Assessment of Tetracycline Pleurodesis in Primary Spontaneous Pneumothorax

Abstract

Background:

This study aims to assess tetracycline chemical pleurodesis through tube thoracostomy in prevention of spontaneous pneumothorax in patients with normal computed tomography (CT) scans following their first episode of primary spontaneous pneumothorax (PSP).

Materials and Methods:

We conducted a prospective, double-blinded, census clinical trial involving 66 patients with spontaneous pneumothorax, referred to Isfahan University of Medical Sciences affiliated Hospitals. The patients were randomly divided into two groups. Tube thoracostomy was embedded for all patients. The first group was treated with tetracycline 2 g, 5 mL of lidocaine 2%, and 50 mL of normal saline injected through an embedded thoracostomy tube. The second group was performed with the same procedure without tetracycline injection. Thereafter, patients were followed up for 12 months.

Results:

This study was conducted on 32 (48.5%) cases and 34 (51.5%) controls. SPS recurrence occurred in 16 patients, with the following distributions: 14 males (P value = 0.627), 14 controls (P value = 0.001), and 12 smokers (P value = 0.207). Tetracycline pleurodesis correlated with a significantly lower recurrence rate (odds ratio [OR] =12.16; P value = 0.014).

Conclusion:

Tetracycline chemical pleurodesis via thoracostomy tube in patients with first episode of PSP may significantly decrease the rate of recurrence. However, further large-scale clinical trials are needed to establish this effect.

INTRODUCTION

Primary spontaneous pneumothorax (PSP) is a condition which occurs most commonly in young, tall, smoker males without underlying disease.[1] A main concern with PSP is the high recurrence rate, accounting for 23–50% after the first episode. This may increase to 60% after a second episode.[2] As a subject of debate, a wide variety of management strategies are recommended for the treatment of PSP, including observation, needle aspiration, tube thoracostomy, chemical pleurodesis, pleural abrasion, bullectomy, and thoracoscopic pleurectomy, which share the common purpose of managing the acute condition and preventing the recurrence of PSP.[3,4] Simple needle aspiration with the aid of a chest tube for drainage has been reported to be accompanied with a recurrence of up to 30% in the first year after the first episode. In this order, trends for PSP treatment lend toward surgical procedures.[4,5] Thoracotomy with pleurectomy and bullectomy is the definitive treatment of PSP that significantly reduces recurrence probability. This procedure has been reported to cause a high rate of morbidity and mortality.[5,6,7] Thus, video-assisted thoracoscopic surgery (VATS) has become the preferred method for the treatment of PSP with a recurrence rate of 5–10%.[5,6,7,8] For persistent or recurrent cases, mechanical or chemical pleurodesis has been used.[8,9] In general, guidelines have indicated that the size of the lesion on computed tomography (CT) scans and the patient’s signs or symptoms should be considered approaching spontaneous pneumothorax. Regarding the guidelines, patients with larger size of lesions on CT scans and/or with unstable conditions could undergo surgical procedures to prevent recurrent episodes of PSP. Patients with smaller size of lesions and/or stable conditions could be managed by simple observation. However, a high recurrence rate and the fear of recurrence for the patients, which affects patient’s quality of life, may be considered as a rationale for preventive treatments.[2,3,8,9] As mentioned above, chemical pleurodesis is a usual method for the treatment of spontaneous pneumothorax. This method is performed using talc or tetracycline. This method has been accompanied up to 80% of prevention success. This procedure can be performed via thoracoscopy, thoracotomy, or tube thoracostomy.[10,11,12,13] In this study, we assessed the efficacy of tetracycline chemical pleurodesis through tube thoracostomy in the prevention of spontaneous pneumothorax in patients with normal CT scans following first episode of PSP.

MATERIALS AND METHODS

The study design and information are registered at ClinicalTrials.gov under identification code NCT03634605. This study was designed as a prospective double-blinded census clinical trial involving 66 patients with spontaneous pneumothorax, referred to Isfahan University of Medical Sciences affiliated Hospitals. The project implementation started on March 2015. The recruitment process started in May 2015 and finished by August 2016, and following a one-year follow-up, the study ended in September 2017.

