Who is at risk for tPA/DNase treatment failure in empyema?—protocol to identify key predictors for early surgical intervention from a retrospective study

Introduction

Empyema, characterized by the accumulation of pus in the pleural cavity, represents a significant clinical challenge due to its complex pathophysiology and high morbidity (1). In the United States, the incidence of parapneumonic empyema is estimated to be around 6 in 100,000 people, with an in-hospital mortality rate of 16% for inpatients over the age of 65 years old (2). This condition often arises as a complication of pneumonia, thoracic surgery, or trauma, and despite advances in medical treatment, it continues to pose substantial treatment difficulties (3). The standard approach to managing empyema includes antibiotic therapy and drainage procedures, with intrapleural administration of tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) emerging as a particularly effective intervention (4-6). tPA and DNase work synergistically to break down fibrinous adhesions and reduce the viscosity of the pleural fluid, thereby facilitating more effective drainage (7,8).

Despite the high success rate of tPA/DNase therapy, approximately 20–30% of patients experience treatment failure and subsequently require surgical intervention, such as video-assisted thoracoscopic surgery (VATS) (9-11). Understanding tPA/DNase treatment failure predictors is crucial for optimizing patient management and outcomes (12). Identifying these predictors can help clinicians stratify patients by risk and direct high-risk individuals towards early surgical intervention, potentially improving prognosis and reducing the duration and costs associated with prolonged illness (13).

A previous study suggested various factors that might influence the success of tPA/DNase therapy, including patient demographics, comorbid conditions, and biochemical markers in pleural fluid (13). However, comprehensive analyses integrating these variables are needed to better understand their impact on treatment outcomes. This study addresses this gap by identifying clinical and biochemical predictors of tPA/DNase treatment failure in a large cohort of empyema patients treated at Northeast Georgia Medical Center. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1256/rc).

Methods

Study design and data source

We retrospectively analyzed patients treated with tPA/DNase for empyema at Northeast Georgia Medical Center between January 2018 and December 2023 (Figure 1). We obtained clinical and demographic details of patients from the Epic^® Caboodle data warehouse (Epic Systems Corporation, Verona, WI, USA). Association Connecting Electronics Industries (IPC) Global provided systems integration, and we leveraged their in-process Data Factory innovation running on an AWS^® VPC (Amazon Web Services, Seattle, WA, USA). Ten percent of collected data was validated to ensure the accuracy of the dataset and deidentified in compliance with federal and institutional guidelines to protect patient health information.

Figure 1 Patient selection and treatment outcomes flowchart. This flowchart illustrates the selection process and treatment outcomes for empyema patients treated at Northeast Georgia Medical Center between January 2018 and December 2023. tPA, tissue plasminogen activator; DNase, deoxyribonuclease; VATS, video-assisted thoracoscopic surgery.

Inclusion and exclusion criteria

We included all hospitalized adult patients (18 years old and older) diagnosed with empyema who received tPA/DNase therapy during the specified period. ICD-10 CM code J86 was used to identify empyema from the electronic health record. We excluded patients who did not complete at least two doses of tPA/DNase therapy, declined treatment, or were transferred to another facility before treatment completion. A complete course of therapy was defined as the administration of at least two doses of tPA (10 mg) and DNase (5 mg), diluted in 50 mL of saline, and instilled through the chest tube with a dwell time of one hour per dose. Therapy was repeated twice daily for up to three days. Patients who received less than two doses due to clinical reasons indicating early treatment failure were included in the analysis, as they may represent cases that benefit from early surgical intervention (VATS). This inclusion allows us to better identify predictors of treatment failure, even in patients who did not receive the full course of tPA/DNase therapy.

In this study, we excluded 639 patients who received either tPA or DNase alone, as our focus was on evaluating the effectiveness of the combined tPA/DNase therapy, which is the standard treatment for empyema. By concentrating on patients who received both agents, we aimed to provide a consistent study population and assess predictors of treatment failure specific to the combined regimen. While some patients may have responded to monotherapy, and others were better surgical candidates for VATS, they were not included in this analysis. Future studies could explore outcomes in these subgroups to provide a broader understanding of treatment responses.

