Comparison of the Effectiveness of Tetracycline and Minocycline as Pleural Sclerosing Agents in Rabbits

doi:10.1378/chest.106.2.577

Chest

Volume 106, Issue 2, August 1994, Pages 577-582

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Parenteral tetracycline, one of the most commonly used agents for producing pleurodesis, is no longer available because of stricter regulations governing the manufacturing process. The objective of this project was to determine whether minocycline, a tetracycline derivative, is an effective sclerosant in an experimental model in rabbits. We also studied the relationship of the dose and the volume injected to the degree of pleurodesis. The following medications were instilled intrapleurally in anesthetized male rabbits: tetracycline, 35 mg/kg; or minocycline, 4, 7, 10, or 20 mg/kg, diluted to a total volume of 1 or 2 ml of bacteriostatic saline solution; or minocycline, 40 mg/kg, diluted to a total volume of 2 ml of the solution. Twenty-eight days after the instillation, the animals were killed. The pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The degree of pleurodesis grossly and microscopically after the injection of 7, 10, 20, or 40 mg/kg of minocycline was comparable to that after the injection of 35 mg/kg of tetracycline, while the dose of 4 mg/kg was less effective. In the animals who received the higher doses of minocycline intrapleurally (ie ≥20 mg/kg), there was an excess mortality both early (x²=3.61, 0.05 < p<0.10) and late (x²⁼11.0, p<0.005) which appeared to be related to the development of hemothorax. The intrapleural injection of the tetracycline derivatives was significantly (p<0.05) more effective when the total volume of the solution was 2 ml rather than I ml. The present study demonstrates that minocycline is an effective agent for producing pleurodesis in the rabbit. Minocycline given intrapleurally at doses of 7 mg/kg or above is comparable to tetracycline, 35 mg/kg. Higher doses of minocycline (≥20 mg/kg) produce a high mortality that seems to be related to hemothorax. Since, in humans, a large experience confirms only 20 mg/kg of tetracycline is needed to produce adequate pleurodesis safely, we recommend a dose of 4 mg/kg of minocycline for the production of pleurodesis.

Section snippets

Methods

New Zealand white male rabbits weighing 2.5 to 4.0 kg were lightly anesthetized with ketamine hydrochloride, 35 mg/kg, plus xylazine hydrochloride, 5 mg/kg intramuscularly. The thorax was prepared for aseptic surgery by shaving the right chest wall and then cleaning it with povidone-iodine and alcohol. A 3-cm skin incision was made midway between the spine and the sternum. The muscles in the seventh or eighth intercostal space were bluntly dissected to allow exposition of the parietal pleura.

Results

There appeared to be a greater mortality both early and late in the animals who received the higher doses of minocycline intrapleurally (Table 1). A total of 11 rabbits died within the first 24 h. Interestingly, 7 of the 11 deaths occurred in animals who had received 20 or 40 mg/kg of minocycline. The early death rate in the rabbits that received 20 or 40 mg/kg minocycline (7/41 = 17 percent) was higher than that in the rabbits that received the other medications (4/82=5 percent), and this

Discussion

The present study demonstrates that minocycline is an effective agent for producing pleurodesis in the rabbit model. Minocycline given intrapleurally at doses of 7 mg/kg or above are comparable to tetracycline, 35 mg/kg, in producing a pleurodesis. Higher doses of minocycline (≥20 mg/kg) produce a high mortality that seems to be related to hemothorax. The degree of pleurodesis is significantly greater when the total volume of the sclerosant is 2 ml rather than 1 ml.

The mechanism through which

Acknowledgments

We would like to acknowledge the contributions of Judi Despars in caring for the animals after the intrapleural injection of the sclerosants and Dory Oliver in preparing the slides for microscopic examination.

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Cited by (83)