Inclusion criteria

• Patients 18 years or older

• Presenting with the first episode of PSP.

Non-inclusion criteria

• Presence of any bullae in chest CT scan

• History of chest trauma or thoracic surgery

• High risk occupations (e.g. divers, pilots).

Exclusion criteria

• Occurrence of chest trauma during the study follow-up period

• Not willing to participate in the study.

Informed consent forms, containing all necessary information about the study, were obtained from the patients. This study was approved by the Research Council and Ethics Committee of School of Medicine of Isfahan University of Medical Sciences, under code IR.MUI.REC.1395.3.351.

A CONSORT diagram of the studied population is shown in Figure 1. The patients were given random numbers for being divided into two groups. A thoracostomy tube was used for patients in both groups.[12] The first group was treated with tetracycline 2 g from a similar brand (provided by Al-Zahra Hospital), 5 mL of lidocaine 2%, and 50 mL of normal saline, injected through an embedded thoracostomy tube. Then, the tube was clamped for an hour. In the next step, within 48 hours, a chest X-ray was taken. In the case of normal radiography and acceptable chest expansion, the patient was discharged. For the second group, the same procedure without tetracycline injection was performed. Thereafter, patients were followed in a 12-month visit. In follow-up visits, patients were asked about signs or symptoms of recurrence. They underwent accurate physical examinations and chest auscultation. In case of suspicion for recurrent pneumothorax, further radiologic evaluations were considered.

Figure 1.

CONSORT diagram of the studied population

The data were analyzed with IBM SPSS20 – United States software. Descriptive data were reported in mean ± standard deviation. For analytic data, Chi-square and logistic regression tests were used. A P value of less than 0.05 was considered significant.

RESULTS

This study was performed on 32 (48.5%) cases and 34 (51.5%) controls. A total of 60 (90.9%) patients of the studied population were males. The mean age was 40.87 ± 17.35 years (range: 16–90 years). The mean age of the controls was 47.62 ± 18.56, while the cases had a mean age of 34.53 ± 13.56 years (P value = 0.002). The mean body mass index (BMI) the of studied population was 24.89 ± 2.32, with a range of 19.40–28.30. The mean value for BMI in patients who underwent chemical pleurodesis was 24.81 ± 2.06, while in the control group, it was 24.95 ± 2.58 (P value = 0.811). In general, 16 (24.2%) patients experienced recurrent pneumothorax, and others were completely symptom-free at the 12-month follow-up. Table 1 demonstrates the characteristics of patients based on recurrence occurrence among cases.

Table 1.

Pneumothorax recurrence in patients

Characteristics		No-recurrence		Recurrence		Level of significance
Sex (male) Number (percentage)		46 (0.76)		14 (0.24)		0.627*
Group (case) Number (percentage)		30 (0.94)		2 (0.06)		0.001*
Smoking (yes) Number (percentage)		44 (0.78)		12 (0.22)		0.207*
Age (year) Mean±SD		44.44±17.84		29.75±9.53		0.003**
BMI (kg/m2) Mean±SD		24.90±2.21		24.86±2.76		0.951**

*Chi-square test specially fisher exact test, **T – independent sample

Based on Table 2, the chance of permanent recovery after pneumothorax was 12 times higher in patients who underwent tetracycline therapy compared to controls (P value = 0.014). Other information has been demonstrated in Table 2.

Table 2.

