"Intrapleural Use of Tissue Plasminogen Activator and DNase in Pleural Infection". The New England Journal of Medicine. 2011. 365:518-526. PubMed
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Does the use of intrapleural tissue plasminogen activator (t-PA) and DNase improve drainage of infected pleural fluid in patients with pleural infection compared to placebo?
In patients with pleural infection, intrapleural t-PA and DNase therapy improved fluid drainage and reduced the need for surgical referral and duration of hospital stay. Treatment with DNase or t-PA alone was not effective.
Pleural infection carries significant mortality and often requires surgical drainage when antibiotics and standard tube drainage fail. Although intrapleural fibrinolytic therapy has been proposed as a treatment, earlier trials including MIST1 showed no benefit of streptokinase. This study investigated the use of a different fibrinolytic agent, t-PA, and the addition of DNase to reduce fluid viscosity.
The double-blind, factorial randomized trial (MIST2) included 210 patients with pleural infection randomized to receive t-PA and DNase, each agent alone, or placebo, for 3 days. The change in pleural opacity by day 7 showed significant improvement with the t-PA and DNase combination compared to placebo, and no improvement with either agent alone. Additionally, patients receiving combined treatment had fewer surgical referrals and shorter hospital stays.
As of the current knowledge cutoff date, no updated guidelines reflecting the results of this trial have been published.
- Multicenter, double-blind, double-dummy, 2-by-2 factorial, randomized, placebo-controlled trial - N=210 patients with pleural infection - Interventions: - Intrapleural t-PA and DNase (n=52) - Intrapleural t-PA and placebo (n=52) - Intrapleural DNase and placebo (n=51) - Double placebo (n=55) - Duration: 3 days of treatment, with a primary outcome measured on day 7 - Setting: 11 centers in the UK
- Inclusion criteria: Clinical evidence of infection and pleural fluid that was purulent, had positive culture for bacteria, positive Gram's staining, or pH<7.2 - Exclusion criteria: Age <18 years, previous treatment with intrapleural fibrinolytic agents or DNase, known sensitivity to either agent, stroke, major hemorrhage, major surgery, or pregnancy/lactation - Baseline characteristics: Similar across all groups
- Intrapleural t-PA (10 mg) plus DNase (5 mg) - Intrapleural t-PA plus placebo - Intrapleural DNase plus placebo - Double placebo - t-PA and DNase or their respective placebos were given intrapleurally twice daily for 3 days
- Primary: Mean change in pleural opacity from day 1 to day 7 on chest radiography - Secondary: Referral for surgery by 3 and 12 months, duration of hospital stay, volume of pleural fluid drained, change in inflammatory markers, death from any cause by 3 and 12 months, frequency of adverse events
- No explanation for why t-PA alone did not show efficacy despite its fibrinolytic properties - The mechanism of negative outcomes with DNase monotherapy was not fully elucidated
- Supported by an unrestricted educational grant from Roche UK to the University of Oxford and by grants from the UK National Institute for Health Research (NIHR) and the UK Medical Research Council.
The trial protocol, statistical analysis plan, and additional details are available in the Supplementary Appendices and at NEJM.org.