Title: Early Video Assisted Thoracoscopic Surgery (VATS) or Intrapleural Enzyme Therapy (IET) in Pleural Infection - a feasibility randomised trial.
Funder: Department of Health and Social Care

Abstract: Pleural Infection, where infected fluid develops between the lung and chest wall, is common(5-7) and increasing (5, 7). Treatment involves antibiotics and drainage of infected material using a chest tube (inserted between the ribs)(8). Despite treatment, the disease has a mortality of 20% (8) and 20% fail initial treatment which requires surgery, that is invasive, costly(2, 3, 9, 10) and associated with high morbidity (11, 12). Surgery is avoided in the most ill (7, 13), in whom mortality is 40%(14). Average length of hospital stay is 14 days(2, 3, 8) and treatment costs around &pound;6000 / patient(3). Novel Treatment Newer surgical &ldquo;keyhole&rdquo; techniques (Video Assisted Thoracoscopic Surgery, VATS) are now used when initial treatment fails after 3 to 5 days, as they are less invasive than traditional surgery(15). However, we do not know the role of early VATS treatment in this disease (8). A recent placebo-controlled trial(3) by the Oxford Respiratory Trials Unit (ORTU) suggests the non-surgical treatment of Intrapleural Enzyme Therapy (IET, which involves medications given through the chest tube as part of early treatment) improves drainage and reduces the need for surgery and hospital stay. IET is available to all patients, not requiring the patient to be &ldquo;fit&rdquo; enough for an operation. Aims of the Work and Questions to be addressed Assessing the early use of VATS or IET requires a randomised phase III direct comparison. Before undertaking a large trial, key outcomes of importance to patients require development, and feasibility of recruitment, patient acceptability and outcome collection requires assessment. We therefore propose a randomised study to address feasibility of randomising patients to standard care, early VATS or early IET, and we will create a patient involvement group with personal experience of the disease, to understand acceptability of randomisation and priorities in care. Plan of Investigation Our aims will be achieved by: 1. Formation of a Patient / Carer Group (n=10) to allow exploration of the patient centred impact of this disease and priorities of care, via 2 monthly focus groups, meetings with the trial team, and membership for patients to key oversight committees for the feasibility trial. 2. In-depth Patient Interviews where 20 patients assessed for inclusion in the study (see below) will undergo structured interviews, exploring patient and carer experience, impact on quality of life and priority areas of care. 3. A Randomised Feasibility Trial will be conducted in 75 pleural infection patients treated in routine clinical care, in centres with a track record of delivery to previous ORTU pleural infection studies (n>1000). Patients will be randomised to: Standard care (chest tube drainage and antibiotics) IET - through the chest tube, intrapleural tPA (10mg bd) and DNase (5mg bd) will be administered for 72 hours (3), immediately after randomisation. VATS - referred immediately after randomisation to local surgical services The Primary outcome is the feasibility of randomizing 75 patients over 18 months recruitment in 5 UK centres. Exploratory secondary outcomes include trial related (proportion accepting randomization, patient acceptability), healthcare related (hospital stay, mortality, need for further surgery, adverse events) and patient outcomes (patient reported pain, breathlessness, health-related quality of life). Summary of the Potential Benefits An in-depth understanding of patient reported priorities and experience would provide the required outcome tools to conduct an applicable and important larger study. Demonstration of feasibility of recruitment is a vital step in conducting a larger, potentially practice changing study. Eventually, evidence demonstrating the utility of early treatment with VATS or IET has the potential to reduce mortality, reduce hospital stay, reduce suffering, improve quality of life and reduce healthcare costs.

Lay abstract: Pleural infection is a serious complication of pneumonia where infected fluid collects around the lung in a large abscess. It can affect anyone, and occurs in 40 patients every day in the UK. Treatment requires antibiotics and drainage of fluid using a chest tube inserted with local anaesthetic between the ribs, and admission to hospital for 2 weeks. When these treatments fail, patients either die (about 20% of cases) or are referred for major surgery (a further 20%). Surgery is important when initial treatment fails, but has several side effects and is not an option for elderly and sick patients, where the death rate is 40%. A new treatment (called Intrapleural Enzyme Therapy or IET) can be given through the chest tube early in treatment, which improves drainage and reduces the need for surgery and the time spent in hospital. Keyhole surgery is also now available to drain infected fluid (Video Assisted Thoracoscopic Surgery or VATS), and some people believe that this should occur early in treatment to prevent death and long hospital admissions, but this has not been proven. Early treatment with either IET or VATS may therefore improve care but we do not know the long-term effects (e.g. restriction in breathing) or impact on quality of life. We aim to consult with patients to understand what factors are important to them when treating this disease. This will help us to understand what should be measured in a study to best improve care. We will then use this information to conduct a study where patients are randomised (assigned by computer) to usual treatment (chest tube and antibiotics), early VATS or early IET. We will measure whether it is acceptable to patients to be randomised in this way and whether a larger study in the future is important and possible.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health categories: INFECTION