From the initial cohort of 12,034 patients identified using the ICD-10 code for empyema, only 223 patients met the inclusion criteria after applying our selection process (Figure 1). To ensure diagnostic accuracy, 10% of the total cohort charts were reviewed. The exclusion of patients who received only monotherapy or went directly to VATS reduced the cohort size but allowed for a more focused evaluation of combined tPA/DNase therapy outcomes. We acknowledge that surgery as an outcome can be subjective and may vary by clinical judgment or institutional guidelines. The observed tPA/DNase failure rate (12.6%) was higher than previously reported rates, possibly reflecting differences in practice patterns or patient selection. Lastly, we ensured that failure rate references were updated to reflect comparable adult empyema populations rather than pediatric or other conditions.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Northeast Georgia Health System IRB reviewed the study and approved it for exemption. Informed consent was not required for this study due to the retrospective nature and no identifying personal information being included.

Outcomes

At the start of treatment, we collected demographic data, comorbidities, pleural fluid analysis, radiological data, and laboratory data. Our primary outcome of interest was the failure of tPA/DNase therapy, which required surgical intervention, specifically VATS.

Group A included all patients with empyema admitted to Northeast Georgia Medical Center between 2018 and 2023 who received tPA/DNase and were successfully treated with tPA/DNase. Successful treatment was defined based on established clinical and radiographic criteria, such as resolution of symptoms, normalization of white blood cell counts, and clear chest X-ray or computed tomography (CT) scans.

Group B consisted of patients admitted to Northeast Georgia Medical Center between 2018 and 2023 who failed to respond to at least 2 doses of tPA/DNase treatment during the same admission and subsequently required VATS and decortication. Failure was determined by the lack of resolution of empyema, as evidenced by persistent symptoms, elevated white blood cell counts, and/or unchanged or worsening radiographic findings.

Statistical analysis

We performed all statistical analysis using STATA MP 16.0 (Stata-Corp.). We describe categorical data using frequency counts and percentages. We report means, standard deviation (SD), medians, and interquartile ranges for continuous variables as appropriate for their distribution. We used Chi-square and Wilcoxon Rank tests to compare categorical and continuous variables. For all analyses, we deemed statistical significance a P value <0.05.

We performed multivariable logistic regression to examine the association between the variables and tPA/DNase failure. First, we tested the univariate association of putative risk factors with tPA/DNase failure. Variables associated with failure at a P value of <0.2 were candidates for inclusion in our final model. We also examined pleural fluid pH, lactate dehydrogenase (LDH), and protein level markers to examine their association with tPA/DNase failure. These variables were log-transformed (natural logs) as they were not normally distributed.

We then used the backward elimination method and kept significant variables at a P value of <0.05. The model was then bootstrapped using 1,000 bootstrap replicates and case resampling with replacement from the original dataset.

Results

Study population

The study included 223 empyema patients treated with tPA/DNase at Northeast Georgia Medical Center between January 2018 and December 2023. Among these, 28 patients (12.6%) experienced treatment failure and required subsequent VATS (see Figure 1). The demographics and baseline characteristics of the study population are summarized in Table 1. The median average age of patients was lower in those with tPA/DNase failure (60.5 vs. 67 years old, P=0.03). No significant differences were observed regarding gender, race, or ethnicity. We did not observe any significant differences in co-morbidities, including smoking status, between the two groups.

The rate of positive body fluid cultures was higher in patients who experienced tPA/DNase treatment failure compared to those who did not (50% vs. 20.2%, P=0.002). While a positive culture can provide confirmation of empyema, the diagnosis in our study was not solely dependent on culture results. Empyema was diagnosed based on a combination of clinical, radiographic, and pleural fluid characteristics (e.g., low pleural fluid pH, elevated LDH, and imaging findings suggestive of infection). Negative cultures may occur due to prior antibiotic use or other factors, but these cases were still classified as empyema if the clinical and radiographic evidence supported the diagnosis. The most common organisms isolated were Streptococcus (n=25), Staphylococcus aureus (S. aureus) (n=17), Escherichia coli (E. coli) (n=3), Klebsiella (n=3), and Pseudomonas (n=2) (Table 1). We did not observe any radiological findings associated with treatment failures. Similarly, we did not observe any admission vitals or labs associated with treatment failure.

