Comparison of outcome between sole operation and operation after tube thoracostomy in late phase empyema

Abstract

Empyema is a severe and potentially life-threatening condition characterized by infection in the pleural cavity with pus collection. Treatment options include antibiotics, tube thoracostomy, video-assisted thoracic surgery (VATS) decortication, or open thoracotomy. This study investigated whether decortication without pre-operative tube thoracostomy results in better outcomes for stage II and III empyema. We included 1042 patients with stage II or III empyema who underwent surgical decortication from January 2012 to December 2021. Among these patients, 713 underwent sole operation, and 329 underwent operation after tube thoracostomy. Patients were classified into two groups: sole operation (713 patients) and operation after tube thoracostomy (329 patients). Primary outcomes were peri-operative and in-hospital characteristics. Secondary outcomes analyzed 1-year overall survival rate and 1-year event-free survival. After 1:1 propensity score matching, 620 patients were included, with each group consisting of 310 patients. The sole operation group had significantly lower hospital mortality and 30-day re-intervention rates and shorter time between diagnosis and operation, operation time, ICU stay, ventilator duration, and hospital stay. The sole operation group also had higher 1-year overall survival and 1-year event-free survival. The first intervention for advanced-stage empyema is crucial. Even when patients ultimately require surgery, pre-operative tube thoracostomy could lead to poorer outcomes. Direct surgical management for stage II and III empyema is simpler and more effective.

Introduction

Empyema is a severe and potentially life-threatening condition characterized by infection in the pleural cavity with pus collection^{1, 2–3}. It is categorized into three stages based on pleural fluid and radiological characteristics: the exudative (stage I), fibrinopurulent (stage II), and organized stages (stage III)^4,5. As the disease progresses, stages II and III are associated with higher mortality and morbidity rates^6,7. The main goals of empyema management are infection control and adequate drainage of pleural fluid^7,8.

Treatment options for initial therapy include antibiotic treatment, tube thoracostomy, intrapleural fibrinolytic therapy, VATS decortication, and open thoracotomy^{8, 9, 10–11}. Surgical management of decortication for stages II and III empyema has a higher success rate than tube thoracostomy alone, with success rates around 80–90%^{12, 13, 14–15}. Tube thoracostomy as initial management has a higher failure rate, approximately 30–60%, and patients may need a second intervention after tube thoracostomy^{14, 15, 16–17}. The first intervention for late-stage empyema is crucial to the outcome.

Recent guidelines, such as the European Respiratory Society (ERS) Task Force report in 2023, emphasize the importance of early surgical referral and intervention in the management of empyema^5,11. Delays in surgical treatment are associated with worse outcomes. This study aimed to determine which strategy is associated with better outcomes in the management of empyema.

Methods

All methods were performed in accordance with the relevant guidelines and regulations. The study was approved by the Internal Review Board of Changhua Christian Hospital, approval number 230323, and the need for obtaining informed consent was waived due to the retrospective nature of the study.

Patient selection

Empyema was diagnosed based on clinical presentation, radiological findings (chest radiograph and chest computed tomography), and pleural fluid analysis from thoracentesis, following established diagnostic criteria^4,18,19. Radiological diagnostic criteria included evidence of pleural fluid with features suggestive of empyema, such as loculated pleural effusion, pleural thickening, enhancement of the pleura (split pleura sign), air-fluid levels, and signs of lung compression on CT imaging^20,21. Pleural fluid diagnostic criteria included the presence of purulent pleural fluid, positive Gram stain or culture from pleural fluid, or biochemical analysis showing pleural fluid pH < 7.2, glucose < 40 mg/dL, or lactate dehydrogenase (LDH) > 1000 IU/L, consistent with complicated parapneumonic effusion or empyema^4,18,22.

Exclusion criteria were patients who were unsuitable for surgery (unstable hemodynamic status requiring inotropic agents or ventilator support) or had incomplete comorbidity data or therapy records.

Treatment groups

Treatment Decision Criteria: We agree that further clarification is necessary regarding the criteria for choosing initial treatment strategies.

1. Choice Between Tube Thoracostomy and Direct Surgery: The decision was influenced by a combination of clinical factors and patient preferences. While all patients included in the study were deemed fit for surgery, some patients opted for the less invasive option of tube thoracostomy after discussing the risks and benefits of each procedure. Factors influencing this choice included the patient’s personal preference for minimally invasive procedures, their understanding of the potential outcomes, and the desire to avoid surgery if possible.

