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TraumaPhase 4TRAUMOX2NCT05146700

Restrictive Vs. Liberal Oxygen in Trauma

A Phase 4 study testing Restrictive oxygen and Liberal oxygen in people with Trauma and Oxygen Toxicity, run by Copenhagen University Hospital, Rigshospitalet at 5 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Victims of trauma are often healthy individuals prior to the incident, but acquire numerous complications including sepsis and pulmonary complications and diminished quality of life after trauma. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Trauma, Oxygen Toxicity, Wounds and Injuries
What is being tested?
Restrictive oxygen and Liberal oxygen
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,508 participants
Where
5 sitesin 3 countries
Study dates
10 Dec 2021to 12 Oct 2024
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients aged ≥18 years, including fertile women
  • Blunt or penetrating trauma mechanism
  • Direct transfer from the scene of accident to one of the participating trauma centers
  • Trauma team activation
  • The enrolling physician must initially expect a hospital length of stay for 24 hours or longer

Who cannot join

  • Patients in cardiac arrest before or on admission
  • Patients with a suspicion of carbon monoxide intoxication
  • Patients with no/minor injuries after secondary survey will be excluded if they are expected to be discharged <24 hours

Trial locations and contacts

5 sites in 3 countries.

5 sites in 3 countries

Denmark3 sites

  • Aarhus University Hospital

    Aarhus, 8200

  • Rigshospitalet, Copenhagen University Hospital

    Copenhagen, 2100

  • Odense University Hospital

    Odense, 5000

Other trials in Denmark

Netherlands1 site

  • Erasmus MC, University Medical Center Rotterdam

    Rotterdam, Rotterdam, 3000

Other trials in Netherlands

Switzerland1 site

  • Inselspital University Hospital Bern

    Bern, 3010

Other trials in Switzerland

About this study

Official title: Comparing Restrictive Vs. Liberal Oxygen Strategies for Trauma Patients: the TRAUMOX2 Trial

Victims of trauma are often healthy individuals prior to the incident, but acquire numerous complications including sepsis and pulmonary complications and diminished quality of life after trauma. According to Advanced Trauma Life Support guidelines, all severely injured trauma patients should receive supplemental oxygen.

The objective of TRAUMOX2 is to compare the effect of a restrictive versus liberal oxygen strategy the first eight hours following trauma on the incidence of 30-day mortality and/or major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days (combined primary endpoint).

Read the detailed description

In trauma resuscitation, supplemental oxygen is often administered both to treat and prevent hypoxemia as recommended both by the Advanced Trauma Life Support (ATLS) manual and the Pre-hospital Trauma Life Support (PHTLS) manual. Oxygen is administered in many other situations too, sometimes in a non-consistent manner and very often without even being prescribed. In a recent systematic review, our group found the evidence both for and against the use of supplemental oxygen in the trauma population to be extremely sparse. However, a recent systematic review and meta-analysis comparing liberal versus restrictive oxygen strategy for a broad mix of acutely ill medical and surgical patients found an association between liberal oxygen administration and increased mortality. Of note, only one small study on trauma patients (patients with traumatic brain injury), which did not report mortality data, was included. Conversely, this study showed that degree of disability was significantly reduced at six months in the group receiving liberal compared to restrictive oxygen.

In mechanically ventilated patients hyperoxemia is commonly observed (16-50%), and hyperoxemia is a common finding in trauma patients in general. In addition to mortality, hyperoxemia has been associated with major pulmonary complications in the Intensive Care Unit (ICU) as well as in surgical patients. For example, a recent retrospective study found hyperoxemia to be an independent risk factor for ventilator associated pneumonia (VAP). Nevertheless, a highly debated recommendation from the World Health Organisation strongly recommends that adult patients undergoing general anesthesia for surgical procedures receive a fraction of inspired oxygen (FiO2) of 80% intraoperatively as well as in the immediate postoperative period for two to six hours to reduce the risk of surgical site infection. Furthermore, a study on 152,000 mechanically ventilated patients found no association between hyperoxia and mortality during the first 24 hours in the ICU, and another study on 14,000 mixed ICU patients found that a partial arterial oxygen pressure (PaO2) of approximately 18 kPa resulted in the lowest mortality. Finally, a recent study randomized 2928 ICU patients to either low or high oxygenation (defined as 8 vs 12 kPa) for a maximum of 90 days and found no difference in mortality. Therefore, whether the trauma population could benefit from a more restrictive supplemental oxygen approach than recommended by current international guidelines presents a large and important knowledge gap.

