VATS Surgery Compared to Drainage in the Treatment of Pleural Empyema

Intrapleural Fibrinolysis and DNase versus VATS for the treatment of pleural empyema: a randomized, controlled trial

BACKGROUND

Pleural empyema is a disease with an infection inside the chest cavity, often as a result of a pneumonia. In Denmark there are approximately 500 new cases per year. Patients often have longer duration of hospitalization, and the disease carries a significant morbidity and mortality rate of approximately 15%. The state of pleura empyema is characterized by the passage of three stages (I - III):

* Parapneumonic effusion (stage I) * Fibropurulent stage (stage II) * Chronic organizing stage (stage III)

The aim of treating the disease is to remove the infection and provide fully expansion of the lung.

In our study we want to find the optimal method for treating patients in stage II and III.

The initial treatment at the early stage of the disease (stage I) is simple drainage and the disease at later stages can be treated with surgical intervention. In clinical practice, stages II and III are treated alike. Current standard treatment for these stages is drainage with ultrasound (ULS) -guided pigtail with a minimum size of 10 F. Simultaneously with drainage, an intrapleural fibrinolyticum can be given, but the indication and evidence for this is discussed. In the MIST II study, fibrinolytic (alteplase) was combined with DNase, and the authors found a positive effect using this combination.

Previously, surgery was associated with a significant morbidity and, to a lesser extent, mortality. The surgery was conducted as open surgery using a thoracotomy. Today, it can often be performed as a Video Assisted Thoracoscopic Surgery (VATS), which can be performed with a very low morbidity and mortality. It has been advocated that patients should be operated very early in the process, but the evidence is weak. In a Cochrane review on surgical versus non-surgical treatment of pleura empyema, two studies with adult patients have been included. None of the studies have a size or methodological quality that makes it possible to determine whether VATS should be included as part of the standard treatment of these patients. In children (aged \<15 years), a randomized, controlled study of 50 patients in each group was conducted. It found no difference in outcome between fibrinolyticum and VATS, but no fixed treatment algorithm has been established for this age group. Furthermore, these results cannot be generalized to an adult population.

The theoretical advantage of early surgery is that patients undergo rapid, definitive treatment and surgery can ensure optimal drain placement. The potential advantages in early surgery are reduced mortality, admission time, and fewer late complications. In addition, it is estimated that an increased number of early-operable patients may reduce the proportion of patients, who will later be thoracotomized, as early surgery may be performed as VATS. However, there is the inherent risk of an operation and thereby the increased costs of the surgical procedure when compared to simple drainage. However, this could possibly be outweighed by reduced drug consumption, reduced need for supplemental drainage, shorter duration of admission, and reduced morbidity after discharge.

Accordingly, it is necessary to determine whether early VATS should be introduced as standard therapy in patients with fibropurulent stage (stage II) and the chronic organizing stage (stage III).

Hypothesis • Patients over 18 years with a fibropurulent stage (stage II) or a chronic organizing stage (stage III) pleural empyema will have a significantly reduced time of hospitalization, if they undergo a VATS operation compared to ULS-guided pigtail drainage and fibrinolyticum (Acitlyse® (altaplasm)) with DNase (Pulmozyne®)

Aim of study

• To determine the difference in outcome in patients diagnosed with complex parapneumonic effusion (stage II), and pleural empyema (stage III) who are treated either VATS surgery or TUS guided drainage and intrapleural therapy (fibrinolytic (Alteplase) with DNase (Pulmozyme®)) as first line treatment.

Expected improvements If this trial is positive for the primary and/or the secondary outcomes, it could potentially change and strengthen the treatment of patients with this disease, both nationally and internationally. We investigate both clinical parameters, patient satisfaction and economical aspects (cost-effectiveness) in relation to pleura empyema treatment, so it will cover many aspects of this disease. If the trial is neutral, it will provide valuable data on intervention that is currently commonly used for this disease and can guide the treating physician to choose the adequate treatment based on the local preferences.

METHODS Design

* Randomized, controlled study * Not blinded (open label) * National multicenter study

Inclusion and exclusion criteria

Inclusion criteria:

* 18 years or more on the day of hospitalization * Must be able to provide informed consent * Acute hospitalization within the last 48 hours * Meeting diagnostic criteria for community acquired pleural infection using the following criteria:

1. A clinical presentation compatible with pleural infection AND 2. Has pleural fluid which is either:

1. purulent pleural fluid or 2. gram stain positive or 3. culture positive or 4. acidic with pH \< 7.2 or 5. low pleural fluid glucose (\< 2 mmol/L) in the absence of accurate pH measurement or 6. septated pleural fluid on ultrasound

Exclusion criteria:

* • Pregnancy. Prior to inclusion of fertile women (defined as the period from menarche to postmenopause) a negative pregnancy test must be available * Breastfeeding * Declared terminally ill or a predicted survival of less than 3 months * Previous intrathoracic surgery (within \<1 year on the same side of the thorax as where the parapneumonic effusion/pleural empyema is located * Previously (within \<1 year) hospitalized with with complex parapneumonic effusion (stage II) or pleural empyema (stage III) * Drainage during the current admission on the same side of the thorax (excluding diagnostic pleural puncture) * Hospitalization within 7 days prior to current hospitalization * Previous allergic reaction to alteplase or DNase * Use of alteplase therapy contraindicated:

* Ongoing treatment with oral anticoagulant incl. new oral anticoagulants (e.g. warfarin (Marevan), Dabigatranetexilat (Pradaxa), Rivaroxaban (Xarelto), Apixaban (Eliquis), Endoxaban (Lixiana)) * Significant ongoing bleeding or within last six months * Known haemorrhagic diathesis * Previous or suspected intracranial hemorrhage * Suspected subarachnoidal hemorrhage or condition following subarachnoidal hemorrhage from aneurysm * All forms of damage to the central nervous system (e.g. cerebral tumors, aneurysm, intracranial / spinal surgery) * Recent (within 10 days) cardiac resuscitation, birth, or perforation of non-compressible blood vessel (e.g. puncture of v. subclavia, v. jugularis) * Severe, uncontrolled arterial hypertension * Bacterial endocarditis, pericarditis * Acute pancreatitis * Documented ulcerative gastrointestinal disease within last 3 months, esophagal varices, arterial aneurysm, arterio-venous malformations * Tumor / malignancy with an increased risk of hemorrhage * Severe liver disease, including liver failure cirrhosis, portal hypertension (esophagal varices), and active hepatitis * Large operation or significant trauma within previous 3 months

Endpoints

Primary endpoint:

• Length of hospital stay, where admission time is defined as the time from first admission in the course of the hospitalization and to the completion of treatment defined as time of discharge from hospital without need of any additional invasive treatment.

Secondary endpoints:

* Hospitalization time when patients are stratified in subgroups (Stage, TUS score, RAPID score) * Length of hospital stay after commencement of intervention * Days at home up to 30 days after intervention (DAH30) * 30-day and in-hospital mortality * Time from randomization to commencement of intervention * Drainage time measured in days * Proportion of patients where primary intervention could be considered as definitive treatment * Complications ranked by Clavien-Dindo classification and Comprehensive Complication Index (CCI) * Need for additional thoracic surgery within 12 months after hospitalization * Consumption of painkillers during hospitalization and within 12 months after hospitalization * Lung physiology within 12 months after hospitalization * Quality of life and patient reported outcomes within 12 months after hospitalization * Health related costs within 12 months after hospitalization

Randomization

Patients will be randomized 1:1 to either:

1. VATS procedure with drainage 2. TUS-guided pigtail catheter placement and intrapleural therapy with Actilyse and DNase Block randomization with varying block size will be used to get an equal number of patients in both groups. There will be stratification for each surgical center in the randomization. The randomization is conducted via a REDCap (Research Electronic Data Capture), (REDCap Consortium, Vanderbilt University Medical Center, Tennessee, USA).

Blinding Patients and responsible health care staff will not be blinded. Research staff not involved in the treatment of the included patients are blinded to treatment allocations until data analyses are complete. Assessment of different scoring systems (e.g. TUS and radiology score) are blinded to the extent that it is practically possible.

Patient population and selection All patients admitted during the diagnosis of pleural empyema or pleural effusion without specification (diagnostic codes: DJ 86, DJ 86.1, DJ 86.9, DJ 90.9), Stages II and III will be potential candidates, whether they are hospitalized at a Regional Hospital or at a University Hospital.

Practical issues regarding inclusion of patients Patients who immediately meet the criteria for inclusion and are interested in participating are informed by one of the project participants or project nurses from the thoracic surgery department or other relevant department where the patient is hospitalized. The physical location of information and randomization will vary with the local organization of hospitals and departments. If the patient is randomized to VATS, the patient is transferred to one of the four centers where there is a thoracic surgical department. If the patient is randomized to ULS guided drainage and intrapleural therapy, the patient is transferred to one of the specialized pulmonology departments participating in the project.

Intervention Drain and intrapleural therapy group Pigtail is applied as soon as possible and within 48 hours after randomisation. Drain placement is carried out using ULS. Operators (conductors of the procedure) must have relevant training and competencies corresponding to the specialist level within the relevant specialty and be approved by the steering committee to conduct the procedure. A pigtail catheter (minimum 10F) is inserted. Operator determines the size of drain and whether drain placement is done with one-step or Seldinger technic.

The intrapleural therapy consists of treatment with the following two drugs: * intrapleural Actilyse® (alteplase) 10 mg twice daily for three days * intrapleural Pulmozyme® (DNase) 5 mg twice daily for three days Both drugs are administered twice daiyly through the pigtail catheter and are left for one hour in the pleural cavity by blocking the drain (e.g. closing the three-way-stopcock / use of a pean forceps). The installation of the drugs in the pleural cavity is performed seperately with a time interval between administrations of at least two hours. Actilyse® (alteplase) is preparred by diluting 10 mg Actilyse® (alteplase) in the solvent liquid (10 ml) supplied alongside the drug in a 50 ml syringe. Thi

• Length of hospital stay in subgroups [Срок оценки: Through study completion, an average of 1 year]
• Length of hospital stay after commencement of intervention [Срок оценки: Through study completion, an average of 1 year]
• Days at home up to 30 days after intervention (DAH30) treatment [Срок оценки: Through study completion, an average of 1 year]
• 30-day and in-hospital mortality [Срок оценки: Through study completion, an average of 1 year]
• Proportion of patients where primary intervention could be considered as definitive treatment [Срок оценки: 30 days]
• Complications ranked by Clavien-Dindo classification and Comprehensive Complication Index (CCI) [Срок оценки: Through study completion, an average of 1 year]
• Need for additional thoracic surgery within 12 months after hospitalization [Срок оценки: 1 year]
• Consumption of painkillers during hospitalization and within 12 months after hospitalization [Срок оценки: Through study completion, an average of 1 year]
• Lung physiology within 12 months after hospitalization [Срок оценки: 1 year]
• Quality of life and patient reported outcomes within 12 months after hospitalization [Срок оценки: Through study completion, an average of 1 year]
• Health related costs [Срок оценки: 1 year]
• Quality of life and patient reported outcomes within 12 months after hospitalization [Срок оценки: Through study completion, an average of 1 year]