2. Switching from Tube Thoracostomy to Surgery: Patients who underwent initial tube thoracostomy were closely monitored. If there was no clinical improvement, persistent infection, or radiological evidence of disease progression, they were subsequently recommended for surgical decortication. This step-wise approach was part of shared decision-making with the patient, respecting their initial preference while ensuring optimal care based on their clinical response.

Tube thoracostomy procedure

Tube thoracostomy was performed using a standard technique. A chest tube of size 24 to 28 French was inserted under local anesthesia, usually at the mid-axillary line in the 5 th or 6 th intercostal space, guided by imaging. The chest tube was connected to an underwater seal drainage system with continuous negative suction, and the position was confirmed with chest radiography. Pleural fluid samples were collected for analysis and culture.

Surgical procedure

The patient was initially placed in a supine position and intubated with a double-lumen endotracheal tube for lung isolation before being repositioned to a lateral decubitus position. The surgical area was sterilized and draped in a standard manner. Preoperative ultrasonography guided the placement of thoracoports at the 5 th and 8 th intercostal spaces for video-assisted thoracoscopic surgery. Through the thoracoscope, pleural effusion was aspirated for analysis, and any fibrinous tissues were carefully removed to prevent residual space and promote lung expansion. Lung abscesses, bronchopleural fistulas, air leaks, and bleeding sites were inspected and addressed as needed. Chest tubes were placed and secured in position.

Clinical features of patients

Clinical characteristics of the entire study population included age, sex, Charlson Comorbidity Index (CCI) score, empyema stage, location, pathogen, cause, and laboratory data. The CCI score was calculated to assess comorbid conditions, as described by Charlson et al.²³ Clinical data, including laboratory data, chest radiograph, and electrocardiography for preoperative anesthesia evaluation, were collected within two weeks before surgery.

Outcome measurement

Primary outcomes measuring peri-operative and in-hospital characteristics included time between diagnosis and operation, operation time, peri-operative pleural fluid amount, positive culture rate, duration of ICU stay, ventilator use, hospital stay, readmission rate, re-intervention rate, and mortality rate. Secondary outcomes analyzed the 1-year overall survival (OS) rate and 1-year event-free survival (EFS). Readmission was defined as any unplanned hospital admission within 30 days after discharge from the index hospitalization for surgical decortication. Readmissions were primarily due to persistent or recurrent pleural infection, respiratory complications, or other medical issues. Re-interventions included repeat tube thoracostomy, additional surgical decortication, or intrapleural fibrinolytic therapy.

Postoperative management

Postoperative care included monitoring in the ICU if necessary, antibiotic therapy based on culture and sensitivity results, pain management, and chest physiotherapy to promote lung expansion. Chest tubes were typically removed when the drainage was less than 100 mL per day, and there was no air leak or signs of ongoing infection. Patients were discharged when they were clinically stable, ambulatory, and able to tolerate oral intake. Follow-up visits were scheduled to monitor recovery and detect any complications.

Statistical analysis

Overall survival (OS) was measured from the date of surgery to the date of death from any cause or the date of the last follow-up visit before 2021. Event-free survival (EFS) was measured from the date of the surgery until any re-intervention or re-operation for empyema. All cumulative OS and EFS rates were estimated by Kaplan–Meier curves, and differences in variables were determined using the log-rank test. The baseline characteristics were compared between patients using a Mann-Whitney U test for continuous variables and a chi-squared test for categorical variables. Univariable and multivariable analyses for OS and EFS were performed using a logistic regression model and presented via odds ratio. A p value less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed using SPSS statistical software (SPSS package, version 23.0; SPSS, Chicago, IL, USA).

Results

Baseline characteristics

The clinical characteristics of the sole operation group and the operation after tube thoracostomy group are summarized in Table 1. The study included 713 patients in the sole operation group and 329 patients in the operation after tube thoracostomy group. There were no significant differences in age or gender between the groups. However, the operation after tube thoracostomy group had a higher CCI score (3.13 vs. 2.74, p = 0.006) and a higher proportion of patients with a CCI score of 3 or more (52.3% vs. 44.6%, p = 0.020). After 1:1 propensity score matching, we included 620 patients; their baseline characteristics are shown in Table 2. There was no statistically significant difference in age, sex, comorbidity index score, empyema stage, location, or laboratory data between the two groups.

