Restrictive vs. Liberal Oxygen in Trauma (TRAUMOX2)

• ClinicalTrials.gov Identifier: NCT05146700
• Recruitment Status: Recruiting
• First Posted: December 7, 2021
• Last Update Posted: December 7, 2022
• Sponsor: Rigshospitalet, Denmark
• Collaborator: The Novo Nordic Foundation
• Information provided by (Responsible Party): Jacob Steinmetz, Rigshospitalet, Denmark

Study Description

Brief 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. 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).

Condition or disease	Intervention/treatment	Phase
Trauma; Oxygen Toxicity; Wounds and Injuries	Drug: Restrictive oxygen; Drug: Liberal oxygen	Phase 4

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1420 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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 (Outcomes Assessor)

Masking Description

Open-label, primary outcome assessor- and analyst-blinded, randomized, controlled clinical trial with regards to treatment: treating staff will be aware of the trial participants' randomization group.

While including patients for the study, the research team and treating staff will be aware of the trial participants' oxygen allocation strategy. However, at least two allocation blinded primary outcome assessors (specialists in anesthesiology, intensive care, emergency medicine or similar) will be appointed at each center to assess in-hospital major lung complications (pneumonia and acute respiratory distress syndrome). Blinding will be ensured by concealing all information indicative of the allocation prior to assessment. The statistician and manuscript writers will be blinded towards the allocation of treatment once the trial ends when data is being analysed and the manuscript is drafted.

• Primary Purpose: Treatment
• Official Title: Comparing Restrictive vs. Liberal Oxygen Strategies for Trauma Patients: The TRAUMOX2 Trial
• Actual Study Start Date: December 10, 2021
• Estimated Primary Completion Date: June 1, 2023
• Estimated Study Completion Date: June 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Restrictive oxygen; - 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	Drug: Restrictive oxygen; Lowest oxygen delivery possible (≥21%) ensuring an SpO2 target = 94%
Active Comparator: Liberal oxygen; - 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%	Drug: Liberal oxygen; 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%

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   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

Secondary Outcome Measures :

1. 30-day mortality [ Time Frame: Day 30 after enrollment ]
   Assessed in the patient's medical record/register
2. 12-month mortality [ Time Frame: 12 months after enrollment ]
   Assessed in the patient's medical record/register
3. Major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days [ Time Frame: Day 30 after enrollment ]
   Data from the combined primary endpoint assessment
4. Hospital length of stay [ Time Frame: From date of admission to discharge from the hospital, up to 12 months after enrollment ]
   Number of days
5. ICU length of stay [ Time Frame: From date of admission to discharge from the ICU, up to 12 months after enrollment ]
   Number of days
6. Time on mechanical ventilation [ Time Frame: From initiation of mechanical ventilation to being ventilator-free within 30 days after enrollment ]
   Number of hours; only mechanical ventilation in the ICU should be considered
7. Days alive outside the ICU [ Time Frame: ICU-free days within 30 days after enrollment ]
   Number of days
8. Days alive without mechanical ventilation [ Time Frame: Ventilator-free days within 30 days after enrollment ]
   Number of days; only mechanical ventilation in the ICU should be considered
9. Re-intubations [ Time Frame: Within 30 days after enrollment ]
   Number of re-intubations; only re-intubations in the ICU should be considered
10. Pneumonia post-discharge [ Time Frame: From discharge to a maximum of 30 days after enrollment ]
    Number of trial participants; evaluated through medicines prescribed after hospital discharge in countries where this information is available
11. Episode(s) of hypoxemia during intervention (saturation <90%) [ Time Frame: During the 8 hours of the oxygen intervention arms ]
    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
12. Surgical site infections [ Time Frame: Within 30 days after enrollment ]
    Defined as per the Centers for Disease Control and Prevention (CDC) criteria for a surgical site infection event
13. 5-level EQ-5D version (EQ-5D-5L) score [ Time Frame: 6 and 12 months post-trauma ]

