Title: Targeted oxygen therapy in mechanically ventilated critically ill patients
Funder: Department of Health and Social Care

Abstract: Population: Adult patients at the two participating hospitals, in whom respiratory failure has led to them requiring mechanical ventilation via an endotracheal tube on a critical care unit (CCU). Intervention: Targeted oxygen therapy (TO2T) to achieve an arterial oxygen partial pressure (PaO2) target of 7.0-9.0 (predicted mean = 8.0) kPa Control: TO2T to achieve a PaO2 of 11.0-13.0 (predicted mean = 12.0) kPa [normal PaO2 for healthy adults and therefore standard practice] Primary outcome: Feasibility. Assessed by: # Ability to recruit patients at the two sites (recruitment rate) # Support for the trial from involved clinicians # Rate of withdrawal from intervention and control protocols # Reasons for withdrawal from the study Secondary outcomes: # Safety of the proposed intervention compared to standard treatment # To gain an understanding of underlying biological mechanisms that link PaO2 to clinical outcomes (funded through a separate source) Hypothesis: The correction of severe hypoxaemia in mechanically ventilated critically ill patients may cause more harm than benefit. Targeting a lower PaO2 than normal could lead to improved outcomes by minimising exposure to harm. Rationale: Whilst severe hypoxaemia is undoubtedly harmful, it is now clear that using high concentrations of oxygen to resolve this can also be harmful, particularly in critically ill patients with underlying lung injury. Striking a balance between the benefits of normoxaemia and the harms that may occur in achieving it is therefore essential. Using lower blood oxygen targets than usual may be beneficial through the avoidance of high oxygen concentrations. There is limited data available currently to guide clinicians in this complex area. Aim: To conduct a prospective randomised controlled study study to evaluate the feasibility of targeting two different PaO2 ranges in patients, and assessing the safety of this intervention. Additional information about biological mechanisms relating oxygenation to outcomes. Design: A prospective dual centre, randomised controlled trial to compare normal versus low blood oxygenation targets in critically ill patients. Patients will be randomly allocation (1:1) to one of two groups. TO2T will be maintained throughout the study intervention period. There will be no specific protocol for clinicians to follow to achieve these targets; management of the patient will be at their discretion. Routine CCU measures and outcomes will be collected and a series of blood tests taken to allow storage of plasma for later analysis. Sample size: We shall recruit 60 patients into this trial; 30 at Southampton General Hospital and 30 at the Royal Free Hospital. Duration of study: The study will be 25 months in length: # Set up = 3 months # Recruitment = 15 months # Last intervention = 0.5 months (average two weeks) # Follow-up = 3 months # Analysis and write up = 3.5 months We expect to see 10 patients per month at each site who fulfil the criteria for enrolment. Based on previously published data and our own experience we estimate to successfully recruit 20% of these into the study. Therefore we will require 15 months to recruit 60 patients in total at two sites. Statistical analysis: Outcomes will be summarised by treatment arm for this feasibility study. Expertise in team: Critical care consultants, experienced clinical trialists, anaesthetic consultants, intensive nurses, a clinical trials unit and the involvement of the public. Potential benefits to patients and the NHS: If successful, this study will lead to a larger multi-centre trial to evaluate TO2T. Ultimately this may change the way we manage critically ill patients in the NHS, reducing the harm them comes to them and improving length and quality of life.

Lay abstract: Aims: Our aim is to determine whether lowering standard targets for blood oxygen levels in patients requiring mechanical breathing support on a critical care unit is both feasible and safe. Background: We know that giving too much oxygen to patients can cause them harm, because high concentrations of oxygen are toxic. Very unwell patients requiring mechanical breathing support may be most prone to this harm, yet this is a group that often requires high oxygen concentrations to keep their blood oxygen level normal. Using lower blood oxygen targets than usual may be beneficial through the avoidance of high oxygen concentrations to achieve normal targets. It has therefore been proposed that targeting lower blood oxygen levels in these patients may reduce harm but this has not been studied thoroughly. Design: This trial will establish whether it is possible to conduct a trial in which blood oxygen levels are carefully targeted by the critical care team, to achieve specific targets. Patients will be allocated into one of two groups: i) normal blood oxygen levels, and ii) blood oxygen levels that are slightly lower than normal but within a range that is considered to be safe. Sixty patients will be enrolled at two sites and the data collected from them will also be used to ensure that patients are not harmed by the low blood oxygen level intervention. The information will be used to design a subsequent much larger study of this intervention. Impact: Limited work has been undertaken to date to understand whether lowering blood oxygen levels is achievable or safe. If lower blood oxygen levels improve survival in critically ill patients implementation of this intervention could have an immediate and cost-effective impact across the entire National Health Service.

Research activity codes: 6.7 PHYSICAL
Health categories: GENERIC HEALTH RELEVANCE