(Chest. 2004;125:50-55.)
© 2004
American College of Chest Physicians
Effects of Additional Minocycline Pleurodesis After Thoracoscopic Procedures for Primary Spontaneous Pneumothorax*
Jin-Shing Chen, MD;
Hsao-Hsun Hsu, MD;
Shuenn-Wen Kuo, MD;
Pi-Ru Tsai, RN;
Robert J. Chen, MD, MPH;
Jang-Ming Lee, MD, PhD and
Yung-Chie Lee, MD, PhD
* From the Division of Thoracic Surgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Correspondence to: Yung-Chie Lee, MD, PhD, Department of Surgery, National Taiwan University Hospital, No. 7, Chung Shan South Rd, Taipei, Taiwan; e-mail: wuj{at}ha.mc.ntu.edu.tw
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Abstract
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Study objectives: To evaluate the safety and efficacy of additional minocycline pleurodesis after thoracoscopic treatment of primary spontaneous pneumothorax.
Design: Retrospective comparative study with a historical control.
Setting: Thoracic surgical division of a university-affiliated tertiary medical center.
Patients and methods: Between April 1994 and April 2001, 313 consecutive patients (minocycline group) with primary spontaneous pneumothorax were treated by video-assisted thoracoscopic surgery. The procedures included resection of the blebs and mechanical pleurodesis by scrubbing the parietal pleura. After operation, minocycline hydrochloride, 7 mg/kg, was instilled into the pleural space through a thoracostomy tube. The control group consisted of 51 consecutive patients who underwent the same thoracoscopic procedures alone for primary spontaneous pneumothorax between January 1992 and April 1994.
Results: There was no significant difference between the two groups in terms of demographic data, operative findings, and operation time. Chest pain was a common complaint after minocycline pleurodesis, but the total doses of requested analgesics were comparable in both groups. The rate of prolonged air leaks was significantly lower in the minocycline group (7.0% vs 17.6%, p = 0.025). Patients treated with minocycline had shorter periods of postoperative chest drainage and hospitalization. The ipsilateral recurrence rate was also significantly lower in these patients (2.9% vs 9.8%, p = 0.033).
Conclusions: Minocycline pleurodesis is a safe and convenient procedure that may improve the outcome and reduce the rate of recurrence after thoracoscopic treatment for primary spontaneous pneumothorax. A randomized control study may be needed to confirm the findings.
Key Words: minocycline • pleurodesis • primary spontaneous pneumothorax • thoracoscopy
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Introduction
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Primary spontaneous pneumothorax most commonly occurs in young, tall, lean male subjects.1
2
The estimated recurrence rate is 23 to 50% after the first episode and increases to 80% after the third pneumothorax.3
Optimal management of this benign disease has been a matter of debate until recently, when some consensus of treatment guidelines were reached.4
Traditionally, open thoracotomy has been considered the definite treatment for patients with recurrence to find the offending bleb, remove it, and do some manipulation (pleurodesis or pleurectomy) to encourage adhesion formation.5
6
7
Physicians, however, are reluctant to refer patients for this treatment because of a long postoperative recovery period, considerable postoperative pain, and a high instance of complications. Recent advances in video-assisted thoracoscopic surgery (VATS) that combine bullectomy with pleural abrasion provide a feasible alternative for treating primary spontaneous pneumothorax.8
9
Unfortunately, the recurrence rate of this procedure ranges between 4% and 7% in most series and is generally higher than open thoracotomy.10
11
12
In addition, a leaking bleb may also be missed or pleural abrasion may be incomplete. As a result, the efficacy of VATS is questioned, and more aggressive procedures such as pleurectomy are sometimes performed to enhance the effects of pleural symphysis.
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 nonsurgical patients.13
14
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.15
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.16
The safety and long-term efficacy on preventing recurrence of pneumothorax have never been addressed. In the present study, we report our experience of additional minocycline pleurodesis in treating primary spontaneous pneumothorax in patients after thoracoscopic procedures. The effects of this adjuvant therapy were evaluated by comparing the outcomes of the patients who underwent thoracoscopic procedures alone with those who underwent additional minocycline pleurodesis.
