title: New strategies to manage complicated pleural effusions.
abstract: BACKGROUND
  More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is the key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial therapy (Multicenter Intrapleural Sepsis Trial [MIST1]).
  
  
  METHODS
  Objective: To evaluate the efficacy and safety of intrapleural DNase alone, alteplase alone, or the combination of both, to improve pleural drainage. Design: Multicenter, double-blind, double-dummy, 2 × 2 factorial randomized trial. Setting: Eleven centers in the United Kingdom (UK). Subjects: Adult patients (mean age 59 years, 72% men), who had clinical evidence of infection, and pleural fluid that had macroscopic purulence, a positive culture or Gram stain for bacteria, or a pH < 7.2. Intervention: Patients were assigned to 1 of the 4 study interventions for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. Outcomes: The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events.
  
  
  RESULTS
  The mean (± SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5 ± 23.3% vs. -17.2 ± 19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P = 0.005). The change observed with t-PA alone and with DNase alone (-17.2 ± 24.3 and -14.7 ± 16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P = 0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P = 0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P = 0.006). Hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups.
  
  
  CONCLUSIONS
  Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of hospital stay. Treatment with DNase alone or t-PA alone was ineffective.
authors.forename: Majed
authors.initials: M
authors.lastname: Safiyeh
authors.forename: David
authors.initials: D
authors.lastname: Huang
mesh_terms: D003851:Deoxyribonucleases / Q000627:therapeutic use*; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D010995:Pleural Diseases / Q000188:drug therapy*; D010996:Pleural Effusion / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D003851:Deoxyribonucleases; D010959:Tissue Plasminogen Activator