Table 1. Clinical characteristics of the sole operation group and the operation without pre-operative tube thoracostomy.

	Sole operation	Operation after tube thoracostomy	p value
Number of patients	713	310
Age(years) mean ± SD	62.36 ± 15.20	61.82 ± 15.62	0.525
Gender
Male	563(79.0%)	234(75.5%)	0.218
Female	150(21.0%)	76(24.5%)
CCI score	2.74 ± 2.53	3.13 ± 2.46	0.006*
CCI score
0	154(21.6%)	45(14.8%)	0.020*
1 ~ 2	241(33.8%)	102(32.9%)
≧ 3	318(44.6%)	162(52.3%)
Phase
II	568(79.7%)	239(77.1%)	0.355
III	145(20.3%)	71(22.9%)
Location
Right	421(59.0%)	202(65.2%)	0.098
Left	285(40.0%)	103(33.2%)
Bilateral	7(1.0%)	5(1.6%)
Pathogen
No growth	340(47.7%)	104(33.5%)	< 0.001*
Single	288(40.4%)	135(43.5%)
Multiple	85(11.9%)	71(22.9%)
Cause
Pneumonia	627(87.9%)	201(64.8%)	< 0.001*
From abdomen	19(2.7%)	18(5.8%)
From neck/mediastinum	3(0.4%)	3(1.0%)
Cancer related	30(4.2%)	33(10.6%)
Iatrogenic	9(1.3%)	23(7.4%)
Trauma	3(0.4%)	15(4.8%)
From esophageal	5(0.7%)	3(1.0%)
Others	17(2.4%)	14(4.5%)
Lab data
WBC, Mean ± SD (/µL)	14107.98 ± 6669.87	13493.71 ± 6493.04	0.169
ANC, Mean ± SD (/µL)	11828.31 ± 6691.97	11389.00 ± 6119.64	0.493

CCI Charlson comorbidity index; WBC white blood count; ANC absolute neutrophil count.

Table 2. Clinical characteristics of the patients after 1:1 propensity score matching.

	Sole operation	Operation after tube thoracostomy	p value
Number of patients	310	310
Age (years), mean ± SD	62.61 ± 14.68	61.82 ± 15.62	0.495
Sex
Male	247(79.7%)	234(75.5%)	0.211
Female	63(20.3%)	76(24.5%)
CCI score, mean ± SD	3.00 ± 2.48	3.13 ± 2.46	0.404
CCI score
0	51(16.5%)	46(14.8%)	0.438
1 ~ 2	113(3.5%)	102(32.9%)
≧ 3	146(47.1%)	162(52.3%)
Phase
II	250(80.6%)	239(77.1%)	0.279
III	60(19.4%)	71(22.9%)
Location
Right	177(57.1%)	202(65.2%)	0.097
Left	129(41.6%)	103(33.2%)
Bilateral	4(1.3%)	5(1.6%)
Pathogen
No growth	139(44.8%)	104(33.5%)	< 0.001*
Single	132(42.6%)	135(43.5%)
Multiple	39(12.6%)	71(22.9%)
Cause
Pneumonia	263(84.8%)	201(64.8%)	< 0.001*
From abdomen	11(3.5%)	18(5.8%)
From neck/mediastinum	1(0.3%)	3(1.0%)
Cancer related	17(5.5%)	33(10.6%)
Iatrogenic	3(1.0%)	23(7.4%)
Trauma	0(0.0%)	15(4.8%)
From esophagus	3(1.0%)	3(1.0%)
Others	12(3.9%)	14(4.5%)
Lab data
WBC (/µL), mean ± SD	14,082.10 ± 7,223.08	13,493.71 ± 6,493.04	0.435
ANC (/µL), mean ± SD	11,915.09 ± 7,505.23	11,389.00 ± 6,119.64	0.716

CCI Charlson comorbidity index; WBC white blood count; ANC absolute neutrophil count.