Pleural fluid analysis

Pleural fluid analysis data were missing in about 50% of the cases, with fluid pH missing in 60%. For the patients with complete pleural fluid analyses, we compared several markers between those who experienced treatment success and those who experienced failure. The median LDH levels in pleural fluid were 643 U/L [interquartile range (IQR), 307–1,380 U/L] in the success group and 858 U/L (IQR, 485–1,681 U/L) in the failure group (P=0.31). The median pH levels were 7.28 (IQR, 7.15–7.39) in the success group and 7.29 (IQR, 6.94–7.3) in the failure group (P=0.17). The median protein levels were 4 g/dL (IQR, 3.2–4.5 g/dL) in the success group and 3.8 g/dL (IQR, 3.2–4.25 g/dL) in the failure group (P=0.93). Despite these comparisons, no significant associations were observed between these biochemical markers and treatment failure (Table 1).

Treatment outcomes

Out of the 223 patients, 195 (87.4%) were successfully treated with tPA/DNase (Group A), while 28 (12.6%) required VATS due to treatment failure (Group B). The variables associated with treatment failure included age [odds ratio (OR) =0.97; 95% confidence interval (CI): 0.94–0.99] and the presence of staphylococcal empyema (OR =4.1; 95% CI: 1.2–14.5).

The model demonstrated good predictive performance with an area under the curve (AUC) of 0.76, indicating a fair discriminative ability to differentiate between treatment outcomes.

Discussion

This study provides critical insights into tPA/DNase treatment failure predictors in empyema patients treated at Northeast Georgia Medical Center. By analyzing a substantial cohort of 223 patients over a 5-year period, we identified several factors like younger age and presence of S. aureus in pleural fluid cultures that significantly influence treatment outcomes and necessitate surgical intervention like younger age and presence of S. aureus in pleural fluid cultures.

Our findings indicate that younger patients are more (median age of 60.5 vs. 67 years old) likely to experience treatment failure with tPA/DNase therapy, requiring subsequent VATS. This contrasts with the general expectation that older patients with more comorbidities would fare worse. The association between younger age and treatment failure (OR =0.97; 95% CI: 0.94–0.99; P=0.03) suggests that younger individuals might present with more aggressive or advanced stages of empyema or delay seeking treatment, leading to poorer outcomes. This points to the importance of not underestimating the severity of empyema in younger patients and considering early, aggressive interventions when necessary.

The presence of S. aureus in pleural fluid cultures was another significant predictor of treatment failure (OR =4.1; 95% CI: 1.2–14.5; P=0.03). The higher prevalence of staphylococcal infections among those who failed tPA/DNase therapy emphasizes the critical role that bacterial etiology plays in treatment outcomes. This finding aligns with the need for prompt identification and management of specific bacterial infections to enhance the efficacy of non-surgical treatments. Clinicians should be particularly vigilant in monitoring for S. aureus in patients undergoing tPA/DNase therapy and consider adjunctive therapies or early surgical consultations to mitigate the risk of treatment failure.

Interestingly, biochemical markers such as pleural fluid pH, LDH, and protein levels, which were initially hypothesized to be significant, did not show a strong association with treatment outcomes in our study. These markers may still hold clinical relevance despite the lack of statistical significance. Their variability or the influence of other overriding clinical factors could contribute to the observed outcomes. The missing data in pleural fluid analysis, particularly for pH, which was absent in 60% of cases, could have also influenced these findings. Future studies should address this data gap further to elucidate the role of biochemical markers in empyema management, as these markers might still provide valuable clinical insights despite their statistical insignificance.

