Frequently Asked Questions

Coenrolment

Co-enrolment is permitted with all observational studies, including those collecting samples.

We have co-enrolment agreements in place for the following trials:
REMAP-CAP, A2B, EFFORT, VITDALIZE UK Trial, VACIRiSS, BLING III, STRESS-L, ADAPT-SEPSIS, RECOVERY

We are happy for co-enrolment with the following trials, but we are not yet aware of the other trial's team decision on co-enrolment:
INHALE WP3, REVISE

General

Q: When are the recruitment start and end dates?
A: 03/05/2021 to 02/05/2023

Q: When is the overall study end/closing date?
A: 30/11/2023

Q: Can a nurse or allied health professional be PI?
A: Yes, we are happy for the PI to be an appropriately qualified doctor, nurse, or allied health professional. The PI would need to have GCP training in place. We would also suggest identifying a doctor as a Sub/Associate PI to ensure that there is also medical oversight.

Q: What training is required to randomise a patient?
A: 
Staff members solely involved in the screening and/or randomising of patients do not need to be on the Delegation Log or have GCP training. These staff members should be given trial-specific training in how to screen/randomise patients, and should be recorded on the separate Training Log.

Trial-specific training can include attending an SIV, watching the recording of an SIV, running through the SIV or shorter training slides and/or reviewing the relevant SOPs within the ISF. Further details on training are available here.

QCan we have the SIV slides?
A: The slides are available here.

Q: Who is responsible for sending out the follow-up questionnaires to patients?
A: We will send out the questionnaires from ICNARC to the ‘enhanced data collection’ patients. The only exception would be where the patient is still in your hospital at 90 days, in which case we would get in touch with your team to see if they are able to approach the patient in person (we don’t anticipate this will be very common though).

Eligibility

Q: How should we interpret the exclusion criteria “The treating clinician considers that one trial intervention arm is either indicated or contraindicated”?
A: We acknowledge that equipoise varies across sites – therefore, if a treating clinician feels that conservative oxygen therapy is contraindicated for a particular patient or patient group, they can be excluded using this criterion, at their discretion.

With regards to conservative oxygen therapy being indicated for a patient – we are referring to situations where the treating clinician has already decided that they will actively manage a patient’s SpO2 according to a target of 90 (±2)% (i.e. 88-92%), regardless of the outcome of the randomisation, for the patient’s entire stay on ICU (i.e. whilst intubated and extubated). There are no exclusions for specific patient groups (e.g. COPD or ARDS) under this criterion, however, it is important to ensure that, if a patient is randomised to the conservative group, that the treatment would be different to ‘usual’ oxygen therapy.

We would encourage that patients are assessed for randomisation on a case-by-case basis rather than excluding a whole patient groups, however, individual sites may choose to apply this criterion in a standardised way. Reasons for exclusion should be documented on the screening log.

Q: Our team have concerns about delivering the intervention in patients with traumatic brain injury, can we exclude these patients?
A: Our Protocol includes the following exclusion criteria: “The treating clinician considers that one trial intervention arm is either indicated or contraindicated”. Therefore, if the treating clinician(s) felt that this particular patient subgroup was not suitable for randomisation, then they can be excluded on this basis (and the reason documented on the Screening Log).

It is worth keeping in mind that there is very little trial evidence to guide oxygen therapy in brain injury and, if possible, we would encourage that patients are assessed for randomisation on a case-by-case basis rather than excluding a whole patient population. However, we anticipate that equipoise in certain subgroups may vary across sites and the above exclusion criteria is in place to cover this.

Q. A patient is currently eligible, but due to be extubated in the next few hours. Should we randomise?
A: If a decision has already been made to extubate shortly, we would advise not randomising as there would appear to be limited scope for the interventions (conservative or usual oxygen therapy) to have an impact. Please add a note on the Screening Log.

Q: A patient is due to be transferred to another hospital in the next few hours. Should we randomise?
A: If a decision has already been made to transfer the patient shortly, we would advise not randomising as there would appear to be limited scope for the interventions (conservative or usual oxygen therapy) to have an impact. Please add a note on the Screening Log.

Q: A patient was extubated in ICU a few days ago, but has now been re-intubated. Are they eligible?
A: No - Patients must be randomised within 12 hours of starting invasive mechanical ventilation in ICU. This must be the first time the patient received invasive mechanical ventilation in ICU during this hospital stay.

Q: Are elective surgical patients eligible? What if they develop a complication during surgery and come to ICU afterwards?
A: Elective surgical patients would not be considered ‘unplanned’ (as per the inclusion criteria), regardless of what happened in theatre. There was discussion amongst our team that often these types of patients would be ventilated for only a short amount of time once admitted to ICU.

