Pleural Space Diseases and Their Management: What is the Role of Intrapleural Fibrinolytic Therapy?

Parapneumonic Effusions to Empyema

Parapneumonic effusions, pleural space infections, and empyemas represent significant clinical challenges, often contributing to considerable morbidity and mortality. ¹¹ These conditions typically arise from viral and bacterial pneumonia, and approximately 60% of empyema cases are linked to a primary pneumonic process.^11,12

Parapneumonic effusions occur when inflammation extends to the pleural cavity, resulting in fluid exudation. ¹¹ When this fluid becomes infected, it can progress to a pleural space infection and potentially an empyema, characterized by loculated, thick, purulent material.^11,12 Other etiologies include complications from thoracic surgery, trauma, esophageal perforation, thoracentesis, and subdiaphragmatic infections.^11,12

The evolution of parapneumonic effusion typically follows three stages ¹² :

1. Exudative stage: The initial stage involves inflammatory cell accumulation in the pleural space fluid due to high capillary microvascular permeability driven by proinflammatory cytokines, like interleukin-8 and tumor necrosis factor-α. ¹³ At this stage, pleural fluid is a simple parapneumonic effusion, requiring treatment with antibiotics but rarely needing formal drainage. ¹⁴

The clinical course can range from spontaneous resolution to chronic empyema, which carries high risk of bronchopleural fistula or spontaneous perforation through the chest wall.^12,15

Retained Hemothorax

Hemothorax is the accumulation of blood or fluid in the pleural space with a hematocrit level greater than 50% and accounts for significant morbidity and mortality with approximately 300 000 cases in the United States annually. ⁸ Hemothorax can resolve within weeks or progress to retained hemothorax (RH), fibrothorax, or empyema. ¹⁶ The etiology of a hemothorax is commonly following traumatic hemothorax or surgery. RH is specifically defined as the presence of blood clots greater than 500 mL or when one-third of the blood remains undrained by a chest tube after 72 hours. ¹⁶ RH is a risk factor for pneumonia, empyema, and fibrothorax as well as increased morbidity and mortality. ¹⁶

The pathophysiology of retained hemothorax involves a complex interplay between the inflammatory, fibrinolysis, and coagulation systems. Fibrin loculations form over time and prevent effective drainage. ⁷ This clotted blood product leads to an inflammatory response and the progression to fibrothorax, restricting appropriate drainage even further. This progression underscores the importance of deeper understanding into the exact underlying mechanisms of retained hemothorax.

Malignant Pleural Effusions

MPE is characterized by significant accumulation of exudate within the pleural space coinciding with malignant cells or tumor tissues. ¹⁷ Common causes include metastases from lymphomas, lung cancer in men, and breast cancer in women.^9,10 Annually, up to 150 000 cases of MPE are diagnosed in the U.S. with financial impacts reaching the billions of dollars. ¹⁸ Patients often present with dyspnea and can have associated dry cough, chest pain, or early satiety from pressure against the stomach. ¹⁹ Prognosis is generally poor and signifies the presence of advanced, metastatic disease. ²⁰ The LENT score, which incorporates pleural fluid lactate dehydrogenase, the Eastern Cooperative Oncology Group performance score, utilizing neutrophil-to-lymphocyte ratio and tumor type, is often used to assess prognosis. ¹⁷ Life expectancy for MPE patients ranges from 3 to 12 months and treatment is often palliative in nature. ¹⁸

General Treatment Approach

The management of pleural space infections typically follows a stepwise approach, focused on antibiotic therapy and source control through drainage via tube thoracostomy and, if necessary, can be escalated to surgical intervention.^5,29 Non-operative management with tube thoracostomy is often hindered by the formation of loculations, impeding effective drainage. ³⁰ Consequently, patients often experience treatment failure, necessitating surgical intervention.^2,29,31 Additionally, many individuals with pleural space infections have comorbid conditions that significantly increase their risk of adverse outcomes from surgical procedures, making alternative therapies necessary. ³²

