ORIGINAL ARTICLE


https://doi.org/10.5005/jp-journals-11010-1070
Indian Journal of Respiratory Care
Volume 12 | Issue 4 | Year 2023

Effectiveness of Chemical Pleurodesis Using Doxycycline in Malignant and Nonmalignant Pleural Disorders: A Retrospective Study from Rural South India


Bimal Raj Rajalingam1https://orcid.org/0000-0002-0475-8092, Priya R Panicker2https://orcid.org/0000-0002-3511-6471, Archana L Peethambaran3https://orcid.org/0000-0003-0335-2864, Alexander Jenish Babu4https://orcid.org/0000-0003-3203-0944, Ravichandran Vijayakumar5https://orcid.org/0000-0003-3715-1833

1,3Department of Pulmonology, Sree Mookambika Institute of Medical Sciences, Kanyakumari, Tamil Nadu, India

2Department of Community Medicine, Sree Mookambika Institute of Medical Sciences, Kanyakumari, Tamil Nadu, India

4,5Department of General Medicine, Sree Mookambika Institute of Medical Sciences, Kanyakumari, Tamil Nadu, India

Corresponding Author: Priya R Panicker, Department of Community Medicine, Sree Mookambika Institute of Medical Sciences, Kanyakumari, Tamil Nadu, India, Phone: +91 7639079014, e-mail: priya.ravipanicker@gmail.com

Received: 01 March 2023; Accepted: 11 October 2023; Published on: 18 January 2024

ABSTRACT

Background: Chemical pleurodesis is an important tool in the management of refractory pleural effusion. Although talc is widely used as a sclerosing agent of choice, alternative agents like doxycycline have emerged as cheaper and safer agents for chemical pleurodesis.

Objective: The aim was to evaluate the effectiveness and clinical outcomes of chemical pleurodesis using doxycycline (500 mg single dose) in the treatment of malignant and nonmalignant pleural effusion and recurrent pneumothorax.

Materials and methods: A total of 36 patients, of which 23 patients with malignant pleural effusion, nine patients with pneumothorax, and four patients with nonmalignant effusion, were included in the analysis. After intercostal drainage (ICD) of air or fluid, xylocaine was instilled for pleural anesthesia, and 500 mg of doxycycline was used as a sclerosant. Successful pleurodesis was defined as expanded lung with close approximation between visceral and parietal pleura and minimal to no effusion or pneumothorax at 2 weeks.

Results: At the end of 2 weeks, all 23 patients with malignant pleural effusion and nine patients with refractory pneumothorax had successful pleurodesis, but four patients with hepatic hydrothorax had no response. The most common adverse events with pleurodesis included chest pain and fever.

Conclusion and clinical significance: Doxycycline was found to be a safe and effective agent for chemical pleurodesis in patients with malignant pleural effusions and recurrent pneumothorax. However, the outcome of hepatic hydrothorax remained unsatisfactory.

How to cite this article: Rajalingam BR, Panicker PR, Peethambaran AL, et al. Effectiveness of Chemical Pleurodesis Using Doxycycline in Malignant and Nonmalignant Pleural Disorders: A Retrospective Study from Rural South India. Indian J Respir Care 2023;12(4):299–302.

Source of support: Nil

Conflict of interest: None

Keywords: Doxycycline, Effectiveness, Malignant, Nonmalignant, Pleurodesis

INTRODUCTION

Pleurodesis is a procedure done to obliterate the pleural space to prevent the recurrence of pneumothorax or pleural effusion or to treat persistent pneumothorax. The pleural space is the potential space between the visceral and parietal pleura, which covers the lung parenchyma and lines the ribs and intercostal spaces, respectively.