Our analysis also indicated that patients with positive pleural fluid cultures, regardless of the specific organism, were more likely to fail tPA/DNase therapy. The significant difference in the culture positivity rate between those who succeeded and those who failed (20.2% vs. 50%, P=0.002) reinforces the importance of microbiological evaluation in treating empyema. Identifying and targeting infectious agents with appropriate antimicrobial therapy could improve treatment success rates.

Furthermore, the model’s predictive performance, with an AUC of 0.76, indicates a fair ability to differentiate between patients likely to succeed or fail tPA/DNase therapy. This predictive capacity suggests integrating clinical and microbiological data into treatment protocols can enhance decision-making and patient outcomes.

The association between younger age and tPA/DNase treatment failure may be influenced by factors beyond disease severity, such as better fitness for surgery, as younger patients are more likely to be considered for early surgical intervention compared to older patients who may be less suitable for surgery due to comorbidities. Additionally, the differing guidelines from the Society of Thoracic Surgeons (STS), which advocates for earlier surgery, and the British Thoracic Society (BTS), which supports a more prolonged trial of tPA/DNase, could have impacted treatment decisions in our cohort. Older patients may have been more acutely ill, leading clinicians to favor non-surgical approaches first. Regarding timing, most patients who underwent surgery did so after 2–3 days of tPA/DNase therapy, although there was some variability. Future studies should further explore the role of age, clinical fitness, and the timing of surgery in relation to treatment failure in empyema management.

These findings emphasize the importance of a multifaceted approach to managing empyema, where early surgical intervention, aggressive infection management, and thorough microbiological assessments are essential. By focusing on these strategies, clinicians can enhance the effectiveness of treatments and potentially reduce the need for invasive procedures, ultimately leading to better patient care and outcomes.

Limitations

One limitation of this study is the reliance on surgical intervention (VATS) as the primary outcome for treatment failure. While surgery provides a clear dichotomous endpoint, it is influenced by the clinical judgment of the treating team, which can vary between institutions, surgeons, and pulmonologists. This subjectivity could potentially affect the consistency of the outcome measure. More objective criteria, such as changes in chest X-ray opacification or CT scan estimates of residual effusion, may offer more standardized and quantifiable metrics for assessing treatment response. Future studies should consider incorporating these radiologic measures to provide a more objective assessment of treatment outcomes.

Unfortunately, data on the duration of symptoms prior to the initiation of tPA/DNase therapy was not consistently available in the patient records and, therefore, was not included in the analysis. We recognize that symptom duration is a critical factor influencing the success of fibrinolytic therapy, as prolonged symptoms can lead to more organized pleural collections that may not respond as well to fibrinolytics.

While our study provides valuable insights into tPA/DNase treatment outcomes, a key limitation is the incomplete availability of pleural fluid analysis and culture data, which were obtained for approximately 50% of the overall cohort. In the surgical group (Group B), all 28 patients had culture data, whereas data were available for only half of the non-surgical group (Group A). This difference could introduce some selection bias. Additionally, pleural fluid cultures were collected using a variety of methods, including blood culture bottles in some cases, which may have enhanced yield by 20%. While this variability in collection techniques could influence the detection of pathogens, it reflects real-world clinical practice. Standardizing culture collection and ensuring comprehensive pleural fluid analysis across all patients in future studies would provide a more uniform data set and further validate these findings.

Conclusions

This study identifies key clinical and microbiological predictors of tPA/DNase treatment failure in empyema patients, offering crucial insights for improving patient management. The findings reveal that younger age and S. aureus infections are significant predictors of treatment failure, indicating that these patients may benefit from more aggressive and early surgical interventions. The lack of association with biochemical markers such as pleural fluid pH, LDH, and protein levels suggests that these variables may have limited utility in predicting treatment outcomes, emphasizing the need for a comprehensive clinical evaluation. The results highlight the necessity for a multifaceted treatment approach, integrating early surgical intervention and robust infection management, to enhance the effectiveness of tPA/DNase therapy.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1256/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1256/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1256/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1256/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Northeast Georgia Health System IRB reviewed the study and approved it for exemption. Informed consent was not required for this study due to the retrospective nature and no identifying personal information being included.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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