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Materials and Methods
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Between January 1992 and April 2001, 398 consecutive patients with spontaneous pneumothorax were referred to our thoracic surgical division for VATS. 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 indications for operation included ipsilateral recurrence, continuous air leaks for > 3 days, contralateral recurrence, presence of hemothorax, or uncomplicated first episode. Informed consents were obtained from the patients after thorough explanations. Patients > 60 years of age or with preexisting pulmonary diseases were excluded from this study to avoid patients with secondary pneumothorax. In addition, patients who had a history of thoracotomy or thoracoscopic procedures on the involved side were also excluded from the analyses.
Operative Technique of VATS
The operation procedures and technique were identical in both groups and were described previously.17
In brief, under general anesthesia using intubation with a double-lumen endotracheal tube, the patients were placed in a lateral decubitus position, and the ipsilateral lung was deflated. A 10-mm, 30° telescope (Karl Storz; Tuttlingen, Germany) was first inserted through the previous chest tube insertion hole to examine the pleural cavity. If the chest tube wound was not available, a 12-mm port was made at the sixth or seventh intercostal space. Two 15-mm skin incisions were made at the third or fourth intercostal space, anterior and posterior axillary lines. Light pleural adhesions were freed using electrocautery. When blebs were identified, they were excised with endoscopic staplers. Blind apical stapling was done if no bleb could be identified. The upper half of the parietal surface was abraded by inserting the dissector with a gauze pledget or strip of a diathermy scratch pad through the port sites. Conversion to transaxillary minithoracotomy was performed when an open suturing technique was indicated, dense or massive adhesions were encountered, or air leaks were not found. After postoperative lung reinflation, normal saline solution was instilled to check for air leaks. A chest tube was placed in the apex through one of the insertion wounds. The surgical specimens were routinely sent for pathologic examination.
Postoperative Care and Minocycline Pleurodesis
The patients were extubated in the operating theater and observed for 1 to 2 h in the recovery room. The tube was connected to a low-pressure suction system of approximately - 10 to - 20 cm H2O. Postoperative analgesics include routine oral nonsteroid analgesics and acetaminophen. IM meperidine hydrochloride (50 mg per ampule) was administered every 4 to 6 h according to the patient’s request if the pain became intolerable, could not be relieved by oral analgesics, and visual analog scale (zero represented no pain and 10 represented intractable pain) was > 7. Chest radiography was performed immediately after operation or the next morning.
In those patients with additional minocycline pleurodesis, 20 mL of 2% lidocaine hydrochloride (400 mg) followed by a solution of 20 mL of normal saline solution containing 300 mg or 400 mg (7 mg/kg) of minocycline was instilled into the pleural cavity through the thoracostomy tube. The rubber tube connecting the chest tube and chest bottle was raised 40 to 60 cm above the patient to trap the minocycline but allow air to pass under pressure.18
Patients were repositioned every 30 min so that the minocycline could contact all pleural surfaces. Side effects and complaints of the patient were recorded. The rubber tube was lowered 6 to 8 h later. To optimize the effects of pleural symphysis, minocycline was usually administered after full expansion of the lung. However, in those patients who had persistent air leaks and could not fully inflate their lung, minocycline was still used after 4 to 7 days of waiting. The tube was removed in both groups when the lung was fully expanded and no air leaks were noted in a 24-h period.
Data Collection and Analysis
The clinical data, operative findings, operation time, durations of postoperative chest drainage, length of hospital stay, and complications were collected from the medical records. The requested doses of meperidine were collected from the nursing records. Patients were followed up between 1 month and 120 months (mean, 39 months) during clinical visits or by telephone conversation. Continuous variables such as age or weight were expressed as the mean ± SD and analyzed by the two-sample t test. Categorical variables such as gender or smoking status were presented by frequency (percentage) and analyzed by the Fisher exact test. Freedom from recurrence was analyzed by the Kaplan-Meier method, and comparisons were made by the log-rank test; p < 0.05 was considered significant.