The incorporation of fibrinolytic therapy during the tube thoracostomy phase of treatment has enhanced successful pleural drainage. ³¹ IPFT offers a valuable option for patients who have not responded to antibiotic therapy and initial tube thoracostomy and are at high risk of poor outcomes from surgical intervention.^29,32 The MIST-2 trial demonstrated that the intrapleural administration of tPA combined with DNase markedly improved the drainage of infected pleural fluid. ³¹ This was evidenced by a 30% reduction in pleural collections on chest x-ray and a decreased need for surgical intervention. Notably, the study also found that using either DNase or tPA alone did not yield effective results. ³¹ Current IPFT follows the original MIST-2 protocol dosing, using 10 mg tPA and 5 mg DNase administered through the chest tube followed by a saline flush and one-hour clamping interval. ³¹ This therapy is repeated twice a day for three days. While lower doses may be effective, the standard regimen remains based on MIST-2 until further randomized clinical control trials have been validated.^33,34

The 2010 British Thoracic Society (BTS), 2015 European Association for Cardiothoracic Surgery, and the 2017 American Association of Thoracic Surgeons (AATS) guidelines recommend against the routine use of IPFT for patients with complicated pleural effusions or early empyema.^35-37 Instead, IPFT is reserved for patients with loculated effusions, non-responsive to tube thoracostomy, or poor surgical candidates. They recommend video-assisted thoracoscopic surgery (VATS) with thoracic washout as the first-line approach.^35-37 These recommendations stem from a lack of long-term outcome data and the heterogeneity of patient populations in existing studies. ³⁵ A 2012 meta-analysis highlighted the benefits of IPFT in managing parapneumonic effusions and empyema but found insufficient evidence to support its routine use for all patients. ³⁸

Similarly, RH can resemble pleural infection and treatment with tPA/DNAse has gained traction in an attempt to avoid the need for surgical intervention or fibrothorax, but with limited efficacy. A recant meta-analysis concluded that IPFT for traumatic RH allowed 81-92% of patients to be discharged without needing additional surgery. However, the authors noted that the analysis was constrained by the limited number of studies and their overall low quality.^7,39-41 Surgical intervention remains the definitive treatment for complex pleural space disease in appropriate patients. ³⁵ VATS is preferred over open thoracotomy technique as it is less invasive with similar rates of morbidity and mortality but lower overall length of hospital stay.^42-44 Kugler and colleagues found that thoracic irrigation during the placement of thoracotomy tubes significantly reduced the rate of retained hemothorax requiring secondary interventions. They also noted that this combination of thoracic irrigation and tube placement effectively removed the majority of blood within the thoracic cavity. ⁴⁵ However, for some patients, the severity of disease makes surgery unfeasible, highlighting the importance of tube thoracostomy and IPFT as source control options.^29,32

The treatment of MPE is unique from that of paraneumonic effusion, empyema and retained hemothorax due to its cancer etiology, Management has evolved over the past 14 years, becoming less invasive and more focused on palliative care and quality of life. ²⁰ Historically, repeated thoracentesis was employed to drain the MPE and manage symptoms as fluid buildup became significant, depending on the patient’s life expectancy. ⁴⁶ Another option for treatment was a surgical pleurectomy; however, the risks associated with complications, perioperative mortality, and deterioration in quality of life have rendered this approach less common in favor of more definitive procedures. ¹⁸ A review by Bibby et al ²⁰ found that there is no significant difference in outcomes between surgical interventions and pleurodesis, but fibrinolytic therapies were not considered in this study. Currently, the preferred treatment for multiloculated MPE involves definitive pleural procedures, such as pleurodesis, indwelling pleural catheter (IPC), or both, to minimize the need for recurrent invasive procedures. Pleurodesis aims to create an inflammatory response between two layers of pleura and facilitate their adhesion to prevent fluid accumulation. ¹⁸ Talc or tetracyclines are the agents of choice for pleurodesis, administered either through a thoracoscope or via thoracostomy tube. ¹⁹ In IPC treatments, silicone tubes are inserted percutaneously, equipped with a one-way valve that allows for the intermittent drainage of pleural fluid. ¹⁸ These management techniques are generally effective as palliative care for MPE, provided the effusions do not become multiloculated leading to complicated drainage of the pleural space. ⁴⁷