    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)

14. The Glasgow Outcome Scale Extended (GOSE) score [ Time Frame: 6 and 12 months post-trauma ]

    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

15. Levels of oxidative stress biomarkers, primarily malondialdehyde (MDA) at hour 24 [ Time Frame: Hour 0, hour 8, hour 24 and hour 48 after enrollment ]
    The unit of the oxidative stress biomarker depends on the chosen analysis of the specific biomarker

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Contacts and Locations

Contacts

Contact: Jacob Steinmetz, MD, PhD; +4535458434; jacob.steinmetz@regionh.dk

Contact: Tobias Arleth, MD; +4535459502; tobias.arleth@regionh.dk

Locations

Denmark

Aarhus University Hospital; Recruiting

Aarhus, Denmark, 8200

Contact: Mikkel Andersen, MD, PhD +4520226661 mikkel.andersen@ph.rm.dk

Contact: Christian Fenger-Eriksen, MD, PhD +4578466912 chfen@dadlnet.dk

Principal Investigator: Mikkel Andersen, MD, PhD

Sub-Investigator: Christian Fenger-Eriksen, MD, PhD

Rigshospitalet, Copenhagen University Hospital; Recruiting

Copenhagen, Denmark, 2100

Contact: Jacob Steinmetz, MD, PhD +4535458434 jacob.steinmetz@regionh.dk

Contact: Tobias Arleth, MD +4535459502 tobias.arleth@regionh.dk

Principal Investigator: Tobias Arleth, MD

Odense University Hospital; Recruiting

Odense, Denmark, 5000

Contact: Søren Mikkelsen, Professor, MD, PhD +4530252225 soeren.mikkelsen@rsyd.dk

Contact: Stine Thorhauge Zwisler, MD, PhD +4565413914 stine.zwisler@rsyd.dk

Principal Investigator: Søren Mikkelsen, Professor, MD, PhD

Sub-Investigator: Stine Thorhauge Zwisler, MD, PhD

Netherlands

Erasmus MC, University Medical Center Rotterdam; Recruiting

Rotterdam, Netherlands, 3000

Contact: Dr. Mark G. Van Vledder, MD, PhD BIG-nummer 79911655801 m.vanvledder@erasmusmc.nl

Contact: Dr. Esther M.M. Van Lieshout, PhD, MSc e.vanlieshout@erasmusmc.nl

Principal Investigator: Dr. Mark G. Van Vledder, MD, PhD

Sub-Investigator: Dr. Dennis Den Hartog, MD, PhD

Sub-Investigator: Dr. Esther M.M. Van Lieshout, PhD, MSc

Switzerland

Inselspital University Hospital Bern; Recruiting

Bern, Switzerland, 3010

Contact: Wolf Hautz, MD, MME +41 31 632 5701 wolf.hautz@insel.ch

Principal Investigator: Wolf Hautz, MD, MME

Sub-Investigator: Dominik Jakob, MD

Sub-Investigator: Matthias Hänggi, Professor, MD

Sub-Investigator: Manuela Iten, MD

Sponsors and Collaborators

Rigshospitalet, Denmark

The Novo Nordic Foundation

Investigators

• Study Director: Jacob Steinmetz, MD, PhD; Consultant
• Principal Investigator: Tobias Arleth, MD; Research assistent

More Information

Additional Information:

The official study website of TRAUMOX2 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Jacob Steinmetz, MD, PhD, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT05146700
• Other Study ID Numbers: 6011; 2021-000556-19 ( EudraCT Number ); NNF20OC0063985 ( Other Grant/Funding Number: Novo Nordisk Fonden )
• First Posted: December 7, 2021
• Last Update Posted: December 7, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jacob Steinmetz, Rigshospitalet, Denmark:

Trauma; Oxygen

Additional relevant MeSH terms:

Wounds and Injuries