the present study, we evaluate the effects of additional minocycline pleurodesis in treating primary spontaneous pneumothorax patients after thoracoscopic procedures by a retrospective study and a prospective randomized clinical trial. We also used animal studies to unveil the underlying mechanisms of minocycline pleurodesis. In addition, we tried to identify markers to predict the degrees of pleurodesis. 1. Minocycline pleurodesis: improved outcome and lower rate of recurrence after thoracoscopic treatment for primary spontaneous pneumothorax Between January 1992 and April 2001, 364 consecutive patients with spontaneous pneumothorax were referred to our thoracic surgical division for VATS surgery. Before April 1994, nothing was administered to the pleural cavity after operation (control group). Since April 1994, additional minocycline pleurodesis was performed for the purpose of decreasing the incidence of prolonged air leaks and ipsilateral recurrence of pneumothorax after operation (minocycline group). The minocycline group consisted of 313 patients; the control group consisted of 51 patients. Their average age of the patients was 25 years (ranging = 13 to 59). Blebs or bullae were identified in 346 (95.1%) patients, and the most common site for blebs was the upper lobe (87 %). The operation duration was 90.3±31.8 minutes (ranging from 40 to 250 minutes). The two groups did not differ in age, sex, weight, smoking status, side involvement, surgical indications, surgical approaches, operative findings, and time of operation. The results of treatment showed that there was no hypersensitivity or adverse reactions for minocycline instillation. Chest pain was a common complaint after minocycline instillation and severe pain that required immediate meperidine injection occurred in 63 patients (20.1%). However, the total amount of meperidine was not significantly different between the two groups. Patients treated with minocycline had significantly shorter periods of chest drainage and postoperative hospital stay. No deaths occurred and no full thoracotomy was needed during and after the treatment. Thirty-one patients (8.5%) had air leaks lasting longer than 5 days. The rate of prolonged air leaks was significantly lower in the minocycline group. Pleural detachment was noted in 6 patients after removal of chest drainage. Hemothorax developed in 2 patients of the minocycline group. In one patient, massive bleeding occurred before instillation of minocycline and mini-thoracotomy was required to stop bleeding. The other patient had hemothorax 10 days after minocycline instillation. He was managed by tube thoracostomy. Wound infection was noted in 2 patients. No patient had pleural empyema in this study. During the postoperative follow-up, recurrent ipsilateral pneumothorax was noted in 14 of the 364 patients, with a significant lower rate in patients with minocycline instillation (2.9% vs. 9.8%, p = 0.033). Using the Kaplan-Meier method, it appears that patients in the minocycline group had a lower rate of recurrence and that the recurrences took place at a later time (p = 0.036 by log-rank test). However, minocycline did not completely prevent recurrence. The median recurrence time was 4.0 (mean = 6.4) months in the control group and 13.3 months (mean = 17.7) in the minocycline group, with a recurrence rate within 6 months of 7.8% and 0.3% respectively (p = 0.002). To determine whether the difference of recurrence was associated with the learning curve of thoracoscopic technique, we stratified the recurrent patients in the minocycline group according to the first, second, and third groups of 100 patients. We found no obvious temporal trends of decreasing recurrence rate during different operation periods. 2. Prospective, randomized trial shows minocycline pleurodesis reduces recurrence rate after thoracoscopic treatment for primary spontaneous pneumothorax Between June 2001 and February 2004, 202 patients with spontaneous pneumothorax were enrolled for this trial. Needlescopic VATS was performed in 142 patients (70%) and conventional VATS in 60 patients (30%). The operation procedures consisted of bullectomy and abrasion of the upper half of the parietal pleura. After the operation, patients were randomized to receive additional minocycline pleurodesis (7mg/kg, minocycline group) or not (control group). The minocycline group consisted of 102 patients, and the control group consisted of 99 patients. Their average age was 25 years (ranging from 15 to 50 years). Of these patients, 57 (28%) were smokers. Blebs or bullae were identified in 190 (94%) patients. Among them, 75 patients (37%) had multiple blebs (> 3 blebs). The mean operation duration was 79 minutes (ranging from 40 to 180 minutes). The two groups did not differ in age, sex, weight, smoking status, side involvement, surgical indications, surgical approaches, operative findings, number of endoscopic stapler cartridge, and time of operation. The results of treatment showed that there was no hypersensitivity or adverse reactions for minocycline instillation. Chest pain was a common complaint after minocycline instillation and around 70% of the patients required meperidine injection. The mean dose of meperidine injection was 2.3 ampules in the minocycline group and 1.4 ampules in the control group (p = 0.002). Patients treated with minocycline had comparable chest drainage duration, postoperative hospital stay, and complication rates as the control group. No deaths occurred and no mini-thoracotomy was needed during and after the treatment. Eight patients (8.5%) had air leaks lasting longer than 5 days. Patients in the minocycline group have trends of a decreased rate of prolonged air leaks (2% vs. 6%, p = 0.1). The patients underwent follow-up for a mean of 15 months (range = 1-32). After discharge from the hospital, patients in each group had a similar duration to return to work or school (with a mean of 8.3 days in the minocycline group vs. 8.2 days in the control group). Postoperative residual neuralgia and pulmonary function were also comparable in both groups. Patients’ pulmonary function test was performed at least 6 month after the operation and showed that the two groups had comparable forced vital capacity (FVC) and forced expiratory volume in one second (FEV1.0). During the postoperative follow-up, recurrent ipsilateral pneumothorax was noted in 2 patients in the minocycline group and 8 patients in the control group (2 % vs. 8%, p = 0.055). When these patients were stratified into low-risk (bleb number = 1 or 2) and high-risk groups (bleb number = 0 or > 3), minocycline pleurodesis decreased the rate of recurrence from 16% to 2 % in the high-risk group (p = 0.03), but had no obvious effects in the low risk group (2% vs. 2%). The results were similar when the Kaplan-Meier method was used to estimate the rate of recurrence after VATS. Part III: Effects and Mechanisms of Additional Minocycline Pleurodesis 1. Combined pleural abrasion and minocycline instillation for best pleurodesis Clinically we have shown that additional minocycline pleurodesis decreases the rate of ipsilateral pneumothorax recurrence in high-risk patients. In addition, minocycline pleurodesis may decrease the rate of prolonged air leaks after thoracoscopic treatment for primary spontaneous pneumothorax. However, the underlying mechanisms remain unknown. We hypothesize that additional minocycline pleurodesis produces better effects of pleurodesis than mechanical pleural abrasion alone, and animal studies were used to test this hypothesis. Thirty six New Zealand white male rabbits weighing between 2.5 and 4.0 kg were randomized into four groups: 1, thoracoscopic parietal pleural abrasion (abrasion group = 10 rabbits), 2, thoracoscopic instillation of minocycline, 7mg/kg (minocycline group = 10 rabbits), 3, a combination of both methods (combination group =10 rabbits), or 4, thoracoscopic examination alone (controlled group = 6 rabbits). After the operation, a soft silastic catheter was inserted into the pleural space. The pleural effusions were collected at 24, 48, and 72 hours, and then the chest tube was removed. The total volume of pleural fluid aspirated was recorded. Pleural fluid analyses included RBC count, WBC count and classification, and IL-6, IL-8, and TGF-
Subjects
minocycline
肋膜沾粘
胸腔鏡手術
氣胸
迷你內視鏡手術
TGF-beta
pleurodesis
thoracoscopy
pneumothorax
needlescope
SDGs
Type
text
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