Complications, such as fibrinous adhesions leading to loculated effusions, can hinder effective drainage and make pleurodesis challenging, ²⁰ resulting in multiloculated effusions. ⁹ While the exact mechanism of fibrinous adhesion formation is unknown, it is well-established that malignancies in the pleural space cause chronic inflammation, creating a procoagulant state characterized by decreased fibrinolytic activity and excessive fibrin deposition. ⁴⁸ Additionally, inflammation from MPEs increases vascular permeability, leading to greater pleural fluid production and more significant accumulations compared to a typical pleural effusion. ⁹ Tumor growth further exacerbates the condition by destroying surrounding lymphatic vessels, complicating pleural fluid drainage. ⁴⁸ Recent studies suggest IPFT are promising for treating multiloculated MPEs. Chan et al found 83% of patients receiving tPA and 80% receiving tPA-DNase had improved drainage, with no significant differences in outcomes or complications between treatments. ⁴⁷

Despite promising results, further research is needed to establish dosing guidelines for IPFT in MPE.^9,47,49 Current case studies have reported success using 10 mg/30 mL doses of tPA, occasionally with a 5 mg/30 mL dose of tPA-DNase.^19,22,49 However, a case study from M. Nemet et al described following their hospital empyema guidelines for tPA dosing of 5 mL of alteplase in 50 mL of normal saline that can be administered up to three times 24 hours apart. ¹⁹ They encountered hemorrhagic drainage fluid after using a 5 mL dose in one patient and reduced dosing to 2.5 mL in all patients with no further complications and a similar improved drainage rate. ⁹ The initial fear in treating multiloculated MPEs with fibrinolytics was that the increased vascular permeability from malignancy-related inflammation would place patients at an elevated risk for bleeding. ⁹ This has not been a significant outcome in many case reports and trials of intrapleural fibrinolytic therapy, but appropriate dosing needs further study to continue to minimize risk of hemorrhage.^9,47,49 Continued research and clinical trials to refine these treatments to ensure maximum efficacy and safety for patients with multiloculated MPEs is paramount.

Historical Context of Intrapleural Fibrinolytic Therapy

In the late 1940s, IPFT was pioneered by utilizing streptokinase and streptococcal DNase derived from partially purified streptococcal preparations, to target fibrinous pleurisy and empyema. ⁵⁰ The inclusion of streptokinase facilitated fibrin breakdown and reduced the thickness of the purulent material within the pleural space. ⁵⁰ By the late 1980s, successful trials of streptokinase in both adults and children underscored its potential.^2,51 This era also saw the emergence of urokinase, a thrombolytic agent sourced from human neonatal kidney cells, which demonstrated enhancements in pleural fluid drainage and a decrease in the need for subsequent surgical intervention.^52,53 A pivotal trial by Bouros et al, ⁵⁴ comparing the efficacy of streptokinase (250 000 IU) and urokinase (100 000 IU) affirmed that both agents effectively increased pleural fluid drainage with no statistically significant difference between them. Subsequent studies have confirmed the efficacy of streptokinase and urokinase in reducing surgical referrals.^55,56

The Multicenter Intrapleural Sepsis Trial (MIST-1), the largest randomized placebo-controlled trial to date examining fibrinolytic therapy for pleural infection, was conducted amidst ongoing debates about the role of fibrinolytics and considering known limitations seen in smaller studies with streptokinase administration. In this trial, 427 patients received either streptokinase (250 000 IU) or a placebo twice daily for 3 days. The results revealed no substantial benefits of streptokinase in terms of surgery rates, survival, radiographic outcomes, or hospital length of stay. ⁵⁷

Adequate drainage remained a challenge in treatment of pleural space disease due to the high viscosity of intrapleural purulent material. This increased viscosity is primarily attributed to the deoxyribonucleoprotein content within the empyema. ⁵⁸ Simpson et al demonstrated that adding DNase facilitated the passage of this material. ⁵⁸ Subsequent studies reported positive outcomes with the combination therapy of DNase and streptokinase, which was shown to reduce the viscosity of the pleural fluid more effectively than streptokinase alone, urokinase or saline. ³⁰ Successful cases of DNase usage in specific patients began to emerge, further supporting its utility.