In a recent pilot randomized clinical trial (TRAUMOX1, ClinicalTrials.gov Registration number: NCT03491644), we compared a restrictive and a liberal oxygen strategy for 24 hours after trauma (N = 41) and found maintenance of normoxemia following trauma using a restrictive oxygen strategy to be feasible. TRAUMOX1 served as the basis for this larger trial. We experienced 24 hours to be slightly excessive to represent only the acute phase post trauma for which reason we have shortened the time-period to eight hours in TRAUMOX2. Furthermore, we found that several physicians had important concerns with the high dosage of oxygen in the liberal arm for which reason the concentration will be reduced. Finally, we did not randomize trauma patients in the pre-hospital phase, but instead on arrival at the trauma bay (median [interquartile range (IQR)] time to randomization: 7 [4-10] minutes, median [IQR] time from trauma to trauma bay arrival: 51 [29.0-67.5] minutes). To limit this inconsistent exposure to oxygen in the pre-hospital phase prior to inclusion we will initiate the intervention in the pre-hospital phase where possible in TRAUMOX2.

The objective of TRAUMOX2 is to compare the effect of a restrictive versus liberal oxygen strategy the first eight hours following trauma on the incidence of 30-day mortality and/or major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days (combined primary endpoint).

We hypothesize that a restrictive compared to a liberal oxygen strategy for the initial eight hours after trauma will result in a lower rate of 30-day mortality and/or major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days (combined primary endpoint).

Being tested
Restrictive oxygen, Liberal oxygen
Keywords
Trauma, Oxygen
Medical subject headings
Wounds and Injuries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Restrictive oxygenDrug

    Lowest oxygen delivery possible (≥21%) ensuring an SpO2 target = 94%

  • Liberal oxygenDrug

    15 L O2/min flow for non-intubated trial participants or FiO2 = 1.0 for intubated trial participants in the initial phase; later in the operating room, intensive care unit, post-anesthesia care unit and ward, the flow/FiO2 can be reduced to ≥12 L O2/min or FiO2 ≥0.6 if the arterial oxygen saturation is ≥98%

Study groups in NCT05146700
Study groupRoleWhat they receive
Restrictive oxygenExperimental- Lowest oxygen delivery possible (≥21%) ensuring an SpO2 target = 94% either using no supplemental oxygen, a nasal cannula, a non-rebreather mask or manual/mechanical ventilation (intubated trial participants) and - Only trial participants receiving an FiO2 = 0.21 can saturate >94% Pre-oxygenation as usual prior to intubation is permitted
Receives: Drug: Restrictive oxygen
Liberal oxygenActive comparator- 15 L O2/min flow for non-intubated trial participants in the pre-hospital phase, the trauma bay and during intrahospital transportation. In the operating room, intensive care unit, post-anesthesia care unit and ward the flow can be reduced to ≥12 L O2/min if the arterial oxygen saturation is ≥98% or - FiO2 = 1.0 for intubated trial participants in the pre-hospital phase, the trauma bay and during intrahospital transportation. In the operating room, intensive care unit, post-anesthesia care unit and ward the FiO2 can be reduced to ≥0.6 if the arterial oxygen saturation is ≥98%
Receives: Drug: Liberal oxygen

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The incidence of 30-day mortality and/or major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days (combined primary endpoint)

    The assessment of the major respiratory complications will be performed by at least two allocation blinded primary outcome assessors (specialists in anesthesiology, intensive care, emergency medicine or similar); blinding will be ensured by concealing all information indicative of the allocation prior to assessment

    Measured: Day 30 after enrollment

Secondary outcomes (15)

  1. 30-day mortality

    Assessed in the patient's medical record/register

    Measured: Day 30 after enrollment

  2. 12-month mortality

    Assessed in the patient's medical record/register

    Measured: 12 months after enrollment

  3. Major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days

    Data from the combined primary endpoint assessment

    Measured: Day 30 after enrollment

  4. Hospital length of stay

    Number of days

    Measured: From date of admission to discharge from the hospital, up to 12 months after enrollment

  5. ICU length of stay

    Number of days

    Measured: From date of admission to discharge from the ICU, up to 12 months after enrollment

  6. Time on mechanical ventilation

    Number of hours; only mechanical ventilation in the ICU should be considered

    Measured: From initiation of mechanical ventilation to being ventilator-free within 30 days after enrollment

  7. Days alive outside the ICU

    Number of days

    Measured: ICU-free days within 30 days after enrollment

  8. Days alive without mechanical ventilation

    Number of days; only mechanical ventilation in the ICU should be considered

    Measured: Ventilator-free days within 30 days after enrollment

  9. Re-intubations

    Number of re-intubations; only re-intubations in the ICU should be considered

    Measured: Within 30 days after enrollment

  10. Pneumonia post-discharge

    Number of trial participants; evaluated through medicines prescribed after hospital discharge in countries where this information is available

    Measured: From discharge to a maximum of 30 days after enrollment

  11. Episode(s) of hypoxemia during intervention (saturation <90%)

    Defined as number of times the valid oxygen saturation is below 90%; if it is below 90%, above 90% and below 90% again, then it should be registered as 2 episodes

    Measured: During the 8 hours of the oxygen intervention arms

  12. Surgical site infections

    Defined as per the Centers for Disease Control and Prevention (CDC) criteria for a surgical site infection event