Pleurodesis is usually done by draining the air or fluid in the pleural space, followed by either a mechanical procedure or instillation of a chemical irritant into the pleural space. This irritant causes intense inflammation and fibrosis. This produces adhesions between the two pleural membranes and obliteration of the pleural space subsequently.1 Cytokines like transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) are involved in the production of fibrosis that results in pleural symphysis.2

Pleurodesis is most commonly used for the treatment of refractory or recurrent pleural effusion, especially malignant pleural effusion, that is, secondary to metastatic carcinoma of the breast, ovaries, and lung. Since the life expectancy of these patients is limited, the purpose of pleurodesis therapy is mainly palliative to reduce discomfort and duration or cost of hospitalization.1 Other common indications for pleurodesis are refractory pneumothorax and refractory nonmalignant pleural effusion.3

Mechanical or surgical pleurodesis can be done via medical thoracoscopy, video-assisted thoracoscopic surgery (VATS), or open thoracotomy. Chemical pleurodesis involves instilling a sclerosing agent into the pleural cavity through a small-bore or large-bore chest tube or indwelling catheter because it is less invasive, more effective, and better tolerated compared to thoracoscopy.1 While the outcomes of both approaches are similar, the surgical approach has an added advantage when chemical pleurodesis fails and the candidate is medically fit to undergo surgery.

Talc is the most common sclerosing agent in use, trailed by tetracycline derivatives like doxycycline.4 Other agents include anticancer agents like bleomycin, cisplatin, cytarabine, and autologous blood.1 However, talc is known to rarely cause acute pneumonitis, ending in acute respiratory distress syndrome and respiratory failure.5 Tetracycline derivatives, on the other hand, have the benefits of low cost, excellent safety profile, reasonable efficacy, and comparative ease of administration. Success rates, both partial and complete response rates, from larger studies have ranged from 50 to 92% (mean rate 65%).6 Adverse events reported after tetracycline pleurodesis include fever (10%) and pleuritic chest pain (30%). However, these are usually transient and easily treatable. The optimal dose for intrapleural administration is reported to be 20 mg/kg or 1–1.5 gm. Lower response rates have been reported with use of smaller doses (500 mg).7

The tetracycline derivative doxycycline has success rates ranging from 65 to 100% in smaller studies. Prevost et al. reported a success rate of 82% with doses >2 gm. Adverse effects are similar to those experienced with tetracycline usage, that is, fever (30%) and mild or moderate pleuritic pain (up to 60%). Doxycycline 500 mg was found to be superior to bleomycin with a 1-month complete response rate of 79% by Patz et al. In a similar study, Seaton et al. reported a complete response rate of 81% with very low incidence of side effects.8

Since the available literature regarding use of low-dose doxycycline pleurodesis from South India is limited, there is a research gap in evaluating the response rates of this cheaper alternative in clinical practice. In this context, this study was designed to evaluate the effectiveness and clinical safety profile of single-dose administration of doxycycline 500 mg for treating malignant and nonmalignant pleural effusion and recurrent pneumothorax.

MATERIALS AND METHODS

This retrospective study was conducted in the Respiratory Medicine department of a tertiary care center in the Kanyakumari district of Southern Tamil Nadu, India. Patients who underwent chemical pleurodesis for the management of malignant or nonmalignant pleural effusion and recurrent pneumothorax over a 2-year period from 2019 to 2020 were included in the study. Patients with hypersensitivity to doxycycline were excluded. Informed consent was obtained from all the 36 patients before the procedure. Intradermal skin testing was done to rule out allergy to doxycycline and xylocaine.

Intercostal drainage tubes (ICD tubes) were inserted to drain air or fluid as per standard guidelines. Following ICD insertion, the patient was monitored to ensure lung expansion for 2–4 days and to confirm partial approximation of the parietal and the visceral pleura. The ICD tube was then disconnected from the collection bag, and 10 mL of 2% xylocaine was instilled into the pleural space to anesthetize the pleural surface. Then, 500 mg of doxycycline, dissolved in 50 mL of normal saline, was instilled into the pleural space through the ICD. The ICD tube was then clamped for a period of up to 2 hours before finally connecting to the collection chamber. Immediate adverse events were carefully assessed in all patients following pleurodesis. Chest X-ray (CXR) was taken 2 days post-procedure. If pleurodesis was achieved, the ICD was removed after checking for air leaks. Repeat CXR was done after 2 weeks to check for pleural symphysis. Successful pleurodesis was defined as expanded lung with close approximation between visceral and parietal pleura with minimal to no effusion or pneumothorax at 2 weeks.

