The 4th Multicentre Intrapleural Sepsis Trial (MIST4) - a definitive randomised clinical effectiveness study comparing initial video assisted thoracic surgery and intrapleural enzyme therapy in adult patients with pleural infection.

Research question

Is Video Assisted Thoracoscopic Surgery (VATS) superior to Intrapleural Enzyme Therapy (IET) in the initial treatment of adult patients with pleural infection? Background

Pleural infection occurs when infected fluid accumulates between the lung and chest wall, affecting 15,000 patients / year, with 40 new cases / day in the UK. Clinical outcomes are poor with 1-year mortality of 20% and median length of stay of 14 days. Treatment is costly at £6000/patient (£18million/year).

Standard treatment requires hospital admission, intravenous antibiotics, and insertion of a tube into the pleural space (chest drain) to remove infected fluid. This standard medical treatment fails in 34% of cases.

Two treatment options are then available; surgical intervention (VATS debridement) or medications inserted through the chest drain to aid removal of fluid [intrapleural enzyme therapy (IET) = tissue plasminogen activator (tPA) + deoxyribonuclease (DNase)]. While VATS is considered “definitive” treatment, it requires a general anaesthetic, and there is a risk of death and procedure related complications.

IET is easily deliverable but may not be as effective as VATS and is associated with some risks (e.g. bleeding).

Thus, optimal treatment (VATS or IET) is not defined in pleural infection and is variable in clinical practice. Based on a successfully completed feasibility study (MIST3), we here propose a definitive clinical effectiveness study to compare these two treatments. Aim To assess whether VATS is superior to IET as initial treatment in pleural infection

Objectives:

1) Conduct a definitive randomised trial to assess whether VATS is superior to IET with respect to treatment failure on objective criteria 2) Estimate differences between groups for patient-reported and clinical outcomes to 3 and 12 months 3) Estimate cost-effectiveness of VATS compared to IET 4) Determine the risk profile of VATS and IET in this population

We hypothesise that treatment failure is lower using initial VATS compared with IET, by providing definitive drainage, avoiding the treatment time required with IET and that benefits will occur despite the clinical reality of NHS surgical capacity. Methods

We will recruit 604 patients to a 1:1 randomised trial comparing IET and VATS in 25 hospitals. Patients with pleural infection and a relevant level of baseline fitness (clinical frailty score =6) will be identified by respiratory physicians; patients who consent to take part will be randomised to either VATS or IET. Subsequent treatment will be based on protocolised care and standard operating procedures, including objective treatment failure criteria.

The primary outcome will be treatment failure over 90 days post randomisation (the key patient priority and the most relevant clinical outcome). Secondary outcomes include health related QoL, total hospital stay, mortality at 12 months, health economics and patient reported outcomes (pain, breathlessness).

Timelines

54-month project including internal pilot phase (9 month set up, 9 months pilot recruitment, 18 months further recruitment, 12 months follow up, 6 months close down / analysis). Impact

Completion of the trial will provide definitive evidence on best initial treatment and inform treatment guidelines, NHSE policy and organisation of respiratory / surgical services. Earlier treatment with definitive intervention may reduce hospital stay and mortality, both of which may improve the costs of care.