    Measured: Within 30 days after enrollment

  13. 5-level EQ-5D version (EQ-5D-5L) score

    Conducted through a telephone interview where the patient is asked to indicate his/her health state

    The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS)

    The EQ-5D descriptive system consists of a scale (minimum score = 5 and maximum score = 25) where the lowest score (5) indicates no problems whereas the highest score (25) indicates extreme problems

    The EQ VAS (visual analogue scale) records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled "The worst health you can imagine" (minimum score = 0) and "The best health you can imagine' (maximum score = 100)

    Measured: 6 and 12 months post-trauma

  14. The Glasgow Outcome Scale Extended (GOSE) score

    Conducted through a telephone interview where the patient/patient's next-of-kin/caretaker is interviewed through a structured questionnaire to assess the functional recovery after trauma

    The GOSE consists of a scale (minimum value = 1 and maximum value = 8); each patient given a score based on the interview:

    1 = Death, 2 = Vegetative state, 3 = Lower severe disability, 4 = Upper severe disability, 5 = Lower moderate disability, 6 = Upper moderate disability, 7 = Lower good recovery, 8 = Upper good recovery

    Measured: 6 and 12 months post-trauma

  15. Levels of oxidative stress biomarkers, primarily malondialdehyde (MDA) at hour 24

    The unit of the oxidative stress biomarker depends on the chosen analysis of the specific biomarker

    Measured: Hour 0, hour 8, hour 24 and hour 48 after enrollment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Dec 2021
  2. Study start10 Dec 2021
  3. Primary completion12 Oct 2023
  4. Study completion12 Oct 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Trial participants are randomized pre-hospital or in the trauma bay to a restrictive or liberal oxygen treatment for eight hours. Experimental (restrictive oxygen): The restrictive group will receive the lowest dosage of oxygen (≥21%) ensuring an SpO2 target = 94% Active comparator (liberal oxygen): The liberal group will receive a flow of 15 L O2/min for non-intubated trial participants or an FiO2 = 1.0 for intubated trial participants in the pre-hospital phase, the trauma bay and during intrahospital transportation; later in the operating room (OR), intensive care unit (ICU), post-anesthesia care unit (PACU) and ward, the flow/FiO2 can be reduced to ≥12 L O2/min or FiO2 ≥0.6 if the arterial oxygen saturation (SpO2) is ≥98%
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
1,508 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05146700
Sponsor's protocol ID
6011
Other IDs
2021-000556-19, NNF20OC0063985
Acronym
TRAUMOX2
Status last verified
Oct 2024
First submitted
30 Nov 2021
Last updated
22 Oct 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes

Publications

  • Arleth T, Baekgaard J, Siersma V, Creutzburg A, Dinesen F, Rosenkrantz O, Heiberg J, Isbye D, Mikkelsen S, Hansen PM, Zwisler ST, Darling S, Petersen LB, Morkeberg MCR, Andersen M, Fenger-Eriksen C, Bach PT, Van Vledder MG, Van Lieshout EMM, Ottenhof NA, Maissan IM, Den Hartog D, Hautz WE, Jakob DA, Iten M, Haenggi M, Albrecht R, Hinkelbein J, Klimek M, Rasmussen LS, Steinmetz J; TRAUMOX2 Trial Group. Early Restrictive vs Liberal Oxygen for Trauma Patients: The TRAUMOX2 Randomized Clinical Trial. JAMA. 2025 Feb 11;333(6):479-489. doi: 10.1001/jama.2024.25786.

    PubMed 39657224

  • Arleth T, Baekgaard J, Siersma V, Klimek M, Hinkelbein J, Rasmussen LS, Steinmetz J; TRAUMOX2 Study Group. Comparing restrictive versus liberal oxygen strategies for trauma patients: The TRAUMOX2 trial-Statistical analysis plan. Acta Anaesthesiol Scand. 2023 Jul;67(6):829-838. doi: 10.1111/aas.14230. Epub 2023 Mar 28.

    PubMed 36906804

  • Baekgaard J, Arleth T, Siersma V, Hinkelbein J, Yucetepe S, Klimek M, van Vledder MG, Van Lieshout EMM, Mikkelsen S, Zwisler ST, Andersen M, Fenger-Eriksen C, Isbye DL, Rasmussen LS, Steinmetz J. Comparing restrictive versus liberal oxygen strategies for trauma patients - the TRAUMOX2 trial: protocol for a randomised clinical trial. BMJ Open. 2022 Nov 7;12(11):e064047. doi: 10.1136/bmjopen-2022-064047.

    PubMed 36344005

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Restrictive oxygen and Liberal oxygen in people with Trauma and Oxygen Toxicity, run by Copenhagen University Hospital, Rigshospitalet at 5 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Denmark, Netherlands, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The incidence of 30-day mortality and/or major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days (combined primary endpoint) (time frame: Day 30 after enrollment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05146700, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2024.

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