Institutional ethical committee approval was obtained. Patient details were obtained from the medical records. Confidentiality was maintained by assigning identification numbers prior to statistical analysis. Data entry was done in MS Excel 2016, and analysis was done using Statistical Package for the Social Sciences (SPSS) version 20. Descriptive statistics, Fisher’s exact tests, and Chi-squared tests were used for statistical analysis, with a significance level fixed at 5%.

RESULTS

A total of 36 patients were included in the study, with equal distribution of both genders. The mean age of the patients was 54.3 years (±8.6 years), with ages ranging from 31 to 69 years. Among the group, 23 patients (63.9%) had malignant pleural effusion. The remaining 36.1% of cases were nonmalignant causes. Recurrent pneumothorax was the indication for pleurodesis in 25% patients with chronic obstructive pulmonary disease (COPD), and hepatic hydrothorax was the reason in 11.1% (four) patients. One patient with hepatic hydrothorax also had associated acute kidney injury. The clinical profile of patients is described in detail in Table 1 below.

Table 1: Clinical profile of patients undergoing chemical pleurodesis
Diagnosis Indication Frequency Percent
Carcinoma breast Pleural effusion 7 19.4
Carcinoma lung Pleural effusion 10 27.8
Carcinoma ovary Pleural effusion 4 11.1
Carcinoma pancreas Pleural effusion 2 5.6
Hepatic failure Pleural effusion 4 11.1
COPD Recurrent pneumothorax 9 25
Total 36 100

Among the 23 patients with malignant pleural effusion, 10 patients had carcinoma of the lung (27.8%), seven patients had carcinoma of the breast (19.4%), four had carcinoma of the ovary (11.1%), and two patients had pancreatic carcinoma (5.6%).

Overall, chest pain was the most common immediate post-procedure adverse event noted in 69.4% of patients (25), followed by fever in 13.9% of patients (five) as described below in detail in Table 2. Serious adverse events like hypotension, acute respiratory distress syndrome, or anaphylactic reactions following the procedure were not observed in any of the patients.

Table 2: Immediate adverse events following pleurodesis
Adverse events Number Percent
Chest pain 25 69.4
Fever 5 13.9
Dyspnea 4 11.1
Hypotension 0 0
Nausea/vomiting 4 11.1
Anaphylactic reactions 0 0

Multiple adverse effects in some patients—percent does not add to 100%

The overall pleurodesis success rate was 88.9%. All the 23 patients with malignant pleural effusion achieved successful pleurodesis. All nine patients with recurrent pneumothorax due to COPD also achieved complete response. However, four patients with transudative pleural effusion following hepatic failure associated with cirrhosis had an incomplete response. The success rates varied from 100% in malignant pleural effusion and recurrent pneumothorax to null in transudative pleural effusion cases. This difference in successful pleurodesis outcomes between malignant and nonmalignant pleural effusions was statistically significant with Fisher’s exact test (p-value < 0.001). There was no statistically significant difference in pleurodesis outcome between patients having effusion and pneumothorax as the indication (Fisher’s exact test; p = 0.55).

DISCUSSION

Pleurodesis is indicated in various pulmonary conditions to achieve pleural symphysis. Chemical pleurodesis is easier and can be done at the bedside. Various agents have been used for the pleurodesis. In this study, we have used plain doxycycline, which is commonly available and inexpensive.