Giants in chest medicine: Richard W. Light, MD
2014, Chest
Chemical pleurodesis for prolonged postoperative air leak in primary spontaneous pneumothorax
2014, Journal of the Formosan Medical Association
Citation Excerpt :
Recently, chemical pleurodesis has been employed in an attempt to stop air leaks and decrease the length of hospital stay after pulmonary resection.7–9 Minocycline, a derivative of tetracycline, is effective in inducing pleural fibrosis and adhesions in rabbits.10,11 In previous studies, we found that minocycline pleurodesis is a safe and convenient procedure that is associated with a lower rate of recurrence after thoracoscopic treatment of PSP.7,8
Prolonged air leak is the most common complication after thoracoscopic operation for primary spontaneous pneumothorax (PSP), and the role of chemical pleurodesis in treating air leaks remains unclear. This study evaluated the safety and efficacy of chemical pleurodesis with a comparison between minocycline and OK-432.
Between 1994 and 2011, 1083 PSP patients were treated by thoracoscopic operation. After the operation, patients with persistent air leak for 3 days or more were managed by minocycline or OK-432 pleurodesis. The demographic and outcome data for these patients were collected by retrospective chart review.
Seventy-nine patients (7.3%) with prolonged air leak after thoracoscopy underwent minocycline pleurodesis (60 patients) or OK-432 pleurodesis (19 patients) as the primary treatment. The primary success rate was 63% (38/60) for minocycline pleurodesis and 95% (18/19) for OK-432 pleurodesis (p = 0.009). Postpleurodesis pain was common and comparable between the two groups. No major complications were noted after a total of 121 treatments. Patients undergoing primary OK-432 pleurodesis had shorter durations of postpleurodesis chest drainage (mean 8.5 vs. 2.3 days; p < 0.001) and postoperative hospital stay (mean 11.9 vs. 6.8 days; p < 0.001) than those undergoing primary minocycline pleurodesis. After a median follow-up of 16 months, recurrence was noted in one patient in the OK-432 group and none in the minocycline group. Long-term pulmonary function in the two groups was comparable.
Chemical pleurodesis using OK-432 or minocycline is safe and convenient for prolonged air leak after thoracoscopic treatment for PSP. Our experience suggested that OK-432 may be more effective than minocycline in reducing air leak.
Chemical pleurodesis for spontaneous pneumothorax
2013, Journal of the Formosan Medical Association
Pneumothorax is defined as the presence of air in the pleural cavity. Spontaneous pneumothorax, occurring without antecedent traumatic or iatrogenic cause, is sub-divided into primary and secondary. The severity of pneumothorax could be varied from asymptomatic to hemodynamically compromised. 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 spontaneous pneumothorax also focused on ceasing air leakage and preventing recurrences by surgical intervention or chemical pleurodesis. Chemical pleurodesis is a procedure to achieve symphysis between the two layers of pleura by sclerosing agents. In the current practice guidelines, chemical pleurodesis is reserved for patients unable or unwilling to receive surgery. Recent researches have found that chemical pleurodesis is also safe and effective in preventing pneumothorax recurrence in patients with the first episode of spontaneous pneumothorax or after thoracoscopic surgery and treating persistent air leakage after thoracoscopic surgery. In this article we aimed at exploring the role of chemical pleurodesis for spontaneous pneumothorax, including ceasing air leakage and preventing recurrence. The indications, choice of sclerosants, safety, effects, and possible side effects or complications of chemical pleurodesis are also reviewed here.
Simple aspiration and drainage and intrapleural minocycline pleurodesis versus simple aspiration and drainage for the initial treatment of primary spontaneous pneumothorax: An open-label, parallel-group, prospective, randomised, controlled trial
2013, The Lancet
Citation Excerpt :
We chose to use minocycline (a tetracycline derivative) because tetracycline is no longer available. Minocycline is widely available, safe, and inexpensive, and the efficacy of minocycline pleurodesis was similar to that of tetracycline pleurodesis in animal experiments.28 Additionally, minocycline is more convenient than talc because it can be easily administered through small-bore aspiration catheters and hospital admission is not necessary.
Simple aspiration and drainage is a standard initial treatment for primary spontaneous pneumothorax, but the rate of pneumothorax recurrence is substantial. We investigated whether additional minocycline pleurodesis after simple aspiration and drainage reduces the rate of recurrence.
In our open-label, parallel-group, prospective, randomised, controlled trial at two hospitals in Taiwan, patients were aged 15–40 years and had a first episode of primary spontaneous pneumothorax with a rim of air greater than 2 cm on chest radiographs, complete lung expansion without air leakage after pigtail catheter drainage, adequate haematological function, and normal renal and hepatic function. After simple aspiration and drainage via a pigtail catheter, patients were randomly assigned (1:1) to receive 300 mg of minocycline pleurodesis or no further treatment (control group). Randomisation was by computer-generated random numbers in sealed envelopes. Our primary endpoint was rate of pneumothorax recurrence at 1 year. This trial is registered with ClinicalTrials.gov (NCT00418392).
