Targeted OXYgen Therapy in Critical Illness (TOXYC)

A Randomised Controlled Trial of Targeted Oxygen Therapy in Mechanically Ventilated Critically Ill Patients

The investigators propose to conduct a feasibility, multi-centre, randomised controlled trial of targeted oxygen therapy in adult critically ill patients receiving mechanical ventilation via an endotracheal tube as part of their treatment for respiratory failure. Participants will be allocated to either a normal blood oxygen target group or a lower than normal blood oxygen target group. The primary purpose of the study will be to assess the feasibility of recruiting complex patients who lack capacity into a clinical trial in which oxygenation is being assessed, and that the clinicians responsible for these patients are able to deliver the intervention effectively. The safety of using a lower than normal blood oxygen target will also be assessed and blood samples taken for subsequent investigation of the biological mechanisms underlying the observed changes.

Participants will be randomised (1:1) into either an intervention or control group. The intervention in this trial is tightly controlled administration of oxygen to patients to achieve a haemoglobin oxygen saturation (SpO2) of 88-92%. The control group will also have tightly controlled oxygen administration, but to achieve an SpO2 of 96% or above. The target for the control group represents a normal SpO2, whilst that in the intervention group is lower than what is considered to be normal. It should be noted that although lower than normal, this SpO2 is close to what the general public experience when travelling by pressurised aircraft as the fractional inspired oxygen concentration in that situation is only 0.15-0.17 (15-17%).

The controlled oxygen administration would commence as soon as possible after admission to the critical care unit and end following removal of the participant's artificial breathing tube. The researchers and clinical team cannot be blinded to treatment allocation, due to the nature of the intervention. Those analysing the data will be blinded to the intervention.

Study Overview

• Status: Completed
• Conditions: Critical Illness; Respiratory Failure
• Intervention / Treatment: Drug: Oxygen

Detailed Description

The investigators aim is to determine whether revising standard targets for blood oxygen levels in patients requiring artificial ventilation on a critical care unit is feasible and whether this affects specific blood biomarker levels.

Investigators in this area of expertise currently lack the information necessary to determine how much oxygen should be given to adult critically ill patients on a mechanical ventilator to assist their breathing in order to achieve the best clinical outcomes i.e. minimal morbidity and mortality. Excessive oxygen administration (both its concentration and duration) and hyperoxaemia (an excessively high blood oxygen level) are known to be harmful to critically ill patients. The reason for this is that oxygen in high concentration is toxic, because it results in the release of molecules called reactive oxygen species (ROS). ROS lead to a state known as 'oxidative stress', in which cells and tissues are rapidly destroyed by these destructive molecules.

The difficulty with treating critically ill patients is that they are usually extremely unwell, requiring artificial ventilation to support their breathing. Unfortunately, these patients appear to be exceptionally prone to the harms of oxidative stress, leading to permanent damage of their lungs. Yet it is precisely this group of patients who require high concentration oxygen to keep their blood oxygen levels within the normal. It has therefore been hypothesised that using lower blood oxygen targets than usual may be beneficial to these patients through the avoidance of excessively high concentrations of oxygen. The investigator proposes that in mechanically ventilated critically ill patients harm (morbidity and mortality) will be reduced by using 'targeted oxygen therapy' (TO2T) to achieve lower blood oxygen levels than normal when compared to standard practice (normal blood oxygen levels). The levels are only moderately lower than normal and well within what most clinicians would consider to be safe in these patients.

Prior to any large-scale study, it is important to understand if this approach to managing critically ill patients is feasible. This prospective, dual site randomised controlled trial will therefore establish whether it is possible to conduct a trial in which blood oxygen levels are carefully titrated by the critical care team, to achieve specific targets. Participants will be allocated into one of two groups: i) normal blood oxygen levels, and ii) low blood oxygen levels. For the time that participants are artificially ventilated by a breathing (endotracheal) tube, they will remain in their allocated treatment group. Information will be collected from the patient's charts and records during their stay on the CCU to assess the impact of the treatment. A series of blood samples will also be collected from participants to quantify the degree of oxidative stress through the measurement of several specific biomarkers. A total of 60 patients will be enrolled at two sites.