Effect of independent variables on pneumothorax permanent recovery in 12-month follow-up

Factors		Odds ratio for recurrence		Level of significance*		95% CI for odds ratio
						Lower		upper
Group (case)		12.16		0.014		1.65		89.67
Smoking (yes)		5.30		0.102		0.72		38.84
Age (year)		1.06		0.031		1.01		1.12

*Logistic regression model

DISCUSSION

This prospective randomized study was conducted to assess primary pneumothorax recurrence in patients with normal CT scans following their first episode of PSP undergoing chemical pleurodesis with tetracycline via a thoracostomy tube. We found that patients who have undergone tetracycline pleurodesis had a significantly lower rate of recurrence in their 12-month follow-up compared to those who have not been treated with chemical pleurodesis. In line with our findings, recent meta-analyzes have indicated that chemical pleurodesis, regardless of the chemical agent, is the only method of PSP treatment that could significantly reduce the recurrence rate.[13] Accordingly, in a network meta-analysis by Muhetaer et al.[14] among the surgical methods, chemical pleurodesis was reported to be superior for the prevention of PSP recurrence. Regarding the sclerosing agent used for pleurodesis, Hallifax et al.[15] in the systematic review have reported that tetracycline pleurodesis could reduce the recurrence rates down to 13%. However, regarding the substantial heterogeneity among the studies, the authors did not perform the meta-analysis.

Regarding other sclerosing agents, in a study by Chen et al.,[16] minocycline pleurodesis administered by a pigtail catheter was reported to reduce the recurrence rate to 29.2% in the treatment arm compared to the 49.1% recurrence in the control arm.

Another chemical substance that has been used previously for pneumothorax recurrence prevention is talc. Nowadays, talc is being extensively used for chemical pleurodesis in patients with recurrent PSP.[17]

Mithiran et al.[18] in a recent study have reported that talc pleurodesis could be as effective as video-assisted thoracoscopy and bullectomy for the treatment of PSP.

Also, other studies in which tetracycline was used as the chemical substance of pleurodesis vs. drainage have only reported similar results. In these studies, patients treated with tetracycline significantly demonstrated better results in their follow-ups.[15] In addition, we found that patients with the first episode of PSP who had been treated with tetracycline pleurodesis had 12.16 times less probability of recurrence. In general, based on our study and previous ones, chemical pleurodesis may have a positive effect in the prevention of pneumothorax recurrence. Eventually, we found that using tetracycline pleurodesis could significantly decrease the recurrence of pneumothorax after the first episode.

In the current study, no correlation between spontaneous pneumothorax recurrence and gender was found. This finding is inconsistent with other studies in which recurrence was found to be significantly associated with the female gender.[19]

We also observed no significant correlation between smoking and PSP. Regarding the previous studies, spontaneous pneumothorax may occur mostly in smokers.[19] This finding is inconsistent with our study. However, few studies, including the study by Tan et al. and Olesen et al., found no statistically significant association between smoking and the recurrence of spontaneous pneumothorax.[20,21] These differences may be due to the study population or type of treatment included in the studies or the heterogeneous definitions used for identifying smoking status.

Furthermore, age was another independent aspect of PSP assessed in the current study. We found that the rate of PSP occurrence was statistically higher in younger patients. This finding is similar to other studies.[9,22] Moreover, we found that by a year of aging, the probability of recurrence decreases 1.06 times. In the study by Noh et al.,[7] they found that rate of recurrence was higher in children compared to young adults, but they did not find significant differences according to age in patients who were treated with thoracostomy or only observation.

We have also evaluated the association between BMI and the recurrence of spontaneous pneumothorax in patients with normal chest CT scans. The results indicated no association between patient’s BMI and the recurrence of pneumothorax. Although these findings are inconsistent with those of Tan et al., the association between BMI and the recurrence of PSP has not yet been established, as several other studies have not yielded robust results.[19,21]

CONCLUSION

Tetracycline pleurodesis for the prevention of recurrent spontaneous pneumothorax following the first episode of PSP in patients with normal imaging may effectively reduce the recurrence rate (OR = 12.16 [1.65–89.67]). The recurrence of PSP is not associated with sex and smoking status, but it is associated with younger age. However, studies with larger populations are suggested to better establish these findings.

Ethics approval and consent to participate

This study was approved by the Research Council and Ethics Committee of School of Medicine of Isfahan University of Medical Sciences

Informed consent

Informed consent was obtained from all individual participants.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

This study was funded by Isfahan University of Medical Sciences, Isfahan, Iran