Intrapleural use of tissue plasminogen activator and DNase in pleural infection

Design

Double-blind, double-dummy, randomized control trial

N= 210

Objective

To determine whether intrapleural deoxyribonuclease (DNase) or tissue plasminogen activator (tPA) therapy could increase the proportion of patients who had a 50% reduction in the area of opacity

Study Groups

tPA only (n= 52)

DNase only (n= 51)

tPA and DNase (n= 52)

Placebo (n= 55)

Inclusion Criteria

Less than 18 years, previous treatment with intrapleural fibrinolytic agents, DNase, or both, known sensitivity to DNase or t-PA, coincidental stroke, major hemorrhage or major trauma, major surgery in the previous five days, previous pneumonectomy on the infected side, pregnancy or lactation, and expected survival of less than three months

Methods

Eligible patients were randomly assigned to receive t-PA plus DNase, DNase plus placebo, t-PA plus placebo, and double placebo. The dose of DNase was 5 mg, and the dose of t-PA was 10 mg. Intrapleural medications were each given twice daily for three days, and each administration was followed by clamping of the drain to permit the study drug to remain in the pleural space for 1 hour.

Duration

December 2005 to November 2008

Outcome Measures

Primary: change in pleural opacity after seven days (measured as the percentage of the hemithorax occupied by effusion)

Secondary: referral for surgery, duration of hospital stay, mortality, and adverse events

Baseline Characteristics

tPA (n= 52)

DNase (n= 51)

tPA and DNase (n= 52)

Placebo (n= 55)

Age, years

Male

Radiographic evidence of loculation

Purulent pleural fluid

Percent of hemithorax occupied by pleural fluid

Results

tPA (n= 52)

DNase (n= 51)

Placebo (n= 55)

Change in hemithorax area occupied by effusion

Percent difference vs. placebo (95% CI)

p-value

−17.2 ± 24.3%

2.0 (−4.6 to 8.6)

0.55

−14.7 ± 16.3%

4.5 (−1.5 to 10.5)

0.14

−29.5 ± 23.3%

−7.9 (−13.4 to −2.4)

0.005

−17.2 ± 19.6%

Reference

N/A

Surgical referral

Odds ratio vs. placebo (95% CI)

p-value

3/48 (6%)

0.29 (0.07 to 1.25)

0.10

18/46 (39%)

3.56 (1.30 to 9.75)

0.01

2/48 (4%)

0.17 (0.03 to 0.87)

0.03

8/51 (16%)

Reference

N/A

Length of hospital stay, days

Percent difference vs. placebo (95% CI)

p-value

16.5 ± 22.8

−8.6 (−40.8 to 3.3)

0.21

28.2 ± 61.4

3.6 (−19.0 to 30.8)

0.73

11.8 ± 9.4

−14.8 (−53.7 to −4.6)

< 0.001

24.8 ± 56.1

Reference

N/A

Mortality

After three months

After 12 months

4/48 (8%)

5/46 (11%)

6/46 (13%)

9/45 (20%)

4/48 (8%)

5/47 (11%)

2/50 (4%)

4/48 (8%)

CI, confidence interval

Adverse Events

Common Adverse Events: chest pain at the drainage site during study drug administration (2 with placebo, 3 with t-PA, 3 with DNase, and 6 with t-PA–DNase), nausea (3 with placebo, 1 with DNase, and 1 with t-PA), transient confusion (2 with placebo, 1 with t-PA–DNase, and 1 with DNase), erythema or rash (2 with t-PA–DNase and 1 with DNase)

Serious Adverse Events: intrapleural hemorrhages (2 in the t-PA–DNase group), hemoptysis (1 in the t-PA–DNase group), gastrointestinal bleeding (2 in the DNase group), clinical deterioration (1 in the placebo group)

Study Author Conclusions

Intrapleural t-PA plus DNase combination therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective.

InpharmD Researcher Critique

Strengths of the trial include the randomized and placebo-controlled design, as well as the fact that it was conducted at 11 separate centers. Specific details on the administration method of tPA and DNase were not disclosed. 

Concurrent Versus Sequential Intrapleural Instillation of Tissue Plasminogen Activator and Deoxyribonuclease for Pleural Infection

Prospective observational study

N= 38

To compare the efficacy and safety of sequential versus concurrent tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) therapy in patients with pleural infection

Sequential group (n= 18)

Concurrent group (n= 20)

Consecutive patients with pleural infection who received concurrent and sequential tPA/DNase therapy

Patients received either concurrent or sequential intrapleural tPA (10 mg) and DNase (5 mg) therapy. In the concurrent group, both drugs were injected using different syringes followed by a saline flush and clamping of the chest tube for 60 minutes. In the sequential group, tPA was administered first, followed by DNase after a 60-minute interval, with clamping and suction procedures in between. Therapy was given twice daily for a maximum of 6 doses.

