New strategies to manage complicated pleural effusions

Expanded abstract Citation 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: N Engl J Med 2011, 365:518-26. PMID: 21830966, available on www.pubmed. gov 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.


Results
Th e 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%; diff erence, −7.9%; 95% confi dence interval [CI], −13.4 to −2.4; P = 0.005). Th e change observed with t-PA alone and with DNase alone (−17.2 ± 24.3 and −14.7 ± 16.4%, respectively) was not signifi cantly diff erent from that observed with placebo. Th e 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 (diff erence, −6.7 days; 95% CI, −12.0 to −1.9; P = 0.006). Hospital stay with either agent alone was not signifi cantly diff erent from that with placebo. Th e frequency of adverse events did not diff er signifi cantly among the groups.

Conclusions
Intrapleural t-PA-DNase therapy improved fl uid 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 ineff ective.

Commentary
More than 65,000 cases of pleural infection occur in the United States and United Kingdom each year [1], and the incidence is increasing in both children and adults [2]. Both community and hospital acquired bacterial pneumonia are complicated by pleural infections [3]. Despite the advances in therapeutic strategies, pleural infections are associated with high mortality rates of 10-20% [4].
Th ere are several classifi cations of pleural eff usions based on evolution (exudative, fi brinoproliferative with evidence of loculation, and formation of fi brous peel) and fl uid characteristics (clear, viscous, or pus). Drainage alone is usually adequate for an uncomplicated eff usion. However, drainage is often insuffi cient for patients with pleural infection who have a complicated eff usion with increased viscosity and loculation [5]. Th e standard management of pleural infections consists of antibiotics and draining the infected pleural fl uid [6]. However, more than 30% of patients fail standard therapy and require surgical referral. Th ese patients incur a longer duration of hospital stay of 12-15 days and increased utilization of healthcare resources [4].
Observational data suggest that using fi brinolytic drugs in the intrapleural space can decrease the failure rate, reduce surgical referral, and improve chest tube drainage by cleaving intrapleural fi brinous septations [7,8]. Th is theory was tested by many randomized controlled trials using diff erent fi brinolytics, but failed to improve clinically meaningful end points [9]. Most notably, the 454 patients in the Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefi t from intrapleural streptokinase. However, the absence of benefi t was felt possibly due to the presence of free extracellular deoxyribonucleic acid (DNA) and other bacterial components in the pleural space, which increase fl uid viscosity and hinder fi brinolysis [8]. Adding DNase to cleave the free DNA may reduce fl uid viscosity and permit pleural clearance by fi brinolytic drugs [10].
To test this hypothesis, the second multicenter trial (MIST2) by Rahman and colleagues was conducted at 11 centers in the UK. In this randomized trial, the authors used a diff erent intrapleural fi brinolytic agent (t-PA rather than streptokinase) and added DNase for cleavage of free DNA. Th e authors conducted a standard factorial study analysis and found a signifi cant interaction between t-PA and DNase with regard to the primary outcome. Th ey therefore compared each of the three intervention groups to placebo.
Th e t-PA-DNase combination was signifi cantly superior to placebo and each drug alone in improving the changes in opacity on chest x-ray on day 7 vs. day 1 (primary end point), decreasing the number of surgical referrals at 3 and 12 months (4% vs. 14%), and decreasing the days of hospitalizations by 6.7 days. However, monotherapy with either t-PA or DNase showed no benefi t when compared to placebo, and DNase alone resulted in an increase in surgical referrals and hospitalization days compared to placebo.
Strengths of this trial include: a well-defi ned study protocol, multicenter, randomized, double-blind, doubledummy design, and complete follow-up. Th ere are a few limitations. First, although only 3 serious adverse events with pulmonary bleeding (intrapleural hemorrhage, hemoptysis) occurred, all three were in the t-PA-DNase group (n = 52). Future use of this drug combination should carefully monitor for pulmonary bleeding. Second, the primary end point was the absolute change in chest x-ray opacity. However, the trial was powered to detect a slightly diff erent endpoint, the proportion of patients who had a 50% relative reduction in opacity. Nevertheless, the overall results were striking, with only one patient in the t-PA-DNase arm not achieving any opacifi cation reduction, compared to several patients in the other arms. Additionally, there was reduction in the number of surgical referrals, a patient-centered endpoint.

Recommendation
Rahman and colleagues should be commended for demonstrating that dual intrapleural therapy with t-PA and DNase in patients with pleural infection improved changes in opacity on chest x-ray and reduced need for surgical intervention and hospital stay. Although larger trials are needed to replicate these results, dual intrapleural therapy may be a useful option, especially for patients who are high-risk for surgery.