Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) Study‐2: Use of 2.5 mg alteplase as a starting intrapleural dose

Abstract

Background and objective: Intrapleural tissue plasminogen activator/ deoxyribonuclease (tPA/DNase) therapy is increasingly used in pleural infection. Bleeding risks and costs associated with tPA remain the clinical concerns. Our dose de-escalation series aims to establish the lowest effective dosing regimen for tPA/DNase. This study assesses the intrapleural use of 2.5 mg tPA/5 mg DNase for pleural infection. Methods: Consecutive patients with pleural infection treated with a starting regime of 2.5 mg tPA/5 mg DNase were included from two centres in Australia and UK. Escalation of tPA dose was permitted if clinical response was inadequate. Results: Sixty-nine patients (mean age 61.0 years) received intrapleural 2.5 mg tPA/5 mg DNase. Most (88.4%) were treated successfully and discharged from hospital without surgery by 90 days. Patients received a median of 5 [interquartile range [IQR] = 3-6] doses of tPA/DNase. Total amount of tPA used per patient was 12.5 mg [median, IQR = 7.5-15.0]. Seventeen patients required dose escalation of tPA; most (n = 12) for attempted drainage of distant non-communicating locule(s). Treatment success was corroborated by clearance of pleural opacities on radiographs (from median 27.0% [IQR = 17.1-44.5] to 11.0% [IQR = 6.4-23.3] of hemithorax, p < 0.0001), increased pleural fluid drainage (1.98 L [median, IQR = 1.38-2.68] over 72 h following commencement of tPA/DNase) and reduction of serum C-reactive protein level (by 45.0% [IQR = 39.3-77.0] from baseline at day 5, p < 0.0001). Two patients required surgery. Six patients with significant comorbidities (e.g., advanced cancer) had ongoing infection when palliated and died. Two patients experienced selflimiting pleural bleeding and received blood transfusion. Conclusion: A starting intrapleural regime of 2.5 mg tPA/5 mg DNase, with uptitration if needed, can be effective and deserves further exploration.

Use of carefully titrated ultra‐low doses of alteplase in infected haemothorax caused by initial alteplase use to drain loculated malignant pleural effusion

“…4 The ADAPT-2 study is the second series of studies lowering the initial dose of alteplase after a previous study looked at 5 mg, reducing the dose to 2.5 mg-it observed an 88.4% treatment success rate without requiring cardiothoracic surgery. 2 In our case, there is proof of concept that despite the initial administration of alteplase causing pleural bleeding, there may well be for each patient an individual therapeutic window for alteplase use in the pleural space. In this case much lower doses of alteplase could be used after pleural bleeding had stopped to safely treat pleural infection.…”

“…Further studies investigating even lower doses of alteplase than what was reported in the ADAPT-2 study are underway 2 which would provide further data into the lowest and safest effective dose of alteplase use in the pleural space.…”

“…The doses of alteplase and dornase used in the original MIST‐2 trial were 10 mg and 5 mg, respectively 1 . The risk of pleural bleeding prompted clinicians to trial lower doses of fibrinolytics to treat pleural infections 2 . A case report also highlighted successful treatment of a case of pleural infection with 1 mg alteplase in a patient with coagulopathy 4 .…”

“…Studies have shown that pleural infections could be successfully managed using intercostal chest drains and intrapleural alteplase and dornase 1 . There has been ongoing interest in using lower doses of intrapleural fibrinolytics to treat pleural infections given the risks of bleeding, although uncommon, can be serious 2 . The optimal dose and dosing regimen of intrapleural fibrinolytics are still unknown.…”

Intrapleural therapy for pleural infection from bronchopleural fistula in an adult with hyper‐IgE syndrome

“…3 Our dose de-escalation series showed that lower tPA doses (5 and 2.5 mg) were similarly effective. 5 In high risks cases, such as ours, a 'test' dose of 1 mg tPA (with 5 mg DNase) was justifiable, and indeed provided complete radiological clearance of the pleural collection after two doses, which facilitated early hospital discharge.…”