Pathological findings and pleural fluid analysis

A substantial proportion of empyema cases in our study were related to pneumonia, with the sole operation group comprising 263 patients (84.8%) compared to 201 patients (64.8%) in the operation after tube thoracostomy group. Tuberculosis (TB) empyema was slightly more common in the operation after tube thoracostomy group, occurring in 12 patients (6.0%) versus 11 patients (4.2%) in the sole operation group. The prevalence of chronic pleuritis (Phase III empyema) was similar between the two groups, affecting 60 patients (19.4%) in the sole operation group and 71 patients (22.9%) in the operation after tube thoracostomy group. Cancer-related empyema was more prevalent in the operation after tube thoracostomy group (10.6%) compared to the sole operation group (5.5%), with the predominant cancer types being lung cancer (adenocarcinoma and squamous cell carcinoma [SqCC]), esophageal cancer (SqCC), liver cancer (hepatocellular carcinoma), and tracheal malignant tumors (SqCC). These cases were primarily due to primary tumors with pleural metastasis, leading to empyema. Cytological analysis revealed a minor presence of atypia and non-small cell carcinoma in both groups, with 4 patients (2.0%) showing atypia in the sole operation group and 7 patients (2.2%) exhibiting atypia or non-small cell carcinoma in the operation after tube thoracostomy group. Additionally, biochemical analysis of pleural fluid characteristics demonstrated no significant differences in pH, glucose, LDH, protein, and ADA levels between the two groups, indicating comparable biochemical profiles.

Univariable analysis of primary outcomes

Univariable analysis was performed to analyze primary outcomes. The operation time and the time between diagnosis and operation were significantly shorter in the sole operation group (Table 3). The ICU stay, ventilator duration, hospital stay, 30-day re-intervention rate, and hospital mortality rate were significantly lower in the sole operation group (Table 4). The 30-day readmission rate was lower in the sole operation group but not statistically significant.

Table 3. Univariable analysis of peri-operative characteristics.

	Sole operation	Operation after tube thoracostomy	p value
Duration between diagnosis and operation (days), mean ± SD	3.19 ± 5.07	9.98 ± 10.74	< 0.001*
Operation time (minutes), mean ± SD	112.49 ± 37.40	127.55 ± 46.32	< 0.001*
Pleural fluid amount (ml), mean ± SD	649.93 ± 457.17	482.97 ± 478.06	< 0.001*
Positive tissue culture	128(41.3%)	133(42.9%)	0.684

Table 4. Univariable analysis of surgical outcome.

	Sole operation	Operation after tube thoracostomy	p value
ICU stay (days), mean ± SD	0.19 ± 0.77	9.11 ± 18.41	< 0.001*
Ventilator duration (days), mean ± SD	0.02 ± 0.19	11.03 ± 40.10	< 0.001*
Hospital stay (days), mean ± SD	15.07 ± 11.37	30.77 ± 41.20	< 0.001*
30-day re-admission	29(10.5%)	43(15.6%)	0.077
30-day re-intervention	1(0.4%)	12(4.3%)	0.002*
Respiratory care center	0(0.0%)	34(11.0%)	< 0.001*
Hospital mortality	12(3.9%)	46(14.8%)	< 0.001*
30-day mortality	5(1.8%)	5(1.8%)	> 0.999

ICU Intensive care unit.

Overall survival and disease-free survival

The 1-year OS rates of patients with sole operation and operation after tube thoracostomy, respectively, were 89.51% and 72.27% (Fig. 1, p < 0.001), and the 1-year EFS rates of patients with sole operation and operation after tube thoracostomy, respectively, were 94.79% and 90.64% (Fig. 2, p = 0.047). We concluded that there was a significant difference between these two treatment strategies in both the 1-year OS rate and the 1-year EFS rate.

Fig. 1 [Images not available. See PDF.]

Kaplan-Meier curves stratified by treatment strategies (operation with or without pre-operative tube thoracostomy) are plotted for overall survival probability. P values were acquired by using the log-rank test.

Fig. 2 [Images not available. See PDF.]

Kaplan-Meier curves stratified by treatment strategies (operation with or without pre-operative tube thoracostomy) are plotted for event-free survival probability. P values were acquired by using the log-rank test.

Discussion

Summary and potential reasons for outcome differences

This study compared outcomes between patients who underwent sole surgical decortication and those who had surgery after tube thoracostomy for late-phase empyema. Our findings demonstrate that the sole operation group had significantly better outcomes, including lower hospital mortality (3.9% vs. 14.8%, p < 0.001), lower re-intervention rates (0.4% vs. 4.3%, p = 0.002), and shorter hospital stays (15.07 vs. 30.77 days, p < 0.001). One potential reason for these differences is the shorter time between diagnosis and operation in the sole operation group (3.19 vs. 9.98 days, p < 0.001). Delays in surgical intervention may allow disease progression, making surgery more complex and less effective.