As oxygen is a drug that is administered to almost every patient admitted to a critical care unit (CCU), it is imperative that decisions regarding oxygenation are based upon evidence rather than conjecture. Limited work has been undertaken to date to understand whether lowering blood oxygen levels is achievable in this complex patient group. The information from this study will be used to design a subsequent much larger study to fully evaluate whether TO2T to achieve lower blood oxygen levels saves lives in critically ill patients. 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.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unplanned admission to a critical care unit
• 18 years of age and above (no upper age limit)
• Respiratory failure forms part of the admission diagnosis
• The patient is mechanically ventilated via an endotracheal tube
• The patient is expected to receive mechanical ventilation for > 24 hours

Exclusion Criteria:

• Admission following surgery (elective or unplanned)
• Those patients expected to die within 24 hours of admission to ICU *
• Pregnant females
• Admission post-cardiac arrest
• Admission post trauma (including traumatic brain injury)
• Known sickle cell trait or disease
• Ongoing significant haemorrhage or profound anaemia
• Severe peripheral vascular disease
• Severe pulmonary hypertension
• Other medical conditions where mild hypoxaemia would be contra-indicated ***

• Patients participating in other interventional clinical trials

  • As determined by the responsible clinical team ** As determined by the responsible clinical team and /or research team

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: SpO2 88-92%; The intervention is targeted oxygen therapy (TO2T) to achieve an arterial haemoglobin oxygen saturation (SpO2) of 88-92%.	Drug: Oxygen; targeted oxygen therapy
ACTIVE_COMPARATOR: Current best practice; The control group will have no specific SpO2 targets. Clinicians will be able to target SpO2 according to parameters they feel are suitable for the patient, according to standard UK practice.	Drug: Oxygen; targeted oxygen therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility to recruit	Ability to recruit	15 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospital stay	Length of hospital stay	90 days
Measurement of arterial blood gases	Measurement of arterial blood gases	up to 21 days
Measurement of oxygen saturation	Measurement of oxygen saturation	up to 21 days
Measurement of fraction of inspired oxygen	Measurement of fraction of inspired oxygen	up to 21 days
Time to extubation / detachment from mechanical ventilation	Time to extubation / detachment from mechanical ventilation	up to 21 days
Mechanical ventilation free days on ICU	Mechanical ventilation free days on ICU	up to 21 days
Measurement of blood pressure	Measurement of blood pressure	up to 21 days
Measurement of heart rate	Measurement of heart rate	up to 21 days
Measurement of cardiac rhythm	Measurement of cardiac rhythm	up to 21 days
Measurement of cardiac output and stroke volume (if measured)	Measurement of cardiac output and stroke volume (if measured)	up to 21 days
Measurement of vasopressor doses	Measurement of vasopressor doses	up to 21 days
Measurement of inotrope doses	Measurement of inotrope doses	up to 21 days
Measurement of daily fluid balance	Measurement of daily fluid balance	up to 21 days
Measurement of inotrope free days on ICU	Measurement of inotrope free days on ICU	up to 21 days
Measurement of vasopressor free days on ICU	Measurement of vasopressor free days on ICU	up to 21 days
Measurement of Urea	Measurement of Urea	up to 21 days
Measurement of creatinine	Measurement of creatinine	up to 21 days
Measurement of urine output	Measurement of urine output	up to 21 days
The need for renal replacement therapy	The need for renal replacement therapy	up to 21 days
Renal replacement therapy free days on ICU	Renal replacement therapy free days on ICU	up to 21 days
Measurement of transaminases	Measurement of transaminases	up to 21 days
Measurement of blood clotting values	Measurement of blood clotting values	up to 21 days
Measurement of bilirubin	Measurement of bilirubin	up to 21 days
Measurement of blood lactate	Measurement of blood lactate	up to 21 days
Measurement of Troponin	Measurement of Troponin	up to 21 days
Adverse events	Adverse events	90 days
SOFA score change	Sequential Organ Failure Assessment (SOFA) score change	up to 21 days
APACHE II score change	Acute Physiology and Chronic Health Evaluation (APACHE) II score change	up to 21 days
Length of ICU stay	Length of stay in intensive care unit	up to 21 days
Mortality rates	Days alive	90 days
Days alive out of Hospital	Days alive out of Hospital	90 days

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: Royal Free Hospital NHS Foundation Trust; University Hospital Southampton NHS Foundation Trust; National Institute for Health Research, United Kingdom; Royal Free Charity

Publications and helpful links

General Publications

• Martin DS, Brew-Graves C, McCartan N, Jell G, Potyka I, Stevens J, Williams NR, McNeil M, O'Driscoll BR, Mythen M, Grocott MPW. Protocol for a feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients. BMJ Open. 2019 Jan 17;9(1):e021674. doi: 10.1136/bmjopen-2018-021674.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 15, 2018
• Primary Completion (ACTUAL): November 30, 2019
• Study Completion (ACTUAL): February 15, 2020

Study Registration Dates

• First Submitted: July 20, 2017
• First Submitted That Met QC Criteria: September 18, 2017
• First Posted (ACTUAL): September 19, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: oxygen; oxygen saturation; oxygen concentration
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Disease Attributes; Respiratory Insufficiency; Critical Illness
• Other Study ID Numbers: UCL/16/0571

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No