Successful drainage of complex haemoserous malignant pleural effusion with a single modified low-dose intrapleural alteplase and dornase alfa

Abstract

Patients with symptomatic complex malignant pleural effusion (MPE) are frequently unfit for decortication and have a poorer prognosis. Septations can develop in MPE, which may lead to failure of complete drainage and pleural infection. Intrapleural fibrinolytic therapy (IPFT) is an alternative treatment. The use of IPFT in patients with anaemia and high risk for intrapleural bleeding is not well established. We report a successful drainage of complex haemoserous MPE with a single modified low-dose of intrapleural 5 mg of alteplase and 5 mg of dornase alfa in a patient with pre-existing anaemia with no significant risk of intrapleural bleeding.

Background

Current literature describes successful intrapleural fibrinolytic therapy (IPFT) with different doses of tissues plasminogen activator (tPA). There is no consensus on the optimum treatment dose of IPFT in malignant pleural effusion (MPE).

Case presentation

A 32-year-old woman with a history of ovarian carcinoma postoophorectomy presented with a suspected solitary lung metastasis on surveillance CT 10 years later. A CT-guided tru-cut needle biopsy of the nodule revealed primary lung adenocarcinoma with no epidermal growth factor receptor, anaplastic lymphoma kinase and ROS-1 mutations. The CT staging was T3N3M1c with pleural, adrenal and bone metastasis. She had disease progression despite six cycles of carboplatin/paclitaxel and went on to have palliative pemetrexed/cisplatin. This was complicated with a left-sided MPE, which was confirmed by the presence of malignant cells in the pleural fluid. She underwent small-bore chest tube drainage with no chemical pleurodesis.

She presented 1 month later with fever and symptomatic recurrent MPE requiring a second 8-Fr chest tube insertion. Pleural fluid cytology showed the presence of malignant cells and pleural fluid culture grew Enterococcus Faecalis. This was treated with amoxicillin–clavulanic acid. The MPE drained more than 200 mL daily for a week with no radiological improvement (figure 1A).

Figure 1.

(A) Chest radiograph showed left massive pleural effusion with Seldinger chest drain in situ. (B) Haemoserous effusion in the underwater seal chest drainage bottle. (C) Chest radiograph postintrapleural fibrinolytic showed resolution of the left massive pleural effusion. (D) Ultrasonography thorax showed multiloculated effusion, thickened pleural with adjacent lung mass.

Ultrasonography of the thorax showed the presence of a multiloculated left-sided pleural effusion, thickened pleura with pleural based-nodules and a lung mass. She was not fit for decortication with an Eastern Cooperative Oncology Group performance status of 3. Given her high risk of bleeding due to the presence of haemoserous pleural fluid, we decided to perform an IPFT using a modified low dose 5 mg of alteplase with 5 mg of dornase alfa. This was done after transfusion of 1 unit (215 mL) of packed red blood cells, which raised her haemoglobin from 78 g/L to 82 g/L. Five mg of alteplase was diluted with 50 mL of normal saline and this was instilled through the seldinger chest tube. This IPFT was allowed to dwell for 45 min, followed by free-flow drainage for an additional 45 min. This procedure was repeated in the same manner with 5 mg of dornase alfa.

Outcome and follow-up

Following the ‘rescue therapy’ of intrapleural alteplase and dornase alfa, we drained 2000 mL (figure 1B) of haemoserous pleural effusion over 24 hours with no significant drop in haemoglobin and no clinical evidence of systemic bleeding. A repeat chest radiograph and ultrasonography of the thorax demonstrated complete resolution of the loculated MPE (figure 1C, D). Her dyspnoea improved and the fever subsided. Oxygen requirement was successfully tapered from 5 L/min to 3 L/min.

Discussion

MPE is associated with a shorter survival and the treatment is aimed at relieving the symptoms of dyspnoea in a minimally invasive method. Treatment can be either drainage followed by chemical pleurodesis or indwelling pleural catheter.

MPE complicated by pleural infection is associated with significant mortality. The initial management includes intercostal chest drainage and antibiotic therapy. Drainage can be difficult due to the presence of thick fibrous septation and empyema is a common complication. IPFT with tPA and human recombinant deoxyribonuclease (DNase) is an option in patients who respond poorly to intercostal chest drainage and deemed unfit for video-assisted thoracic surgery or thoracotomy with decortication.

tPA activates plasminogen and degrades fibrin into soluble products. tPA also prevents ongoing fibrin deposition and reduces the severity of loculations. DNase acts by cleaving the uncoiled extracellular DNA from degraded bacteria and leucocytes. The combination of intrapleural tPA/DNase promotes pleural clearance and reduces fluid viscoelasticity.

The side effect of bleeding following IPFT therapy remains the greatest concern among clinicians and patients. The reported major adverse events in the MIST-2 trial were not significantly different between the tPA/DNase and placebo groups.¹ Two patients developed intrapleural haemorrhage and one reported haemoptysis.¹ Another study involving 120 patients reported no major bleeding following treatment with up to four doses of intrapleural tPA.² The most frequent reported side effect was chest pain typically following the first dose of intrapleural tPA.³ Our patient had mild chest pain and no significant drop in the haemoglobin or systemic bleeding after the tPA/DNase.

The combination of tPA/DNase has proven effective in clinical trials.¹ MIST-2, a randomised, double-blind, placebo-controlled trial involving 196 adult patients with pleural infection showed that intrapleural tPA/DNase improved chest drainage, reduced radiographic pleural opacity, shortened length of hospitalisation and reduced the frequency of surgical referral.¹ Another study using tPA/DNase showed significant increase in pleural fluid drainage with a reduction in C reactive protein and better clearance of pleural opacity on chest radiographs following intrapleural therapy.⁴ In MIST-2 trial, patients were given 10 mg of tPA and 5 mg of DNase, two times a day for a total of up to six doses.

Published literature on the use of IPFT in MPE is limited. In TIME3 trial, 71 patients with non-draining MPEs were randomised to either placebo or intrapleural urokinase of 100 000 IU, three doses at 12 hours interval. This trial showed an improvement in pleural drainage and radiological appearance but failed to show improvement in dyspnoea.² A multicentre observational study on IPFT on symptomatic pleural loculations showed improvement in both pleural drainage and dyspnoea.³ Many studies with IPFT were performed on heterogeneous population where the improvement was seen only in the effusion size and not in the symptoms.⁴ A separate study involving 47 patients with MPE showed significant increase in pleural drainage and radiological improvement with the use of pleural streptokinase.⁵

Current literature describes a wide range of tPA doses ranging from 0.5 to 100 mg.^6–9 Our case is unique as we used a modified single low dose 5 mg of alteplase plus 5 mg of dornase to treat a complex haemoserous MPE successfully with no significant intrapleural haemorrhage. This suggest that IPFT can be considered in a complex parapneumonic infection even on patients with MPE. This modified regimen appears effective with a favourable outcome and our clinical experience adds to the current literature on the safety and effectiveness of modified low dose of tPA/DNase. Future randomised control trials are needed to establish the safety, efficacy and optimal treatment dose of IPFT in MPE.

Learning points.

• Intrapleural tissues plasminogen activator (tPA)/deoxyribonuclease (DNase) can be considered for a patient with a persistent or intractable complex haemoserous malignant pleural effusion (MPE) with careful monitoring.

• Intrapleural fibrinolytic therapy can result in improvement of both symptoms and effusion size in selected patients.

• Further doses of tPA/DNase will not be necessary if the pleural collection is evacuated with clinical and radiological improvement.

• A modified lower dose of intrapleural tPA/DNase may be safe and effective for a patient with infected complex hemoserous MPE.