Pleural infection, including complicated parapneumonic effusion and empyema, is a common complication secondary to pneumonia, and its presence predicts a need of hospitalization, longer hospital stay and higher mortality (10 - 20%). Timely and effective treatment is required to lower the related morbidity and mortality.

The cornerstone of management for pleural infection involves adequate drainage of infected pleural fluid and adequate antibiotics coverage. However, this only works in 70% of cases. Complete evacuation of pleural fluid can become challenging even with an adequately large-bore chest drain, due to its viscous nature and extensive septations partitioning the infected fluid into multiple locules in the pleural space. Although surgical decortication in these refractory cases was once believed to be the definitive treatment, it is now considered as the last resort of treatment due to a high anaesthetic risk whilst uncontrolled sepsis, high rate of chronic post thoracotomy pain (50%) and unavoidable bleeding. The advent of intrapleural therapy using tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has revolutionized the care in pleural infection, as shown in the pivotal MIST-2 trial. Their synergistic effect targeting the pus viscosity and pleural adhesions can greatly improve the drainage of pleural fluid, which avoided the need for surgery in more than 90% of patients.

The optimal dose of intrapleural tPA remains undefined. The dose of 10mg used in the MIST-2 trial was chosen empirically and had not been subjected to conventionally dose-escalation assessment or long-term pharmacovigilance follow-up. In such case any major adverse effects can be a hindering factor of using this medication at the standard dose. An occurrence rate of bleeding complication between 1.8 and 12% using the dose of 10mg tPA has been reported by several large-scale studies. Clinically significant bleeding warrants additional intervention including pack cell transfusion, radiological interventions and even surgical haemostasis. This risk is therefore one of the driving forces urging for finding a safer and lower effective dose. A dose-dependent bleeding risk of intravenous tPA has been established, and such linkage may probably exist for intrapleural tPA. Alemán C et al has reported that a double dose of intrapleural tPA was associated with a doubling of serious bleeding complications (28% for 20mg and 12% for 10mg). Therefore, it appears logical and safe that a lower dose of intrapleural tPA may reduce the bleeding risk.

Several studies have reported that a lower dose (\< 10mg) of intrapleural tPA remains efficacious in pleural infection. In an animal study, a median tPA dose of 3.75mg (range 0.375 - 20mg) was required for the treatment of fibrinous pleuropneumonia in horses, with an average weight 4 to 10 times higher than humans. A multi-centered dose de-escalation study by Popowicz et al has confirmed that a combination of 5mg tPA together with 5mg DNase is safe and effective. They employed a pragmatic approach to begin therapy with a lower tPA dose (5mg) and return to the conventional dose (10mg) if lack of clinical response is observed. The reduced tPA dose was well tolerated with a bleeding complication comparable to previous studies using 10mg tPA. A similar cohort study, ADAPT-2, assessed the clinical outcomes of an even lower starting dose of intrapleural tPA at 2.5mg. The lower dose remained efficacious, with only 2 patients (2.9%) required surgery and a low rate of bleeding complication (2.9%) compared with 4.2% in the landmark MIST-2 trial. The lower dose of tPA, with a potentially lower bleeding risk, provides an attractive alternative especially in patients who require therapeutic anticoagulation and those with acquired coagulopathy due to overwhelming sepsis. A standard dose (10mg) can be employed at any time in an attempt to break non-communicating locules if clinical improvement could not be achieved by a low dose tPA, while it is not practical to do the other way round if clinical efficacy is observed with standard dose tPA.

Till now, there is no high quality data comparing the treatment efficacy and bleeding complications between low dose (\< 10mg) with standard dose (10mg) in pleural infection. It was reflected by a heterogeneous practice in choosing the optimal dose of intrapleural tPA from a recent international survey among practicing physicians expert in pleural medicine. The respondents would consider using a lower starting dose of tPA (with the possibility of escalation if clinically needed) if a median 80% (interquartile range 50-80%) of patients could be successfully treated at that dose. We hypothesize that a lower starting dose (2.5mg) of intrapleural tPA remains as efficacious as standard dose (10mg) with a lower bleeding risk. However, using an unchanged low dose of tPA throughout the course of treatment may put the patients in disadvantage of subjecting them to the need for surgery if failed treatment. Previous dose de-escalation studies employed a low starting dose of intrapleural tPA and allowed an escalation to the standard dose in the midway of treatment course depending on the clinical progress at the discretion of treatment physicians and this practice is also preferred from the international survey. The same study design will therefore be adopted in the current study.