Importance of early surgical intervention

Early surgical intervention in empyema management has been associated with better outcomes. The recent ERS Task Force report emphasizes that surgical referral and discussion should be initiated as early as possible, ideally with surgery occurring within 10 days of medical presentation⁵. This aligns with our findings, where the sole operation group had earlier surgical intervention and better outcomes.

Stages II and III empyema involve fibrin deposition and pleural thickening, leading to lung entrapment^4,6. Early surgical decortication can effectively remove the organized fibropurulent material, allowing lung re-expansion and preventing long-term pulmonary impairment. Delaying surgery may result in a more complex procedure due to dense adhesions and increased risk of complications^24,25.

Comparison with previous studies

Our findings align with previous studies emphasizing the benefits of early surgical intervention. Tong et al.¹⁴ reported that patients who underwent early VATS decortication had shorter hospital stays and lower morbidity. Wozniak et al.¹⁵found that choosing surgery as the first intervention was associated with better outcomes compared to initial tube thoracostomy. In a meta-analysis by Sonnappa et al., early surgical intervention was associated with higher treatment success rates and reduced hospital stays in pediatric empyema cases²⁶. Semenkovich et al.¹⁶ observed that higher readmission and re-intervention rates were seen in patients managed with chest tubes, suggesting that some of these patients may benefit from earlier definitive surgical intervention. This supports the notion that delays in surgical treatment are associated with worse outcomes.

Limitations

This study has several limitations. Firstly, it is a retrospective study from a single center, which may limit the generalizability of our findings. Secondly, although we performed propensity score matching to balance baseline characteristics between the two groups, unmeasured confounding factors may still influence the outcomes. Notably, after propensity score matching, there were slightly more malignant cases in the operation after tube thoracostomy group, which may have affected the outcomes. Additionally, the number of patients in the operation after tube thoracostomy group may not be sufficient to determine if their prognosis is particularly poor after a certain number of days post-procedure.

During the study period (2012–2021), clinical practices varied, and earlier surgical referral was not always implemented. This may have contributed to the longer duration between chest tube insertion and surgery in our operation after tube thoracostomy group. Further prospective studies are needed to confirm our findings and explore the optimal timing for surgical intervention.

Conclusion

Empyema is a serious medical condition that requires timely and appropriate management to minimize complications and improve outcomes. While various treatment options are available, our study suggests that direct surgical decortication without pre-operative tube thoracostomy leads to better outcomes in patients with stage II and III empyema. Immediate surgical decortication upon diagnosis is a simpler and more effective approach. By providing evidence from a large patient cohort, our findings support current recommendations for early surgical management of late-stage empyema and may influence clinical guidelines and decision-making processes.

Acknowledgements

The authors wish to acknowledge the help of the Changhua Christian Hospital Big Data Center in data collection and in serving as statistical advisors.

Author contributions

Shao-Syuan Tong wrote the main manuscript and prepared the Tables 1, 2, 3 and 4; Figs. 1 and 2; Bing-Yen Wang conducted the concept and supervised the project; Yi-Ling Chen collected the data and performed statistical analysis; Ya-Fu Cheng, Ching-Yuan Cheng, Chang-Lun Huang, and Wei-Heng Hung assisted with data analysis and provided critical feedback to shape the research and manuscript. All authors reviewed the manuscript.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to the privacy of individuals that participated in the study but are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Internal Review Board of Changhua Christian Hospital (Approval Number: 230323). The need for obtaining informed consent was waived due to the retrospective nature of the study.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Light, RW. Parapneumonic effusions and empyema. Proc. Am. Thorac. Soc.; 2006; 3, pp. 75-80.1:CAS:528:DC%2BD28XjtV2mu78%3D

2. Davies, HE; Davies, RJ; Davies, CW. Management of pleural infection in adults: British thoracic society pleural disease guideline 2010. Thorax; 2010; 65, pp. ii41-ii53.

3. Bedawi, EO; Hassan, M; Rahman, NM. Recent developments in the management of pleural infection: a comprehensive review. Clin. Respir J.; 2018; 12, pp. 2309-2320.