Not specified

Primary: Treatment success rate

Other: Median pleural fluid drainage, median volume of pleural effusion on chest CT, median hemithorax occupied by effusion on chest radiography

Concurrent (n= 20)

Age, years (IQR)

Male

Comorbid cancer diagnosis

Median peripheral leukocyte count, ×109/L (IQR)

Chest tube size - 14 Fr

Ultrasonographic evidence of loculations

Chest tube location—right

Positive bacterial Gram’s stain or culture of pleural fluid

Median pleural fluid percentage of neutrophils (IQR)

Geometric mean pleural-fluid pH

Median pleural-fluid glucose, mg/dL (IQR)

Median lactate dehydrogenase in pleural fluid, IU/L (IQR)

Abbreviations: IQR, interquartile range.

Concurrent (n= 20)

77.7%

Median pleural fluid drainage, mL (IQR)

Median volume reduction in CT (%; IQR)

Median reduction in % of hemithorax with effusion (%; IQR)

Two patients experienced pleural hemorrhage requiring transfusion, one in each group. Pain requiring escalation of analgesia occurred in three patients in each group. No therapy cessation occurred due to adverse events. Two deaths were reported in each group.

In conclusion, concurrent intrapleural tPA/DNase therapy as compared with sequential therapy in patients with CPPE and empyema guided by clinical and radiographic response is comparable in safety and effectiveness. These findings support the use of a concurrent therapy in patients with pleural infection.

The study provides valuable insights into the administration of tPA/DNase for pleural infections, showing comparable efficacy and safety between concurrent and sequential methods. However, the small sample size and single-center design may limit the generalizability of the findings. Additionally, the lack of standardized criteria for treatment failure and surgical referral could introduce bias.

A Retrospective Cohort Study Evaluating the Safety and Efficacy of Sequential versus Concurrent Intrapleural Instillation of Tissue Plasminogen Activator and DNase for Pleural Infection

Retrospective cohort study

N= 135

To compare the safety and efficacy of sequential versus concurrent intrapleural tissue plasminogen activator/deoxyribonuclease  (tPA/DNase) in the treatment of pleural infection

Sequential intrapleural therapy (n= 84)

Concurrent intrapleural therapy (n= 51)

Patients with pleural infection requiring intrapleural therapy at Singapore General Hospital and Changi General Hospital between January 2017 and September 2022

Not specified

Retrospective review of patients receiving intrapleural tPA/DNase. Sequential therapy involved separate instillation of tPA and DNase with chest drain clamping. Concurrent therapy involved immediate instillation of DNase after tPA. Dosage and frequency were adjusted based on clinical response.

January 2017 to September 2022

Primary: Treatment failure (in-hospital mortality, surgical intervention, or 30-day readmission for pleural infection)

Secondary: Percentage change in pleural opacity on chest radiographs, adverse event rate

Sequential (n= 84)

Age, years (IQR)

Charlson’s comorbidity score (IQR)

RAPID score (IQR)

Percentage of pleural opacity on CXR before intrapleural therapy (IQR)

Abbreviations: IQR, interquartile range.

p-value

0.534

26.6% (9.9 to 38.7)

5 (9.8%)

5 (9.8%)

Overall rates of treatment failure and/or adverse events were similar between sequential and concurrent groups (26.2% vs 25.5%; p= 0.928).

In conclusion, our study adds to the growing literature on the safety and efficacy of concurrent intrapleural therapy in pleural infection and supports this mode of administration as an alternative to sequential intrapleural therapy. In our opinion, with increasing evidence for personalized dosing and frequency of intrapleural alteplase and the potential for complications such as pleural bleeding, there is a need for more research to guide the administration and dosing of intrapleural therapy, particularly in the Asian population where data is lacking.

The study's retrospective design and variability in treatment protocols may limit the generalizability of the findings. The lack of randomization and potential confounding factors, such as differences in dose and timing of therapy, could impact the results. However, the study provides valuable insights into real-world practices and supports the feasibility of concurrent therapy.

Concurrent Versus Sequential Intrapleural tPA–DNase Administration: Comparative Effectiveness and Safety in Pleural Infection

Retrospective cohort study

N= 210

To evaluate whether concurrent co-instillation of tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) is associated with improved effectiveness or altered safety compared with sequential administration in patients with infectious pleural effusions

Sequential (n= 149)

Concurrent (n= 61)

Adults aged 18 years and older who received both intrapleural tPA and DNase during the study period with suspected or confirmed infectious pleural effusions

Patients who received only one agent or therapy delivered via indwelling tunneled pleural catheters for chronic or palliative drainage

Retrospective review of electronic medical records from August 2017 to August 2025. Sequential therapy involved tPA followed by DNase with separate dwells, while concurrent therapy involved co-instillation of both agents. Standard dosing was tPA 10 mg and DNase 5 mg per dose, administered twice daily for up to 12 doses over three days. Primary outcomes included radiographic resolution, need for surgery, and hospital length of stay. Safety endpoints included analgesic utilization and hemoglobin trends.