A significant advancement was noted when a combination therapy involving tissue plasminogen activator (tPA), initially developed for treating coronary artery thrombosis and stroke, and DNase showed substantial improvement in rabbit empyema, resulting in the production of a large amount of pleural fluid. ⁵⁹ The first human use of interpleural tPA was documented by Walker et al in 2003, paving the way for the Multicenter Intrapleural Sepsis Trial 2 (MIST-2). ⁶⁰

The rationale for the MIST-2 trial’s use of tPA and DNase was ground in prior research demonstrating the potential benefits of fibrinolytic therapy in pleural infections. In 2004, Diacon et al conducted a single-center, randomized, placebo-controlled trial that found intrapleural streptokinase administration reduced the need for surgery and improved clinical success in patients with pleural empyema, although no significant differences were observed until after 7 days of treatment. ⁵⁶ Maskell et al (2005) conducted a larger double-blind trial involving 454 patients with pleural infections, which showed no significant difference between intrapleural streptokinase and placebo regarding mortality, rate of surgery, or hospital length of stay. ⁵⁷

In the MIST-2 trial, 210 patients with pleural infections were assigned to one of the four treatment groups for three days—double placebo, tPA and DNase, tPA and placebo or DNase and placebo. ³¹ The combination of intrapleural tPA and DNase therapy demonstrated significant improvements in fluid drainage, resulting in fewer surgical referrals and shorter hospital stays. ³¹ In contrast, treatment with either DNase alone or tPA alone was found to be ineffective. ³¹ The combination of tPA and DNase, as demonstrated in the MIST-2 trial, has since emerged as the standard treatment for medical management of pleural space diseases, offering superior outcomes in fluid drainage and reducing need for surgical referrals.

Pathophysiology of IPFT

The mechanism underlying IPFT and its failures has been the subject of extensive discussion. The combined use of tPA and DNase is beneficial due to their ability to break down fibrin loculations within the empyema in combination with viscosity reduction, facilitating more effective drainage. The MIST-2 trial dosing protocol was predicated on literature indicating that infected pleural space diseases involved high levels of plasminogen activator inhibitor-1 within the loculations (the native inhibitor of tPA), necessitating multiple repeat doses of tPA (and DNase) over days to overcome this. ³¹

In empyema, neutrophils release neutrophil extracellular traps (NETs) and promote inflammation, which contributes to the formation of fibrin loculations, complicating effective drainage efforts. ⁶¹ tPA promotes fibrinolysis by converting plasminogen (PLG) into the active enzyme plasmin, which dissolves fibrin loculations. ⁶² However, neutrophil elastase cleaves PLG at multiple sites, diminishing the efficacy of tPA due to the lack of full-length PLG ⁶³ (Figure 1).

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Figure 1.

General pathophysiology or pleural space disease and failure of lytics. The inflamed environment of pleural space disease leads to activation of neutrophils and neutrophil elastase release. Elastase degrades plasminogen leading to decreased substrate for tPA in intrapleural lytic therapy to activate for proper fibrin degradation. ⁶¹

While much of the literature suggests that elevated plasminogen activator inhibitor-1 (PAI-1) levels inhibit the effectiveness of tPA, necessitating multiple doses of tPA and DNase, ⁶² it has not been widely emphasized that PAI-1 is conformationally labile and the majority of it is likely inactive. ⁶¹ In addition, it is also known that PAI-1 is readily degraded by neutrophil elastase, rendering it unable to inhibit tPA in highly inflamed environments. ⁶⁴ A recent study using turbidity assays of pleural fluid from patients with complex, infected effusions to measure fibrinolytic activity found that only 10% of patients’ pleural fluid could generate a lytic response to tPA without adding supplemental PLG. ⁶¹ This study ultimately found that neutrophil elastase exhausts the functional PLG supply, contributing to the need for repeat IPFT dosing (Figure 1). It also demonstrated that most patients had no detectable PAI-1 activity after just one day of IPFT, ultimately challenging the notion that PAI-1 is responsible for IPFT failures and the need for multiple doses over multiple days. ⁶¹ These findings highlight the potential for more effective treatment with the addition of PLG to the regimen, although further research is needed to advance this promising approach.

DNase works in conjunction with tPA by degrading DNA and other bacterial components, reducing pleural fluid viscosity and biofilm formation.^62,63,65 DNase alone is ineffective because the degradation products are reabsorbed systemically due to insufficient pleural drainage, and ultimately degradation of extracellular DNA alone does not degrade the fibrin loculations. ⁶² This can lead to the persistence of harmful bacteria and inflammatory components post-degradation. ⁶⁶ This understanding of the physiology behind IPFT highlights the importance of both tPA and DNase administration.

