Intrapleural tPA and dornase alfa for pleural infection

A 48 year old male is admitted to the hospital after experiencing a fever and malaise for several days.  He states that he has some shortness of breath and chest pain when he coughs.  Imaging of the chest reveals a large loculated effusion and empyema in the right lower lung.  The decision is made to place a chest tube (thoracostomy) and drain the fluid.  The pleural fluid returns with a pH of 7.18, a glucose of 55 mg/dL, and a lactate of 1,150 units/L.  Initial drainage was 200 mL in the first 24 hours, contained pus, and had a putrid odor.  Cultures are pending.  In addition to drainage and appropriate antibiotic therapy, what else can be done to manage this patient?

Why tPA and dornase alfa in pleural infections?

Under normal circumstances, the pleural space contains a small amount of fluid and usually lacks neutrophils.  Pleural inflammation (from the presence of bacteria) increases the presence of cytokines, chemokines, and pleural permeability which leads to increased neutrophils, coagulability, and fibrosis in the pleural space.  The accumulated infected fluid is viscous, lumpy, and can be resistant to drainage (partially due to the septations or numerous pockets of fluid collections).  Thus, we see the potential role for intrapleural tPA (breaks the fibrinous septations into a larger unified pocket) and dornase alfa (improves viscosity).1

What is the evidence?

One of the first studies to look at the effect of these medications on important clinical outcomes was the MIST1 study.2  This trial only used intrapleural streptokinase versus placebo and found that there was no difference in death, the need for surgical drainage, or length of hospital stay.  This may be because giving streptokinase alone only broke down the barriers between the pockets of pus but didn't improve viscosity and therefore adequate drainage did not occur.  

The first large study to combine both the intrapleural tPA and dornase alfa was the MIST2 study.3  They used a 2x2 factorial design creating four groups: tPA + dornase alfa, tPA + placebo, dornase alfa + placebo, or placebo + placebo.  The regimen for dornase alfa (Pulmozyme) was 5mg intrapleurally and tPA (alteplase) was 10mg intrapleurally twice a day for three days.  Drugs were administered sequentially with each being retained for an hour before the next given.  The combined tPA + dornase alfa group had improved pleural opacity (29.5% vs. 17.2%), reduced need for surgery (4% vs. 16%), and reduced hospitalization duration (11.8 vs. 17 days) compared to placebo.  Meanwhile, the monotherapy regimens of tPA or dornase alfa group had no significant difference compared to placebo.

The positive outcomes of using this combined regimen was confirmed in two more recent studies which both had a clinical success (survival to discharge and avoiding need for surgery) of about 90%.4,5  Although these were single arm studies, this success rate is much better than the historical figures of pleural infections (80-90% mortality, 1/3 requiring surgical intervention, length of stay of 12-15 days).  The Majid study actually modified the administration of these drugs so that both were concurrently administered intrapleurally and retained for 120 minutes before drainage (logistically easier).5  These patients had chest tubes for a median of 5 days and a length of hospitalization median of only 7 days.

Back to the patient case

This patient has numerous characteristics that suggest that combined intrapleural tPA + dornase alfa will benefit him.  The clinical symptoms, radiographic evidence, and pleural fluid analysis are consistent with a bacterial infection (pH <7.2, glucose <60 mg/dL, elevated lactate).  The low pH and pus indicate that chest tube placement is necessary.  Like the patients in the above studies (with low drainage (<250mL) in the first 24 hours), he would likely benefit from chest tube placement and intrapleural administration of tPA + dornase alfa.

Take home points

• tPA 10mg plus dornase alfa 5mg intrapleurally, concurrently, twice daily for three days has large effect on clinically relevant endpoints (length of stay, need for surgery)
• All six doses do not need to be given if drainage is complete
• Monotherapy with each is not likely to be beneficial for bacterial pleural infections
• Give both medications and retain them for 2 hours, then begin drainage - volume should increase significantly within the next 24 hours

References
1.  Septimus EJ. Chapter 65: Pleural effusion and empyema  In: Mandell GL, Bennett JE, Dolin R, eds.  Principles and practice of infectious diseases. 7th ed. Philadelphia, PA: Elsevier; 2010:917-24.
2.  Maskell NA, Davies CW, Nunn AJ, et al.  U.K. controlled trial of intrapleural streptokinase for pleural infection.  N Engl J Med  2005;352:865-74.
3.  Rahman NM, Maskell NA, West A, et al.  Intrapleural use of tissue plasminogen activator and DNase in pleural infection.  N Engl J Med  2011;365:518-26.
4.  Piccolo F, Pitman N, Bhatnagar R, et al.  Intrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection.  Ann Am Thorac Soc  2014;11(9):1419-25.
5.  Majid A, Kheir F, Folch A, et al.  Concurrent intrapleural instillation of tissue plasminogen activator and DNase for pleural infection.  Ann Am Thorac Soc  2016;13(9):1512-8.

photo By Bentplate84