Clinical trial NCT05146700: Restrictive Vs. Liberal Oxygen in Trauma
Official title: Comparing Restrictive Vs. Liberal Oxygen Strategies for Trauma Patients: the TRAUMOX2 Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Trauma
Oxygen Toxicity
Wounds and Injuries
Keywords: Trauma
Oxygen
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: The Novo Nordic Foundation
First posted: 2021-12-07
Enrollment: 1508
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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%
Primary purpose: TREATMENT

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).

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).

Eligibility 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

Primary outcomes:
measure: The incidence of 30-day mortality and/or major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days (combined primary endpoint)
timeFrame: Day 30 after enrollment
Secondary outcomes:
measure: 30-day mortality
timeFrame: Day 30 after enrollment
measure: 12-month mortality
timeFrame: 12 months after enrollment
measure: Major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days
timeFrame: Day 30 after enrollment
measure: Hospital length of stay
timeFrame: From date of admission to discharge from the hospital, up to 12 months after enrollment
measure: ICU length of stay
timeFrame: From date of admission to discharge from the ICU, up to 12 months after enrollment
measure: Time on mechanical ventilation
timeFrame: From initiation of mechanical ventilation to being ventilator-free within 30 days after enrollment
measure: Days alive outside the ICU
timeFrame: ICU-free days within 30 days after enrollment
measure: Days alive without mechanical ventilation
timeFrame: Ventilator-free days within 30 days after enrollment
measure: Re-intubations
timeFrame: Within 30 days after enrollment
measure: Pneumonia post-discharge
timeFrame: From discharge to a maximum of 30 days after enrollment
measure: Episode(s) of hypoxemia during intervention (saturation <90%)
timeFrame: During the 8 hours of the oxygen intervention arms
measure: Surgical site infections
timeFrame: Within 30 days after enrollment
measure: 5-level EQ-5D version (EQ-5D-5L) score
timeFrame: 6 and 12 months post-trauma
measure: The Glasgow Outcome Scale Extended (GOSE) score
timeFrame: 6 and 12 months post-trauma
measure: Levels of oxidative stress biomarkers, primarily malondialdehyde (MDA) at hour 24
timeFrame: Hour 0, hour 8, hour 24 and hour 48 after enrollment
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Copenhagen University Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC, University Medical Center Rotterdam
city: Bern
country: Switzerland
facility: Inselspital University Hospital Bern
Study officials:
affiliation: Consultant
name: Jacob Steinmetz, MD, PhD
role: STUDY_DIRECTOR
affiliation: Research assistent
name: Tobias Arleth, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.