Between Dec 31, 2006, and June 30, 2012, 214 patients were randomly assigned—106 to the minocycline group and 108 to the control group (intention-to-treat population). Treatment was unsuccessful within 7 days of randomisation in 14 patients in the minocycline group and 20 patients in the control group. At 1 year, pneumothoraces had recurred in 31 of 106 (29·2%) patients in the minocycline group compared with 53 of 108 (49·1%) in the control group (p=0·003). We noted no procedure-related complications in either group.
Simple aspiration and drainage followed by minocycline pleurodesis is a safe and more effective treatment for primary spontaneous pneumothorax than is simple aspiration and drainage only. Minocycline pleurodesis should be an adjunct to standard treatment for primary spontaneous pneumothorax.
Department of Health and National Science Council, Taiwan.
Efficacy of tigecycline pleurodesis: A comparative experimental study
2011, Journal of Surgical Research
We investigated whether tigecycline (TIGE) is more effective than talc in inducing pleurodesis in rabbits.
Fifty-six New Zealand rabbits were utilized in a two-phase study: Effects at 14 d (phase I) and at 28 d (phase II) were assessed. Saline solution (SAL n = 3), talc slurry (TALC 200 mg/kg, n = 5), and TIGE at different concentrations (mg/kg): TIGE0.5 (n = 5); TIGE1 (n = 5); TIGE3 (n = 5); TIGE25 (n = 5); TIGE50 (n = 5) were randomly injected, for each phase, through a right chest drainage. TIGE0.5 and TIGE1 were ineffective during phase I and were thus excluded from further investigation. At post mortem examination, pleurodesis was graded grossly and microscopically by three observers blinded to treatment groups.
Phase I: pleurodesis was more effective in TIGE25 and TIGE50 (P < 0.001); TALC was better than TIGE0.5 (P < 0.001), and TIGE1 (P = 0.49), macroscopically. Pleural thickness was significantly higher in TIGE25 compared with SAL, TALC, TIGE0.5, TIGE1, and TIGE3 (P < 0.01). No significant differences were evident between TALC and TIGE3, both macroscopically (P = 0.90) and microscopically (inflammation P = 0.99, fibrosis P = 0.96, pleural thickness P = 0.99). Phase II: better effectiveness of TIGE50 compared with all other groups (P < 0.001) except TIGE 25 (P = 0.29); results similar to phase I for TALC and TIGE3 (P = 0.99), macroscopically. Microscopically greater inflammation in TALC compared with TIGE3 (P < 0.05) and in TIGE50 to TIGE3 (P = 0.05). Significant complications occurred in all TIGE50 group. One of TIGE25 and one of TIGE50 died of respiratory distress and of right hemothorax+ascites, respectively.
Intrapleural TIGE3 mg/kg is as effective as talc in inducing pleurodesis in rabbits. The intrapleural TIGE toxicity threshold was reached at TIGE25 mg/kg concentration.
Intrapleural minocycline following simple aspiration for initial treatment of primary spontaneous pneumothorax
2008, Respiratory Medicine
Citation Excerpt :
In this study, minocycline was selected for the chemical pleurodesis because this tetracycline derivative is comparably safe, inexpensive and widely available. Minocycline also compares favorably with tetracycline in terms of demonstrated efficacy of pleurodesis in a lapin model.20 Most importantly, minocycline hydrochloride is easily administered through aspiration catheters of very small caliber.
The optimal initial management of primary spontaneous pneumothorax (PSP) remains controversial. This study was to evaluate the safety and efficacy of intrapleural minocycline following aspiration for initial treatment of PSP.
Between January 2004 and November 2006, 64 patients with a first episode of PSP were successfully treated by simple aspiration using pigtail or intravenous needle catheter. From December 2005, 31 of the patients also received 300 mg of minocycline hydrochloride post lung expansion, instilled through the catheter into the pleural space (minocycline group). The control group consisted of the first 33 patients of the series who had successfully undergone simple aspiration alone between January 2004 and December 2005.
There was no significant difference between the two groups in terms of demographic data. Patients in the minocycline group had higher doses of meperidine injection. The group hospitalization rates and mean hospital stays were comparable. After a mean follow-up of 13 months (range 3–26), recurrence was noted in 4 of the minocycline group and 11 of the control group (12.9% versus 33.3%, p=0.045). Subsequent thoracoscopic surgery for the recurrent patients revealed that minocycline induced scant loose adhesions which did not significantly affect operation procedures. The long-term pulmonary function and rates of residual pain for the two groups were comparable.
Although associated with immediate chest pain, intrapleural minocycline following simple aspiration is a simple, safe and convenient initial treatment for PSP that may reduce the rates of ipsilateral recurrence.

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: Supported in part by research grants from the Department of Veterans Affairs and by Lederle Laboratories, Wayne, NJ

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Chest

Laboratory and Animal InvestigationsComparison of the Effectiveness of Tetracycline and Minocycline as Pleural Sclerosing Agents in Rabbits

Section snippets

Methods

Results

Discussion

Acknowledgments

Ann Thorac Surg

J Thorac Cardiovasc Surg

Chest

J Thorac Cardiovasc Dis

J Thorac Cardiovasc Dis

Chest

Chest

Gastroenterology

The effect of common sclerosing agents on the rabbit pleural space

Am Rev Respir Dis

Intracavitary bleomycin in the management of malignant effusions

Cancer

Treatment of malignant pleural effusions with intrapleural Corynebacterium parvum or tetracycline

Eur J Respir Dis

Intrapleural minocycline for postoperative air leakage and control of malignant pleural effusion

Kyobu Geka

Laboratory and Animal Investigations
Comparison of the Effectiveness of Tetracycline and Minocycline as Pleural Sclerosing Agents in Rabbits