Elsevier

Journal of Surgical Education

Volume 64, Issue 1, January–February 2007, Pages 41-45
Journal of Surgical Education

Original report
Comparison of Pleurodesis by Erythromycin, Talc, Doxycycline, and Diazepam in a Rabbit Model

Presented at CHEST 2002, San Diego, California. Presented at the Society of Air Force Clinical Surgeons, San Antonio, Texas, April 2003.
https://doi.org/10.1016/j.cursur.2006.07.006Get rights and content

Background

Patients with malignant pleural effusion, recurrent spontaneous pneumothorax, and recurrent benign pleural effusions may have significant relief of their symptoms with chemical pleurodesis. Talc is the most frequently used chemical sclerosant; however, it has been known to induce Adult Respiratory Distress Syndrome (ARDS). Other agents such as doxycycline and erythromycin have documented efficacy as sclerosing agents in the pleura, but they are not in widespread clinical use and have significant documented adverse reactions. Diazepam may represent a potential sclerosing agent in the pleura, because of its local inflammatory profile in other tissues.

Materials and methods

Overall, 33 adult New Zealand White rabbits (Oryctolagus cuniculus) were randomized to 5 treatment groups. Each group received an intrapleural injection via 5 Fr silastic tubes of one of the following agents: 35-mg/kg erythromycin in 2 ml of saline, 70-mg/kg talc in 2 ml of saline, 10-mg/kg doxycycline in 2 ml of saline, 0.4-mg/kg diazepam in 2 ml of saline, or 2 ml of saline as a control. The animals were euthanized and necropsied 30 days after injection. The pleural surfaces were assessed for macroscopic and microscopic evidence of surrounding inflammation and fibrosis.

Results

Doxycycline resulted in severe pleural inflammation and fibrosis with pulmonary hemorrhage, whereas talc-treated animals had less effective fibrosis and granulomas. A trend toward higher mortality occurred in doxycycline-treated animals. Erythromycin demonstrated similar fibrosis (p = 0.487) to doxycycline and had less inflammation (p < 0.001). Diazepam treatment had little effect in the pleural cavity.

Conclusions

This study demonstrates that erythromycin may be the ideal sclerosing agent. It had the advantage of maximal fibrosis with minimal inflammation. Although doxycycline was the most potent pleural sclerosant, it caused severe local tissue damage. Talc treatment resulted in only mild fibrosis, and diazepam was ineffective.

Introduction

The ideal pleural sclerosant should be safe, inexpensive, widely available, and easily administered. None of the popular agents in current clinical usage (talc, doxycycline, and bleomycin) fulfill all criteria. Many different agents have been tested with some success but not without complications. One agent currently in clinical use is talc, which is certainly inexpensive as a sclerosant; however, evidence has shown that intrapleural administration of talc induces Acute Respiratory Distress Syndrome (ARDS) in 8% of patients, with an overall mortality of approximately 1%.1 Doxycycline is another commonly used agent; however, it has been associated with pain, fever, and hepatotoxicity when administered to humans.2 Furthermore, a previous animal study showed that liver transaminases were elevated in rabbits treated with intrapleural doxycycline.3

A recent clinical study reported the use of erythromycin as a pleural sclerosant to treat malignant pleural effusions. In this study, of 26 patients undergoing intrapleural erythromycin instillation, numerous adhesions were present in 15 cases and pleural effusion was reduced in 7 patients. The total response rate was 84.6%, and no severe side effects were experienced.4 Tetracycline and erythromycin demonstrated similar efficacies, using doses of 35 mg/kg, in creating pleurodesis in a rabbit model.5 However, since 1991, the intravenous form of tetracycline used for pleurodesis is no longer available. Diazepam has not been studied with respect to pleurodesis. As diazepam is poorly water soluble, injectable diazepam is dissolved in a solution containing 40% propylene glycol, 10% ethanol, and sodium benzoate. This solution is toxic to veins and, if it extravasates, causes necrosis in surrounding tissues.6 Diazepam was selected as a potential sclerosing agent based on its widespread availability, limited toxicity, and inflammatory properties after soft tissue extravasation.

The purpose of this study was to compare the effectiveness of erythromycin, talc, doxycycline, and diazepam in producing pleurodesis in rabbits compared with saline controls. Erythromycin was hypothesized to be more effective and safer than talc and doxycycline for use as a pleural sclerosant, whereas the effects of diazepam were unknown.

Section snippets

Materials and methods

The Institutional Animal Care and Use Committee (Keesler Medical Center, Biloxi, Mississippi) approved the protocol, and all animals were housed at the Clinical Research Laboratory (Keesler Air Force Base) in facilities fully accredited by the International Association for the Assessment and Accreditation of Laboratory Animal Care.

Overall, 33 adult New Zealand White rabbits (Myrtle’s Rabbitry, Inc., Thompson Station, Tennessee), weighing 3.3 to 3.9 kg, were anesthetized with an intramuscular

Results

Control and diazepam groups produced no appreciable adhesions or pleurodesis on gross observation at 30 days. In the erythromycin group, diffuse adhesions were grossly visible between the parietal and the visceral pleurae in 75% (6/8) of erythromycin-treated rabbits. Microscopically, these animals exhibited fibrosis without inflammation (Fig. 1). Doxycycline had a 100% response rate of induced pleural adhesions and fibrosis in treated rabbits; however, it was also associated with severe

Comment

Pleurodesis is intended to achieve symphysis between the parietal and the visceral pleura to prevent accumulation of either air or fluid in the pleural space. Indications for this procedure include malignant effusion, recurrent spontaneous pneumothorax, and recurrent benign pleural effusions.8 For patients with malignant pleural effusions or recurrent pleural effusions for which the underlying cause cannot be corrected, the least morbid treatment is chest tube drainage with instillation of a

Acknowledgments

The authors thank A. Letch Kline, MD, for his help in the conceptual design of this project. Thanks to Walter T. Brehm, MS, Biostatistician, for his help with statistical analysis and Danny J. Duke, Angela K. Deluze-McCoy, and Cheryl L. Osiek-Comer, Keesler AFB laboratory animal technicians, for their dedication and excellent animal care. Additional thanks to Nancy Pinard at Comparative Biosciences, Inc., Mountain View, California, for preparation of the microscopic tissue photography.

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