August 2017 to August 2025

Primary: Radiographic resolution, need for surgical intervention, hospital length of stay

Secondary: Clinical success without surgery, mortality, readmission, chest tube-related complications, analgesic use, hematologic safety

Overall (n= 210)

70 (59 to 78)

51 (24.3%)

25 (22 to 29)

150 (72%)

88 (42%)

51 (25%)

58 (28%)

64 (31%)

p-value

77 (52%)

45 (30%)

86/102 (84%)

12 (9 to 16)

13 (8.7%)

12/133 (9.0%)

22/129 (17%)

Analgesic utilization did not differ meaningfully between strategies. Hemoglobin trajectories and transfusion rates were similar, and transfusion during therapy was rare.

Concurrent intrapleural tPA/DNase administration was associated with higher radiographic resolution and lower surgical referral compared with sequential dosing, without evidence of increased analgesic burden or bleeding-related safety signals. Prospective comparative studies are warranted to confirm causality and identify patients most likely to benefit.

This study directly addresses sequencing and is strengthened by a relatively large real-world infectious pleural effusion cohort, detailed medication administration records, and serial hemoglobin/transfusion assessment. The main limitation is confounding from its retrospective, nonrandomized design, especially because practice shifted to exclusive concurrent dosing in 2025; still, the magnitude and consistency of benefit for radiographic resolution and reduced surgery make concurrent same-time administration a reasonable evidence-supported workflow option rather than merely a convenience strategy.

A retrospective review of concurrent versus sequential administration of intrapleural tissue plasminogen activator and dornase alfa for empyemas

Single-center, retrospective study

N= 184

To assess the safety and effectiveness of concurrent versus sequential intrapleural tissue plasminogen activator (tPA) and dornase alfa (DNase) in pleural infections

Concurrent group (n= 158)

Sequential group (n= 26)

Patients ≥18 years old, admitted to the inpatient setting, and received either concurrent or sequential administration of intrapleural tPA and DNase for an empyema or pleural infection between July 1, 2014, and January 1, 2023

Patients who received at least one dose of intrapleural tPA without intrapleural DNase or vice versa, or received less than tPA 10 mg or DNase 5 mg or a frequency other than every 12 h

Retrospective review of electronic medical records. Patients received either concurrent or sequential administration of intrapleural tPA and DNase. Sequential therapy followed the MIST2 protocol with tPA followed by DNase after 1-2 hours. Concurrent therapy involved immediate administration of DNase after tPA. Both therapies were administered twice daily.

July 1, 2014, to January 1, 2023

Primary: Treatment failure (30-day mortality and requirement for video-assisted thoracoscopic surgery [VATS])

Secondary: Cumulative pleural fluid drainage, bleeding adverse events, pain requiring analgesia dose escalation

Concurrent (n= 158)

Age, years (IQR)

Female

Cancer

Diabetes mellitus

Hypertension

Congestive heart failure

ICU admission

Abbreviations: ICU, intensive care unit; IQR, interquartile range.

Most patients had one chest tube prior to therapy (74.7% vs 76.9%) with similar duration before therapy initiation (1.2 vs 1.1 days). Chest tube duration was 6.7 days (IQR 4.8 to 9.8) in the sequential group and 7.8 days (IQR 5.2 to 12.8) in the concurrent group.

Pleural fluid cultures were obtained in >75% of patients, and 80% received antibiotics, most commonly piperacillin–tazobactam (50%) and vancomycin (41.8% vs 30.8%).

Concurrent (n= 158)

Treatment failure

22 (13.9%)

Total pleural fluid drainage, mL (IQR)

ICU LOS, days (IQR)

Abbreviations: LOS, length of stay.

Thirty-day mortality (13.9% vs 11.5%; p> 0.99) and need for VATS (4.4% vs 7.7%; p= 0.62) were similar.

Median pleural fluid drainage was higher with concurrent therapy (1,453 mL vs 836 mL; p= 0.05), with greater drainage observed in patients receiving six doses (2,115 mL vs 883 mL; p= 0.04).

Bleeding events were similar between groups (23.4% concurrent vs 19.2% sequential; p= 0.64). Decline in hemoglobin ≥2 g/dL or transfusion occurred in 22.8% vs 15.4% (p= 0.40). Analgesia dose escalation occurred in 41.1% vs 23.1% (p= 0.09) in concurrent versus sequential groups.

In patients with pleural infections, concurrent intrapleural fibrinolytic therapy may have similar effectiveness and safety compared to sequential therapy. However, amongst the sequential therapy group who received two or more doses, this administration technique appeared to be more efficacious as no treatment failures were observed. Further investigation of the stability of co-administration of intrapleural tPA and DNase is warranted to assess whether this administration technique is truly comparable to sequential therapy and to prevent medication overuse and optimize hospital resources.

The study's large sample size and broad inclusion criteria enhance its real-world applicability. However, its retrospective nature and single-center design may limit external validity. The disproportionate group sizes and reliance on physician diagnosis for inclusion criteria could introduce selection bias. Additionally, the lack of radiological improvement as an outcome limits comparability to previous studies.