Discover innovative treatment strategies for infected pleural effusions as the discussion dives into the MIST 2 trial. Learn how the combination of tPA and DNase is reshaping standard care, emphasizing their effectiveness in reducing fluid size and minimizing surgical interventions. The podcast highlights the critical importance of patient selection criteria and protocol adherence in clinical trials. With insights on the dynamics of interventions and patient management, this exploration is a must-listen for anyone interested in advancements in pulmonology.
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insights INSIGHT
Synergistic Effect of tPA and DNase
The MIST-2 trial found that combining intrapleural tPA and DNase improves drainage in infected pleural effusions and empyemas.
Previous MIST-1 trial using streptokinase showed no benefit, highlighting the synergistic effect of this combination therapy.
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Double-Blind Double-Dummy Method
Use a double-blind, double-dummy, 2×2 factorial RCT design to eliminate bias when testing intrapleural therapies.
Ensure placebo controls are included for both agents to maintain blinding in procedural drug administration studies.
insights INSIGHT
Outcome Measures Focused on Drainage & Clinical Benefit
Primary outcome measured was reduction in percentage of hemithorax occupied by effusion on day 7.
Secondary outcomes included referral for surgery, hospital length of stay, mortality, and adverse events to assess clinical impact.
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In this episode, we add another article to our Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the MIST 2 trial published in NEJM in 2011 evaluating enzymatic therapy for complex parapneumonic effusions and empyemas.
Article and Reference
We are talking today about the MIST 2 trial evaluating the use of intrapleural tPa and DNase for intrapleural infections.
Infections in the pleural space are common and morbid, often requiring surgical intervention. Unfortunately, antibiotics and chest tube drainage often fail. The MIST1 trial (NEJM, 2005) of intrapleural streptokinase showed no benefit. MIST2 studied intrapleural tPA and DNase to ease drainage by breaking down septations and thinning pleural fluid.
Study Design (design, primary outcome, participants, etc)
Design:
Double-blind, double-dummy, 2×2 factorial RCT at 11 UK hospitals from 12/2005 to 11/2008
By double dummy, we mean that there was a sham placebo for each of the study drugs
Primary Outcome
Change in the percent of the hemithorax taken up by effusion on CXR at day 7 compared to day 1
Key secondary outcomes:
Referral for surgery
Hospital LOS
All cause 3 month and 12 month mortality
AEs
Participants
Inclusion:
Clinical evidence of infection (assessed by recruiting MD; EG, fever, CRP, WBC) and
Pleural fluid with any of:
Grossly purulent
Positive pleural fluid culture or gram stain
pH < 7.2
Exclusion: aiming to exclude patients with increased bleeding risk or who can’t re-expand the lung after drainage
Age < 18
Previous intrapleural fibrinolytics, DNase, or both for empyema
Allergy to tPA or DNase
Coincidental stroke (hemorrhage risk)
Major hemorrhage or trauma
Major surgery in the last 5 days
Previous pneumonectomy on the infected side
Pregnancy, lactation
Expected survival < 3 months from something other than what caused the pleural problem
Summary: Middle-aged, mostly male patients with complicated pleural effusion or empyema occupying 1/3 to 2/5 hemithorax with mostly small-bore CDs for mostly community-acquired infections
Small-bore here meant < 15 Fr
Intervention/Limitations
N = 210 (193 analyzed) randomized approximately 1:1 to one of the following 4 arms:
tPA/Dnase (10mg and 5mg)
tPA and placebo
DNase and placebo
Double placebo
Medications were given BID for 3 days with clamping of the CD for 1 hour after each dose (to keep the drug in the pleural space)
Outcomes/Safety
Power: with N = 210 (actual analysis = 193), 80% power to detect 1 in 5 more patients with a 50% reduction in pleural opacity on CXR
We’ll discuss the outcomes of tPA/DNase in combination because there was a highly significant interaction between the two (P = 0.002) for the primary outcome
Efficacy:
Primary (pleural effusion size reduction): -29.5% hemithorax vs baseline and -7.9% effusion size vs placebo (P = 0.005)
Neither drug worked on their own
Secondary:
Referral for surgery: 4% vs 16% (OR 0.17, P = 0.03)
Hospital LOS (excluding 391d outlier in placebo group): mean 11.8 vs 17 days (P = 0.006)
Mortality: no difference
Safety:
No difference in AE between groups
6 serious events across all groups, mostly related to bleeding (intra-pleural, GI, hemoptysis); other AE were made up of pain with drug administration, transient AMS, rash
Takeaway
Combination intrapleural enzyme therapy (IET) with tPA and DNase improves drainage of infected pleural fluid, and reduces need for surgery and hospital LOS