FAQs

Answers to Frequently Asked Questions (FAQs) can be found here.

General

03/05/2021 to 31/07/2024

28/02/2025

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

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

The slides are available here

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)

Co-enrolement

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
  • VITDALIZE UK Trial
  • VACIRiSS
  • BLING III
  • ADAPT-SEPSIS
  • RECOVERY
  • MARCH
  • SOS
  • MOSAICC
  • PRONTO
  • MERIT
  • T4P
  • CoMiTED
  • ASEPTIC
  • SWiFT
  • EXTEND
  • iREHAB
  • SINFONIA
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:
REVISE, ROWTATE, ROSSINI2, ASPECT, SIGNET, AIRWAYS-3, EMERALD, EVIS, HAP-FAST, SHORTER, ERASER, CRASH-4

Eligibility

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

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

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

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

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

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

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

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

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

Some of the eligibility criteria refer to the treating clinician’s assessment, therefore these criteria must be assessed by the treating clinician

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

Two recently published trials (EXACT and BOX) set out to evaluate conservative oxygen therapy in patients post cardiac arrest.

The BOX trial reported the oxygenation-related data from a 2-by-2 factorial design that was intended to evaluate both oxygenation targets and blood pressure targets [1]. In this trial, comatose adults admitted to hospital following successful resuscitation post-cardiac arrest were enrolled and randomly allocated to a PaO2 target of 9 to 10 kPa or 13 to 14 kPa. The initial FIO2 was at 0.3 in the conservative oxygen therapy group and 0.6 in the liberal target group, then titrated to achieve the target oxygenation. The primary outcome measure was a composite of death from any cause or discharge from hospital with severe disability or coma, whichever occurred first within 90 days after randomisation. A total of 789 patients were enrolled into the trial. The primary outcome event occurred in 32.0% of the conservative oxygen therapy group and in 33.9% of the liberal oxygenation group (hazard ratio, 0.95; 95% confidence interval, 0.75 to 1.21; P = 0.69). The authors therefore concluded that the targeting of a conservative or liberal oxygenation strategy in comatose patients after resuscitation for cardiac arrest resulted in a similar incidence of death or severe disability or coma.

In the EXACT trial, unconscious adults achieving return of spontaneous cardiac output following out of hospital cardiac arrest of presumed cardiac cause were enrolled by paramedics at the scene of the cardiac arrest [2]. Patients were randomly allocated to receive oxygen targeted to an SpO2 of 90% to 94% (conservative oxygen therapy) or 98% to 100% (usual care). In the conservative oxygen therapy group, oxygen was initially reduced to 4 L/min via an oxygen reservoir bag, or an FIO2 of approximately 0.6 if the patient was receiving mechanical ventilation, and then titrated to maintain the target SpO2. Patients randomised to receive usual care were administered >10 L/min of oxygen via an oxygen reservoir bag or an FIO2 of 1.0 if mechanically ventilated then titrated to their SpO2 target. The intervention continued until the first arterial blood gas measurement in the ICU. The primary outcome was survival to hospital discharge. The study was planned to enrol 1416 patients, however, it was stopped early due to the COVID-19 pandemic. Of the 425 patients who were included in the primary analysis, 38.3% of patients in the conservative oxygen therapy group survived to hospital discharge compared with 47.9% in the usual care group (difference, −9.6% [95% confidence interval, −18.9% to −0.2%]; unadjusted odds ratio, 0.68 [95% CI, 0.46-1.00]; P= 0.05). From this, the authors concluded that commencing a conservative oxygen therapy in a pre-hospital setting until admission to ICU, does not improve survival to hospital discharge compared to usual oxygen therapy in adults achieving return of spontaneous circulation after out-of-hospital cardiac arrest.

The first of these two trials (EXACT) had similarities to UK-ROX in terms of the patients being recruited (patients post cardiac arrest can be enrolled into UK-ROX) and the intervention. One of the key differences was that the conservative oxygen therapy intervention in the EXACT trial was less conservative that UK-ROX (an SpO2 of 90% is approximately equivalent to a PaO2 of 7.5 to 8 kPa). In other words, in UK-ROX we are therefore evaluating the impact of a lower oxygenation target than the EXACT trial. It is reassuring that with a higher conservative oxygenation target, the EXACT trial demonstrated no signal of harm in terms of the primary outcome measure or any of the secondary outcome measures. The BOX trial’s intervention was largely delivered before patients arrived on ICU, so it is less straight forward to determine how relevant the findings were to the UK-ROX population. Whist the difference in the number of patients surviving to hospital discharge was relatively large (9.6 percentage points) this was not statistically significant and the trial was stopped early (due to COVID-19), creating challenges with interpreting the relevance of its findings. In summary, we do not think that the findings of either of these trials affects UK-ROX and that enrolment of patients post cardiac arrest should continue.

References

[1] Schmidt H, Kjaergaard J, Hassager C, Mølstrøm S, Grand J, Borregaard B, et al. Oxygen Targets in Comatose Survivors of Cardiac Arrest. N Engl J Med [Internet]. 2022 Aug 27; Available from: http://dx.doi.org/10.1056/NEJMoa2208686

[2] Bernard SA, Bray JE, Smith K, Stephenson M, Finn J, Grantham H, et al. Effect of Lower vs Higher Oxygen Saturation Targets on Survival to Hospital Discharge Among Patients Resuscitated After Out-of-Hospital Cardiac Arrest: The EXACT Randomized Clinical Trial. JAMA. 2022 Nov 8;328(18):1818–26.

Intervention

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.

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.

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.

The trial does not specify any time schedule for doing ABGs, this should be determined as per local practice.

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 SaO2https://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.

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.

Firstly, it is important to establish whether the patient is being considered for the donation after brainstem death (DBD) or donation after circulatory death (DCD) pathway:

  • Donation after brainstem death: for these patients, once death has been confirmed using neurological criteria (according to the Academy of the Medical Royal Colleges 2008 guidance) the UK-ROX intervention should cease.

Prior to the confirmation of death (completion of the two tests) we advise the following:

  1. While the nationally endorsed testing forms provide guidance that ‘attempts should be made to maintain relatively normal cardiovascular and respiratory physiological parameters in the preceding hours prior to testing’ the forms recognise, ‘this may not be possible and does not necessarily preclude testing.’ We recommend therefore that in the preceding hours prior to testing the UK-ROX intervention should continue.
  2. At the time of testing the PaO2 should be greater than 10 kPa and this target should be achieved if possible and may require an alteration to inspired oxygen.
  3. For the apnoea test pre-oxygenation with 100% oxygen will be required and this should not be omitted.
  4. If death is not confirmed during testing, our advice would be to continue the UK-ROX intervention until a decision has been made about the management plan for the patient.
  • Donation after circulatory death: this situation would be relevant when planned / controlled withdrawal of life-sustaining treatments is being considered for a patient in the UK-ROX trial. During consideration and assessment for DCD we would suggest the UK-ROX conservative oxygen therapy intervention is continued. Once consent for organ donation via a DCD pathway has occurred, we would suggest stopping the UK-ROX intervention.

Consent

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.

No.

No – the personal consultee can be a relative or close friend of the patient.

Yes, but the Nominated Consultee must not be in the Delegation Log or Training Log for the trial.

Data Collection

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.

Please use the below conversion table from the Case Mix Programme (CMP) Data Collection Manual V3.1:

Conversion table from the Case Mix Programme (CMP) Data Collection Manual