97. Rapid Fire Journal Club – MIST 2

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.

Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, Bentley A, Kahan BC, Wrightson JM, Davies HE, Hooper CE, Lee YC, Hedley EL, Crosthwaite N, Choo L, Helm EJ, Gleeson FV, Nunn AJ, Davies RJ. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011 Aug 11;365(6):518-26. doi: 10.1056/NEJMoa1012740. PMID: 21830966.

Key Learning Points

  •  
  •  
    • Background:
      • 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:
      1. tPA/Dnase (10mg and 5mg)
      2. tPA and placebo
      3. DNase and placebo
      4. 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

Infographic

 

37. Top Consults: Approach to Parapneumonic Effusions

We continue our Top Consult Series on Pleural Disease and bring you a dedicated episode on Parapneumonic effusions. We are joined by two guest experts, Dr. David Feller-Kopman and Dr. Mihir Parikh. Listen in as we discuss the spectrum of parapneumonic effusions, including simple parapneumonic effusions, complicated parapneumonic effusions, and empyema. You will hear what to look for on imaging, what tests to send with pleural drainage as well as discuss the need for surgical consultation.

Meet our Guests

Dr. Mihir Parikh is currently an Assistant Professor of Medicine and academic interventional pulmonologist at Beth Israel Deaconess Medical Center. He is a highly esteemed educator and has worked to incorporate simulation training to improve procedural training for trainees and is a master of pleural disease.

Dr. David Feller-Kopman is a Professor of Medicine and the Section Chief of Pulmonary and Critical Care Medicine at Darmouth whose clinical and research expertise span the field of interventional pulmonology. Dr. Feller-Kopman is a true master of pleural disease, and has authored more than 225 peer-reviewed manuscripts and has been a leader for both ATS and CHEST committees.

36. Top Consults Series: Approach to Pleural Effusions

Today the PulmPEEPs are joined by two amazing educators as we start off our Top Consult series on Pleural Disease. Join us today as we go through cases to learn a systematic approach for evaluation and management of pleural effusions.

Meet our Guests

Dr. Mira John received her medical degree from Tulane University School of Medicine in New Orleans and completed internal medicine residency at Icahn School of Medicine at Mount Sinai. She is currently a second-year pulmonary and critical fellow at the University of Washington.

Dr. Ylinne Lynch completed her fellowship training at the University of Washington and is currently a Clinical Instructor at the UW. She is a great medical educator and spends her clinical time on the pulmonary consult service as well as in the ICU. 

Learning Points