Q: Are emergency surgical patients eligible?
A: Yes, these patients would be considered ‘unplanned’ (as per the inclusion criteria). The 12-hour window for randomisation would start when they arrive in the ICU on invasive mechanical ventilation.

Q: A patient previously received invasive mechanical ventilation during this hospital stay and has now been intubated again. Are they eligible?
A: Patients must be randomised within 12 hours of starting invasive mechanical ventilation in ICU. This must be the first time the patient received invasive mechanical ventilation in ICU during this hospital stay.

Q: If the patient has been intubated outside of ICU, when does the 12-hour window to randomise the patient start?
A: The 12-hour window starts when the patient receives invasive mechanical ventilation in the ICU for the first time. So in the situation where a patient is intubated in ED or emergency surgery, the clock only starts when they reach the ICU.

Q: Does a doctor need to confirm eligibility?
A: Some of the eligibility criteria refer to the treating clinician’s assessment, therefore these criteria must be assessed by the treating clinician.

Q: The post-resuscitation care section of the 2021 European Resuscitation Council and European Society of Intensive Care Medicine Guidelines state that patients who have sustained a cardiac arrest should have an SpO2 of 94-98% or PaO2 of 10-13 kPa. Can these patients still be enrolled into the UK-ROX trial?

A: The 2020 International Consensus on Cardiopulmonary Resuscitation Science published by the International Liaison Committee on Resuscitation (ILCOR) summarises all the supporting science and provides headline treatment recommendations [1]. The treatment recommendations relating to oxygen dose after return of spontaneous circulation set out in this document are based on a systematic review and meta-analysis conducted by the ILCOR Adult and Pediatric Advanced Life Support Task Forces [2]. The majority of studies identified by this systematic review did not reach statistical significance and were limited by high risk of bias. Furthermore, the meta-analyses of two randomised trials comparing low- with high-concentration oxygen therapy were inconclusive. The point estimates of individual studies generally favoured normoxaemia. ILCOR recommends avoiding hypoxaemia (strong recommendation, very low certainty evidence) and suggests avoiding hyperoxaemia (weak recommendation, low certainty evidence) following resuscitation from cardiac arrest.

The 2021 ERC/ESICM guidelines provide more detailed, practical advice on how to manage patients admitted to the ICU after a cardiac arrest [3] but there is very little evidence to inform clinical guidance in this patient cohort and the ERC/ESICM guidelines highlight that the role of blood oxygen values in the disease process is poorly understood. An individual-level patient data meta-analysis of randomised controlled trials of conservative or liberal oxygen therapy in adults after cardiac arrest concluded that conservative oxygen therapy was associated with a statistically significant reduction in mortality at last follow-up compared with liberal oxygen therapy, but the certainty of evidence was low or very low [4].

Some recent data from a post-hoc, sub-group analysis of 166 patients with suspected hypoxic-ischaemic encephalopathy from the ICU-ROX trial provides information on this patient cohort [5]. In this trial, the conservative oxygen therapy SpO2 target was 91-96% [ICU-ROX]. In this sub-group analysis, 43 of 78 patients (55.1%) assigned to conservative oxygen and 49 of 72 patients (68.1%) assigned to usual oxygen died or had an unfavourable neurological outcome at day 180 (odds ratio 0.58; 95% CI 0.3–1.12; P = 0.1 adjusted odds ratio 0.54; 95% CI 0.23–1.26; P = 0.15). A total of 37 of 86 patients (43%) assigned to conservative oxygen and 46 of 78 (59%) assigned to usual oxygen had died by day 180 (odds ratio 0.53; 95% CI 0.28–0.98; P = 0.04; adjusted odds ratio 0.56; 95% CI 0.25–1.23; P = 0.15). The authors of this study concluded that conservative oxygen therapy was not associated with a statistically significant reduction in death or unfavourable neurological outcomes at 180 days. Therefore, the potential for important benefit or harm from conservative oxygen therapy in patients with suspected hypoxic-ischaemic encephalopathy could not be excluded by these data.

Our conclusion from this is that taking into consideration the evidence currently available today, it is not clear what the correct oxygenation target should be for post-cardiac arrest patients, which is why we have chosen to include them in the UK-ROX trial. This patient group has also been included in the MEGA-ROX trial [https://www.anzics.com.au/current-active-endorsed-research/mega-rox/]. From the outset of the study, we have requested that patients with a suspected hypoxic-ischaemic encephalopathy are identified on the randomisation form, so that our data monitoring committee can regularly look at data from these patients. We also work closely with the MEGA-ROX team, so investigators from both teams can learn from one another as the trials progress. 

