VATS or Intrapleural Enzymatic Therapy for Patients With Empyema.

In the Netherlands, each year 24.000 patients are hospitalized for pneumonia, 50% of which develop pleural effusion: fluid accumulation in the cavity between the lungs and the chest wall. In every 6-7 cases, this fluid gets infected with bacteria; parapneumonic pleural infection or empyema; leading to high morbidity and mortality (up to 30% in immunocompromised and/or frail patients). Parapneumonic pleural infection is associated with prolonged hospitalization, high healthcare costs and significant societal impact. Patients complain of pain, prolonged chest tube drainage, long hospital stays and long rehabilitations. Standard care of parapneumonic pleural infections consists of placement of a chest tube and antibiotic treatment. Approximately 50% of patients with a parapneumonic pleural infection can be treated successfully with this strategy. When standard care fails, two main treatment modalities are available in daily practice. One is IET (intrapleural enzymatic therapy), where fibrinolytic agents are inserted through the chest tube to dissolve the fibrin formed in the pleural fluid. The other modality is minimally invasive surgery by VATS (video assisted thoracoscopic surgery).

No consensus exists on which modality is superior in terms of clinical outcomes (mortality, length of hospital stay (LOS), etc) and cost-effectiveness, since no studies with head-to-head comparisons of IET and VATS have been published yet. This has led to extensive practice variation throughout hospitals in the Netherlands and to protracted treatment episodes. In a national survey on treatment of parapneumonic pleural infection among pulmonologists and thoracic surgeons in the Netherlands both IET and VATS were used in daily practice, but the heterogeneity in treatment approach and - results was substantial. The scarce literature on the subject to date appears to favour VATS in terms of LOS, but this is not supported by solid scientific evidence. Because of the frequent occurrence of parapneumonic pleural infection, the high mortality and morbidity and the lack of consensus about the best treatment modality, this subject has been identified as a knowledge gap by the national societies of both pulmonary surgeons and pulmonologists. Both IET and VATS are considered usual care in the Netherlands for patients with a parapneumonic pleural infection. This is reflected by international guidelines which advocate the use of either IET or VATS in patients who deteriorate despite initial treatment with chest tube drainage and intravenous antibiotics.

Since no studies with head-to-head comparisons of IET and VATS have been published yet; the investigators want to research what the optimal treatment modality is for patients with a parapneumonic pleural infection (not responding to initial treatment with antibiotics and chest tube drainage).

Video-assisted thoracic surgery (VATS), is already commonly used in daily practice for the treatment of parapneumonic pleural infection. In this study, VATS should be commenced no later than 48 hours after randomization. The VATS will be performed through one to three ports, to the discretion of the operating surgeon. The pleural fluid should be drained, the thorax purified, and decortication must be performed if necessary. Preferably one chest tube is inserted at the end of the procedure, size 20-32 French. Pain management is by paravertebral/intercostal nerve block with ropivacaine 7.5%. Suction on the chest tube is applied until a maximum of 24 hours after surgery, and water seal should than be applied if the lung is fully expanded and drained fluid is \<400ml/24hr.

Procedure: VATS group

Intrapleural enzymatic therapy (IET), refers to the instillation of fibrinolytic agents through a chest tube in order to facilitate the evacuation of infected pleural fluid. In the current study, the first dose of IET through the chest tube should be administered no later than 48 hours after randomization. Intrapleural therapy consists of two drugs: Alteplase 10mg and DNase 5mg. IET is administered twice daily through the chest tube and left in the thorax for one hour by blocking the chest tube. The drugs are prepared separately and administered concurrently, in random order. Only properly trained medical personnel is allowed to prescribe and perform the administration of IET. This dose, alteplase 10mg and DNase 5mg intrapleurally twice a day for six doses, will be administered through a chest tube in this study.

Drug: IET

VATS procedure to remove the infected fluid and facilitate re-expansion of the infected lung.

Intrapleural Enzymatic Therapy Consisiting of Alteplase 10mg and DNase 5mg

Plazo: Within the first 30 days after chest tube insertion.

This is defined as the number of days from chest tube insertion to hospital discharge.

Plazo: 30 days

Number of days between chest tube insertion and removal of chest tube

Plazo: 30 days

The number of hospital days between completion of treatment and actual hospital discharge that are unrelated to the treatment of the parapneumonic pleural infection (e.g. awaiting nursing home placement, rehabilitation facility placement, home care arrangements, or other administrative or logistical delays).

Plazo: 30 days

The need for additional drainage procedures or surgery

Plazo: 30 days

Need for re-admission

Plazo: 30 days

Defined as any deviation from the expected clinical course, including complications and (serious) adverse events

Plazo: 30-day and 1-year mortality

Mortality (30-day and 1-year)

Plazo: Up to 3 months after initiation of antibiotic therapy

Type of antibiotic therapy

Plazo: Up to 3 months after initiation of antibiotic therapy

Duration of antibiotic therapy (in days)

Plazo: 30 days

Type of analgesic use

Plazo: 30 days

Duration of analgesic use (in days)

Plazo: Through study completion (at 1, 3, 6, 9, and 12 months after randomization)

Healthcare consumption will be assessed using the iMTA Medical Consumption Questionnaire (iMCQ), an instrument designed to measure medical consumption, including contacts with healthcare providers, hospitalizations, medical procedures, medication use, and other healthcare services. The questionnaire will be used to assess healthcare consumption following randomization.

Plazo: Through study completion (at 1, 3, 6, 9, and 12 months after randomization)

Productivity losses will be assessed using the iMTA Productivity Cost Questionnaire (iPCQ), a standardized instrument for measuring productivity losses for use in economic evaluations of healthcare. The questionnaire will be used to assess productivity losses following randomization.

Plazo: Through study completion (at baseline, 1 week, 2 weeks, 1, 3, 6, 9, and 12 months after randomization)

Health-related quality of life will be assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L). The questionnaire assesses five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five response levels, ranging from no problems to extreme problems. Responses will be used to assess health-related quality of life.

VATS or Intrapleural Enzymatic Therapy for patientS With Empyema (the VIETS Trial).