4. Light, RW. Parapneumonic effusions and empyema. Chin. Chest Med.; 1985; 6, pp. 55-62.1:STN:280:DyaL2M3ivFalsg%3D%3D

5. Bedawi, EO; Hassan, M; Rahman, NM. ERS/EACTS statement on the management of pleural empyema. Eur. Respir J.; 2023; 61, 2201062.

6. Hassan, M; Cargill, T; Harriss, E. The medical and surgical management of pleural empyema. Curr. Respir Med. Rev.; 2019; 15, pp. 330-339.

7. Rahman, NM; Chapman, SJ; Davies, RJ. The management of parapneumonic effusions and empyema. Curr. Opin. Pulm Med.; 2008; 14, pp. 345-352.

8. Li, Y; Wang, J; Chen, P. Clinical characteristics and outcomes of patients with thoracic empyema: a retrospective study. Ann. Palliat. Med.; 2021; 10, pp. 1295-1303.

9. Bédat, B; Goudjil, F; Radu, DM. Management of pleural empyema: a comparative analysis of medical thoracoscopy and video-assisted thoracic surgery. BMC Pulm Med.; 2019; 19, pp. 1-8.

10. Rahman, NM et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl. J. Med.; 2011; 365, pp. 518-526.1:CAS:528:DC%2BC3MXhtVars7nN

11. Scarci, M et al. EACTS expert consensus statement for surgical management of pleural empyema. Eur. J. Cardiothorac. Surg.; 2015; 48, pp. 642-653.

12. Son, HS et al. Early surgery versus conventional treatment in complicated parapneumonic effusion and empyema: a meta-analysis. Ann. Thorac. Surg.; 2019; 108, pp. 1916-1927.

13. Liu, F; Chen, X; Wang, Y. Video-assisted thoracoscopic surgery versus open thoracotomy for thoracic empyema: a meta-analysis. Interact. Cardiovasc. Thorac. Surg.; 2020; 30, pp. 359-366.

14. Tong, BC et al. Outcomes of video-assisted thoracoscopic decortication. Ann. Thorac. Surg.; 2010; 89, pp. 220-225.

15. Wozniak, CJ et al. Choice of first intervention is related to outcomes in the management of empyema. Ann. Thorac. Surg.; 2009; 87, pp. 1525-1531.

16. Semenkovich, TR; Olsen, MA; Puri, V. Current state of empyema management. Ann. Thorac. Surg.; 2018; 105, pp. 1589-1596.

17. Park, JS et al. Early versus late surgical treatment in patients with pleural empyema: a propensity-matched analysis. Ann. Thorac. Surg.; 2011; 92, pp. 225-229.

18. Light, RW; Macgregor, MI; Luchsinger, PC; Ball, WC. Jr. Pleural effusions: the diagnostic separation of transudates and exudates. Ann. Intern. Med.; 1972; 77, pp. 507-513.1:STN:280:DyaE3s%2FmsFGkug%3D%3D

19. Hooper, C; Lee, YC; Maskell, N. Investigation of a unilateral pleural effusion in adults: British thoracic society pleural disease guideline 2010. Thorax; 2010; 65, pp. ii4-ii17.

20. Heffner, JE; Klein, JS; Hampson, C. Diagnostic utility and clinical application of imaging for pleural space infections. Chest; 2010; 137, pp. 467-479.

21. Porcel, JM et al. Pleural fluid analysis and radiographic, sonographic, and CT imaging for identifying complicated parapneumonic effusions. Chest; 2010; 137, pp. 1363-1369.

22. Porcel, JM. Advances in the diagnosis of tuberculous pleuritis. Ann. Transl Med.; 2016; 4, 282.

23. Charlson, ME; Pompei, P; Ales, KL; MacKenzie, C. R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chronic Dis.; 1987; 40, pp. 373-383.1:STN:280:DyaL2s7ms1GnsQ%3D%3D

24. Park, JS et al. Early versus late surgical treatment in patients with pleural empyema. Ann. Thorac. Surg.; 2011; 91, pp. 225-229.

25. Maskell, NA et al. U.K. Controlled trial of intrapleural streptokinase for pleural infection. N Engl. J. Med.; 2005; 352, pp. 865-874.1:CAS:528:DC%2BD2MXhvFGkt7s%3D

26. Sonnappa, S et al. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Am. J. Respir Crit. Care Med.; 2006; 174, pp. 221-227.