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Results
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Between 1992 and 2001, a total of 364 patients with primary spontaneous pneumothorax were enrolled in this study. The minocycline group consisted of 313 patients, and the control group consisted of 51 patients. The demographic data and operative findings of these patients are shown in Table 1
. Their average age was 25 years (range, 13 to 59 years). Blebs or bullae were identified in 346 patients (95.1%), and the most common site for blebs was the upper lobe (87%). Conversion to transaxillary minithoracotomy was performed owing to dense adhesions (4 patients), air leaks that cannot be identified (17 patients), or open suturing technique for pulmonary resection (57 patients). The operation durations were 90.3 ± 31.8 min (range, 40 to 250 min). 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 are summarized in Table 2
. There were 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 > 5 days. One of them had a large air leak from the staple line. He underwent minithoracotomy and apical pleurectomy 10 days after the original operation. The remaining patients were managed conservatively. The rate of prolonged air leaks was significantly lower in the minocycline group. Pleural detachment was noted in six patients after removal of chest drainage. Hemothorax developed in two patients of the minocycline group. In one patient, massive bleeding occurred before instillation of minocycline, and minithoracotomy was required to stop bleeding. The other patient had hemothorax 10 days after minocycline instillation, and he was managed by tube thoracostomy. Wound infection was noted in two 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). The difference in recurrence between the two groups was not affected by conversion transaxillary minithoracotomy. When those minithoracotomy patients were excluded, the recurrence rate was 2.4% (6 of 248 patients) in the minocycline group and 10.5% (4 of 38 patients) in the control group (p = 0.031). Using the Kaplan-Meier method, the rates of freedom from recurrence in both groups are plotted in Figure 1
. The two curves diverged almost immediately after operation. During the total follow-up period, there was no convergence between the two curves. 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), although minocycline did not completely prevent recurrence. The median recurrence time was 4.0 months (mean, 6.4 months) in the control group and 13.3 months (mean, 17.7 months) 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 minocycline group according to the first, second, and third groups of 100 patients and found that there were no obvious temporal trends of decreasing recurrence rate during different operation periods (Fig 2
). We also investigated whether the recurrence was associated with multiple blebs (three or more blebs) of the involved lung. In the control group, multiple blebs were noted in 40% (2 of 5 patients) of the recurrent patients and 24% (11 of 46 patients) of the nonrecurrent patients. In the minocycline group, multiple blebs were noted in 22% (2 of 9 patients) of the recurrent patients and 29% (89 of 304 patients) of the nonrecurrent patients. However, the difference of multiple-bleb rates between recurrent and nonrecurrent patients in either group was not statistically significant. The recurrent pneumothoraces were managed in a variety of fashions. In six patients with a small loculated pneumothorax, observation was undertaken. One patient was treated with a chest tube, six patients underwent repeated VATS procedure with pleural abrasion, and one patient underwent minithoracotomy with partial pleurectomy.
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Figure 1.. Freedom from recurrent pneumothorax in each group after thoracoscopic procedures (p = 0.037 by the log-rank test). The follow-up time is divided into two periods by hatch marks because all recurrences occurred within 48 months and the cumulative recurrence-free curves became constant from 48 to 120 months. The number of patients at risk for each 6-month period is indicated under the corresponding time.
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Figure 2.. Stratification of recurrence rate by different treatment groups and operation periods. The number of recurrent patients over the number of patients operated on in the specific time period is indicated in parentheses.
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Discussion
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Since the introduction of VATS in the management of spontaneous pneumothorax in 1990,19
several modalities in the management of blebs and pleurae have been reported with variable results. Blebs are generally removed or ligated under standardized procedures. Controversies, however, have developed concerning pleural symphysis. Methods of pleural symphysis have included mechanical abrasion and instillation of chemical irritants. Each method can reduce the rate of recurrence to a certain degree.10
11
12
20
However, a combination of two methods after thoracoscopic bullectomy has rarely been mentioned in the literature. In our study, additional minocycline pleurodesis resulted in significant decrease in the rate of prolonged air leaks, duration of postoperative chest drainage and hospital stay, and the incidence of ipsilateral recurrence (from 9.8% to 2.9%) of primary spontaneous pneumothorax after VATS bullectomy and pleural abrasion. In addition, the recurrence rate of 2.9% in the minocycline group was also favorable as compared with series of VATS bullectomy with either mechanical abrasion (4.6 to 7%)10
11
12
or chemical pleurodesis (4 to 9%).20
21
The beneficial effect of minocycline may be due to combined chemical and mechanical pleurodesis that inflames the entire pleural surface more evenly and thoroughly. This effect hastens the healing of blebs that are occasionally missed during the thoracoscopic procedures and prompts symphysis of pleura to prevent the recurrence of pneumothorax.