References

[1] Soar et al. Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2020;156:A80–A119 doi.org/10.1016/j.resuscitation.2020.09.012

[2] Holmberg et al. Resuscitation. 2020 doi:10.1016/j.resuscitation.2020.04.031

[3] Nolan et al. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines 2021: Post-resuscitation care. Resuscitation 2021;161:220–269 doi.org/10.1016/j.resuscitation.2021.02.012

[4] Young et al. Resuscitation 2020;157:15–22. doi.org/10.1016/j.resuscitation.2020.09.036

[5] Young et al. Intensive Care Medicine volume 2020. doi.org/10.1007/s00134-020-06196-y

Intervention

Q: Why are we using SpO2 as the target, rather than SaO2 or PaO2?
A: We are using SpO2 because it is continuously monitored, whereas SaO2 and PaO2 are intermittently monitored when arterial blood gases are taken. It would be very difficult to target an intermittent oxygenation measure.

Q: If a patient goes to theatre or radiology during their ICU stay, should we continue to deliver the intervention during this time?
A: We appreciate it may be difficult to deliver the intervention during such procedures – therefore the intervention only needs to be applied when the patient is physically in the ICU. Once the patient returns from the procedure, the intervention should resume.

Q: Can we still pre-oxygenate patients for procedures such as intubation?
A: Yes. If a patient requires high concentration oxygen to treat or prevent an acute life-threatening event (e.g. intubation, cardiopulmonary resuscitation) the intervention should be temporarily suspended during this time and the reason for the deviation recorded.

Q: If saturations are not accurate on probe, how often are we to do ABGs?
A: The trial does not specify any time schedule for doing ABGs, this should be determined as per local practice.

Q: What should we do if PaO2 is low, discordant with the SpO2?
A: There is purposely no lower PaO2 threshold, because no data exists to guide what this should be and it is impossible to target SpO2 and PaO2 simultaneously.

PaO2 describes the amount of oxygen dissolved in the blood and only contributes <2% of overall oxygen carriage. SpO2 (or SaO2) is what determines oxygen delivery to tissues and is therefore the major contributor to overall arterial oxygen content (CaO2). As such, PaO2 is not a more accurate measure of oxygenation than SaO2 or SpO2, because they are measuring different things. Very roughly, an SpO2 of 90% will give a PaO2 of around 8.0 kPa according to the oxygen-haemoglobin dissociation curve (OHDC). The problem with this is that the data used to make the classic version of this curves are extremely old and more up to date data show the PaO2 to be nearer 7.5 kPa for an SpO2 of 90%. Also, some patients will experience shifts in the OHDC, which is why we have allowed the 2% leeway around 90%, in case there was concern over the PaO2.

Our advice is to be sure that SpO2 and SaO2 are aligned (due to the report that pigmented skin can lead to an over-estimation of SaO2 - https://www.nejm.org/doi/full/10.1056/NEJMc2029240). If there is discrepancy between SaO2 and SpO2 then SaO2 should be targeted, as it is the more accurate if your blood gas machine is a co-oximeter. If clinicians feel that a low PaO2 is inappropriate/ unsafe/ unwanted whilst a patient is within the SaO2 or SpO2 target range, our advice would be to aim for the upper end of the range.

Q: What should we do if SaO2 is very low, discordant with the SpO2?
A: SpO2 should be compared to the SaO2 measurements from arterial blood gas measurements (if being taken) and if there is a significant discrepancy between the two, the SaO2 should be used in preference. Pigmented skin has been highlighted as causing such a discrepancy. 

Consent

Q: Can the consultant on call fulfil the Nominated Consultee role?
A: The on-call consultant can take on the role of nominated consultee for patients, providing that they are not listed on the Delegation Log or Training Log.

Q: Does the witness for the telephone calls need to be GCP trained or on the Delegation Log?
A: No.

Q: Does the Personal Consultee need to be the next of kin?
A: No – the personal consultee can be a relative or close friend of the patient.

Q: 
Can the Nominated Consultee be involved in the patient's care?
A: Yes, but the Nominated Consultee must not be in the Delegation Log or Training Log for the trial.

Data Collection

Q: If a patient is discharged from ICU and then readmitted, should we recommence data collection?
A: No. The treatment data collection ends when the patient is first discharged from the ICU – so it is not necessary to recommence data collection if the patient is readmitted. Once the patient is discharged from hospital, the follow-up page should then be completed (for enhanced data collection patients). If the patient is readmitted to ICU within the 90 days, the intervention should be recommenced.

Q: How should we convert l/min to FiO2, for recording in the CRF?
A: Please use the below conversion table from the Case Mix Programme (CMP) Data Collection Manual V3.1:

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