MIST2

Published

Rahman NM, et al. "Intrapleural Use of Tissue Plasminogen Activator and DNase in Pleural Infection". The New England Journal of Medicine. 2011. 365(6):518-526.
PubMed • Full text • PDF

Clinical Question

Among patients with empyema, does the combination of tPA and DNAse improve resolution of pleural loculation, as evidenced by radiographic pleural fluid density?

Bottom Line

The addition of DNAse to intrapleural tPA via chest tube is likely beneficial to resolving loculated pleural effusion and empyemas. This benefit may only exist in combination, and not for either agent alone.

Major Points

Parapneumonic effusions and empyema are significant sources of morbidity and mortality. Antibiotics have difficulty penetrating the fibrinopurulent phase of pleural space infections. Video assisted thoracoscopic surgery (VATS) with decortication and washout are the gold standard for suitable candidates, however the procedure is invasive and many patients are not operative candidates. The investigation of intrapleural agents therefore are of interest as an additional treatment modality. However, the 2005 MIST1 study found no clinical benefit from infusion of the fibrinolytic streptokinase into the infected pleural fluid collection. Streptokinase's fibrinolytic activity is systemic while tPA's fibrinolysis tends to be more localized to thrombi, which might drive more effective lysis of pathological thrombi, which might be advantageous in degrading the loculations in pleural infections. DNase degrades DNA, and reduces the viscosity of fluids with breakdown products of bacteria. Use of a DNase agent might also improve locular breakdown in pleural infections, without compounding the bleeding risk associated with thrombolytics. Whether either of these agents improves outcomes in pleural infections was unresolved.

Published in 2011, the Second MIST trial (MIST2; MIST1 stands for "First Multicenter Intrapleural Sepsis Trial") randomized 210 patients with a pleural infection that would commonly be considered to be complicated parapneumonic effusions or empyemas to tPA or placebo (level 1) and DNase or placebo (level 2) in a 2x2 factorial design. Infusions of the agent occurred BID for 3 days. The primary outcome was percent change in hemithorax area occupied by the effusion, which was lowest in the combination tPA+DNase group vs. the double placebo group (-7.9% difference; 95% CI -13.4 to -2.4%; P=0.005). This group also had lower referrals to surgery and shorter hospital stays compared to placebo. Curiously, the DNase+placebo group had might higher proportion of surgical referral than the double placebo group (39% vs. 16%). The proportion of serious adverse events was similar in each group.

MIST2 provides initial evidence for the use of fibrinolytics plus DNase in management of empyemas, but does not support routine use of either fibrinolytics or DNase alone. A 2019 Cochrane review concluded that the use of fibrinolytics is associated with lower risk of progression to surgery and less risk of overall treatment failures. However, there is no mortality benefit with this therapy, and risk for serious adverse events with this therapy. This review did not consider DNase in addition to tPA.

Guidelines

As of December 2020, there are no US-based guidelines for use of DNase in addition to tPA for pleural infections. tPA-only guidelines follow.

The American Association for Thoracic Surgery consensus guidelines for the management of empyema.

• Class IIa: intrapleural fibrinolytics should not be routinely used for complicated pleural effusion and early empyemas, although it is potentially beneficial, particularly in early loculations and empyema

Design

• Multicenter, double blinded, placebo-controlled, 2x2 factorial trial
• N=210
  • tPa+placebo (n=52)
  • DNase+placebo (n=51)
  • tPA+DNase (n=52)
  • Double placebo (n=55)
• Enrollment: 2005-2008
• Primary outcome follow-up: 7 days
  • Other endpoints were assessed at 3 and 12 months.
• Analysis: Modified intention-to-treat
• Primary outcome: Change in pleural opacity of hemothorax 1 week after treatment, or last radiographic prior to surgery/death

Population

Inclusion Criteria

• Clinical evidence of infection, as was determined by the treating physician (eg, fever, elevated WBC count, elevated inflammatory biomarkers)
• ≥1 of the following:
  • Macroscopically purulent pleural fluid
  • Gram's stain of pleural fluid with bacteria
  • Pleural pH <7.2

Exclusion Criteria

• Age <18 years
• Prior intrapleural treatment with a study agent
• Known sensitivity to tPA/DNAse
• Coincidental stroke
• Major hemorrhage/trauma
• Major surgery within 5 days
• Ipsilateral previous pneumonectomy
• Pregnancy/lactation
• Life expectancy < 3 months due to a pleural condition other than empyema
• Pleural opacity < 5% hemithorax area

Baseline Characteristics

From the tPA-DNase Group

• Demographics: Age 60 years, 60% men
• Pleural infection details: 44% of hemithorax occupied by fluid, median symptom duration 13 days, community-acquired infection 87%, radiographic evidence of loculations 94%
  • Pleural fluid details: Positive Gram's stain or culture 8%, pH 6.9, LDH 3,418

Interventions

• Participants were randomized to two levels of a 2x2 factorial design, so there were 4 approximately equal groups:
  • tPA+placebo
  • DNase+placebo
  • tPA+DNase
  • Double placebo
• The dose of tPA was 10 mg and the dose of DNase was 5 mg.
• Intrapleural injections occurred BID for 3 days. Chest tubes were clamped for 1 hour to allow for administration.

Outcomes

Primary Outcomes

Pleural opacity change from day 1 to day 7 or last radiograph prior to surgery/death (percentage differences presented)

tPA+DNase vs. double placebo: -29.5% vs. -17.2% (-7.9%, 95% CI -13.4 to -2.4%; P=0.005)

There was a statistically significant interaction between tPA and DNase for this outcome (P=0.002)

tPA+placebo vs. double placebo: -17.2% vs. -17.2% (2.0%, 95% CI -4.6 to 8.6%; P=0.55)

DNase+placebo vs. double placebo: -14.7% vs. -17.2% (4.5%, 95% CI -1.5 to 10.5%; P=0.14)

Secondary Outcomes

Surgical referral

tPA+DNase vs. double placebo: 4% vs. 16% (OR 0.17, 95% CI 0.03 to 0.87; P=0.03)

tPA+placebo vs. double placebo: 6% vs. 16% (OR 0.29, 95% CI 0.07 to 1.25; P=0.10)

DNase+placebo vs. double placebo: 39% vs. 16% (OR 3.56, 95% CI 1.30 to 9.75; P=0.01)

Hospital Stay

tPA+DNase vs. double placebo: 11.8±9.4 vs. 24.8±56.1 days (Percent different -14.8%, 95% CI, -53.7 to -4.6%; P<0.001)

tPA+placebo vs. double placebo: 16.5±22.8 vs. 24.8±56.1 days (Percent different -8.6%, 95% CI -40.8 to 3.3%; P=0.21):

DNase+placebo vs. double placebo: 28.2±61.4 vs. 24.8±56.1 days (Percent different -3.6%, 95% CI −19.0 to 30.8%; P=0.73):

Subgroup Analysis

• No differences were noted in preplanned analysis: purulent vs. nonpurulent fluid, large bore vs. small bore chest tube, loculation vs. no loculation

Adverse Events

• 3% mortality before 7 days
• 2 intrapleural hemorrhages
• 2 GI bleed
• 30 non-serious adverse events (pain, altered mental status, erythema, rash)

Criticisms

• 30% of patients did not show radiographic evidence of consolidation.
• The statistical analysis did not control for variables incorporated in the randomization scheme.

Funding

• Unrestricted educational grant to the University of Oxford from Roche UK
• One author received lecture fees from ResMed UK, and another received lecture fees from Boehringer Ingelheim UK.
• No other conflicts of interest