This study had an overall success rate of 90%, which is higher than the 81.5% success reported among a similar group of recurrent and malignant pleural effusion by Hemmati et al. in Iran.9 Baranitharan et al. also reported lower immediate success rates of 80% with oxytetracycline pleurodesis in pneumothorax, along with death in their single malignancy case.10 There were no deaths in our study.

In our study, doxycycline pleurodesis attained 100% success in malignant pleural effusions. A meta-analysis done by Xia et al. reported that talc pleurodesis had better long-term (>1 month) outcomes than doxycycline or other sclerosant agents in cases with malignant pleural effusion, especially when administered via thoracoscopic talc poudrage. However, at 1-month follow-up, the efficacy of talc pleurodesis was similar to pleurodesis using doxycycline and other agents and superior only to bleomycin.11 Talc pleurodesis was also found to be superior to indwelling pleural catheters in terms of success rates (88 vs 56%) in a meta-analysis by Wang et al. in 2010.12

In the case of refractory hepatic hydrothorax, pleurodesis was ineffective in achieving a successful outcome in all hydrothorax patients (4) in this study. Chemical pleurodesis with talc, taurolidine, and viscum album showed better success rates (73%) in a study by Lee et al. in South Korea.13 However, they had opted for video-assisted thoracoscopic surgery (VATS) in some patients and adjunct therapy of low salt, diuretics, and ICDs for all their enrolled patients. This could be the reason for their better outcomes. Spontaneous pleurodesis was also achieved in hepatic hydrothorax through indwelling tunneled pleural catheters with a success rate of 60% in a tertiary care center in India, though the majority of these patients received at least one systemic shunt procedure.14

The most common adverse event in this study is pain following procedure (70%). Post-procedure pain was also common in talc pleurodesis use as reported by Wang et al.12 Pain was less common (33.3%) post-procedure in the oxytetracycline group in the study by Baranitharan et al. However, they had a higher incidence of pain in the talc group (66.7%).10 Post-procedure fever was seen in 15% of our patients, which was similar to the 14% fever incidence reported by Hemmati et al.9 There was no hypotension or empyema reported in our study. Allergic reaction to doxycycline is a common concern, though it was not encountered in this study. Allergic reactions to doxycycline can range from mild skin reactions to life-threatening toxic epidermal necrolysis and organ damage. Anaphylactic reaction to doxycycline 300 mg presenting as hypoxia, progressing to acute respiratory failure requiring ventilation, has also been reported.15 Allergy screening with intradermal tests for doxycycline and xylocaine is recommended to avoid allergic reactions. Though a negative skin test will lessen the likelihood of immediate reaction, the possibility of delayed allergic reactions cannot be ruled out.

Despite the favorable successful outcomes in this study, the long-term effects of pleurodesis after 1 month could not be captured. Moreover, a higher sample size, particularly including more cases of refractory hepatic hydrothorax and pneumothorax, would shed more light on the effectiveness of doxycycline pleurodesis in pleural disorders.

CONCLUSION

Doxycycline was found to be a safe and effective agent for chemical pleurodesis, with high success rates, especially in cases of malignant pleural effusion. The postprocedural adverse reactions were also very low. In view of this study, doxycycline can be considered a cheaper and safer agent for bedside pleurodesis.

Clinical Significance

Doxycycline 500 mg has been shown to be a cheaper and safer agent for chemical pleurodesis, especially in the case of malignant pleural effusions and recurrent pneumothorax. The ease of administration and low side effects make it optimum for use in malignant pleural effusions.

ORCID

Bimal Raj Rajalingam https://orcid.org/0000-0002-0475-8092

Priya R Panicker https://orcid.org/0000-0002-3511-6471

Archana L Peethambaran https://orcid.org/0000-0003-0335-2864

Alexander Jenish Babu https://orcid.org/0000-0003-3203-0944

Ravichandran Vijayakumar https://orcid.org/0000-0003-3715-1833

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