April 08, 2025

97. Rapid Fire Journal Club – MIST 2

15 minutes

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:

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

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