Complications of IPFT

Although IPFT offers a valuable option for enhancing drainage in patients at high risk for surgical management, it comes with its own set of risks. The most reported side effect of local tPA and DNase therapy is pain, which is typically most intense after the first dose. ² Clinical pleural bleeding, defined as requiring a blood transfusion, occurs in only 4.1% of cases. ⁶⁷ Importantly, systemic bleeding was found to be exceedingly rare following local IPFT. Overall, the complications of IPFT are minimal and it remains a safe therapeutic option in high-risk patients. While opting for IPFT may delay definitive treatment with surgical intervention, our ability to predict who will fail remains poor, and the significant surgical morbidity and mortality in this patient population mandates a careful consideration of the risks and benefits of each approach and the need for future research. ³¹

Future Directions, Knowledge Gaps, and Ongoing Research

Knowledge gaps remain in our understanding and management of pleural space diseases, which result in high mortality and mobidity. ³¹ Understanding the underlying causes of the approximately 20-25% failure rate of IPFT is essential, as is exploring the molecular reasons behind its unusually low per-dose efficacy. ² Unlike conditions such as stroke, myocardial infarction, and pulmonary emoblism, IPFT requires multiple doses over multiple days to achieve an effect, highlighting an underlying difference in pathophysiology and therapeutic challenge. These failures and poor efficacy necessitating multiple days of therapy can lead to prolonged hospital stays, increased health care costs, and mortality rates approaching 50%. ² While a historically accepted reason for the failure and poor per-dose efficacy of IPFT is the high levels of plasminogen activator inhibitor-1 (PAI-1), tPA’s native inhibitor, in infected pleural fluid, this has now been challenged with recent studies.^61,68,69

A significant gap in the literature is the insufficient investigation into inflammatory degradation of plasminogen (PLG) into non-functional fragments. When the PLG pool is depleted, fibrinolysis fails due to lack of PLG present to generate plasmin in response to tPA. ⁷⁰ A recent study by Barrett et al ⁷⁰ suggests that PLG depletion via inflammatory degradation by neutrophilic inflammatory proteases, rather than inhibition of tPA by PAI-1, may be responsible for intrapleural lytic failure. If this mechanism is indeed the underlying cause of IPFT failure, it could be addressed clinically. The recent FDA approval of Ryplazim™, the first-ever plasminogen product for clinical use, offers a promising solution for this issue, although this is only approved in use in plasminogen deficiency type 1 and its use as an adjunct in IPFT remains in the pre-clinical stages of study. ⁷¹

Further research is essential to validate the benefits of IPFT in treating pleural space diseases. A well-powered randomized controlled trial (RCT) is needed to assess the impact of fibrinolytic agents and DNase on the clinical outcomes of these patients. Additional studies must investigate the long-term follow-up and complications in patients who have undergone IPFT, comparing these results with those of patients treated with definitive surgical intervention. An intriguing avenue for future research is the potential use of plasminogen in conjunction with current IPFT protocols. ⁶¹ Exploring this combination has the potential to enhance non-surgical management of pleural space diseases, offering a potential valuable alternative to patients who are poor candidates for surgery. Additionally, there is a need to examine the roles of other fibrinolytic regulatory molecules to better understand their exact impact on fibrinolysis in pleural space diseases.

Conclusion

IPFT has emerged as a valuable intervention in the management of pleural space diseases, including intrapleural infections, RH and MPE. ¹ This therapy reduces the need for more invasive surgical procedures by administering fibrinolytic agents into the pleural space to break down fibrinous adhesions and loculations. ² Evidence strongly supports the success of combination therapy with tPA and DNase with several trials demonstrating positive outcomes, such as reduced hospital stays and decreased need for surgical referral. ³¹ However, limitations and potential failures still exist. A deeper understanding of the host, organism, and intrapleural-specific factors linked to success is necessary. ⁷² Scientifically evaluating and optimizing dosing regimens and frequencies is essential. ⁶⁶ These approaches could improve clinical outcomes for patients with pleural space diseases by ensuring more effective treatments, leading to better recovery and reduced hospital stays and invasive procedures.

In summary, while IPFT has made significant strides in the management of pleural space diseases, ongoing research and optimization are key to fully realize its potential. By addressing the current limitations and enhancing our understanding of the underlying mechanisms, we can improve treatment outcomes and offer patients more effective and less invasive therapeutic options.