Intrapleural instillation of chemical irritants (tetracycline, minocycline, and talc) has been used to decrease the rate of recurrence or hasten the healing of air leaks in nonsurgical treatment of spontaneous pneumothorax. Tetracycline, which was the most widely used agent, reduced the recurrence rate from 41 to 25% in a randomized clinical trial,14
but it is no longer available. Talc poudrage has the lowest recurrence rate,22
23
but it causes granuloma formation and is reserved for malignant effusions. In this study, minocycline was used for chemical pleurodesis because it is a derivative of tetracycline and shares the same merits of easily administered, safe, inexpensive ($5 in US dollars for 100 mg), and widely available. Minocycline also compared favorable to tetracycline for producing pleurodesis in rabbits.15
In addition, the instillation of 7 mg/kg of minocycline obtains satisfactory results in controlling postoperative air leaks and malignant pleural effusions in humans.16
Chest pain was the most common problem associated with minocycline pleurodesis. While a large dose of intrapleural lidocaine (400 mg) was administered in this study, meperidine was immediately required in 20.1% of our patients to relieve severe pain. Nevertheless, the total amount of meperidine requested in minocycline group was not significantly increased. Another possible complication of minocycline instillation is hemothorax. In the experimental rabbit model, hemothorax developed when > 20 mg/kg was instilled.15
One of our patients also acquired hemothorax 10 days after minocycline instillation. Because he was treated with only 7 mg/kg of minocycline, the causal relationship between minocycline and hemothorax in this patient remained unknown. In general, minocycline instillation was safe, and no patient had pleural empyema. However, we did witness a postoperative lobectomy patient who acquired a severe anaphylactic reaction after minocycline instillation. Bronchoscopy revealed a leaking fistula at the bronchial stump, which may have caused aspiration of the irritant drug into the airway. We therefore discourage the use of intrapleural minocycline for secondary pneumothorax patients with a visible fistula on bronchoscopy. Other systemic side effects of minocycline such as neutropenia, thrombocytopenia, jaundice, or abnormal renal function were not noticed in our patients, but the possibility still cannot be completely eliminated because blood tests were not routinely performed after minocycline instillation.
Although combined mechanical and chemical pleurodesis seemed to offer a promising alternative in treating primary spontaneous pneumothorax, our results also showed that additional minocycline pleurodesis did not completely prevent recurrence after thoracoscopic procedures. When compared with the control group, ipsilateral recurrence also developed in the minocycline group, albeit with a lower rate and slower trends. This suggests that the effect of pleural adhesions induced by minocycline may not persist with time. The same phenomenon was also observed in rabbits that early pleural fibrosis induced by minocycline faded gradually after 6 months.24
However, the effect of minocycline is still significant in this study because many of the recurrences happened within this period.14
We acknowledge that this is a retrospective study and the comparison was based on a historical control. The relatively poor outcome and higher recurrence rate after thoracoscopic treatment in the control group may partially be related to the initial learning curve of the procedures or uneven distribution of patients between treatment groups, although the distribution of recurrence in minocycline group did not reveal obvious trends during different time periods. Nevertheless, the large cohort of patients in this study did provide the rationale that minocycline pleurodesis can be safely applied in primary spontaneous patients undergoing thoracoscopic procedures. In addition, this adjuvant also shows a trend toward improved outcome and decreased recurrence of these patients. Further prospective research that includes randomized design and long-term follow-up are needed to rigorously test the efficacy of this treatment.
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Footnotes
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Abbreviation: VATS = video-assisted thoracoscopic surgery
Received for publication February 27, 2003.
Accepted for publication July 30, 2003.
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References
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Abstract
Introduction
