Restrictive vs. Liberal Oxygen in Trauma

Study Overview
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Brief Summary
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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
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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).

Official Title
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Comparing Restrictive vs. Liberal Oxygen Strategies for Trauma Patients: The TRAUMOX2 Trial

Conditions
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Trauma, Oxygen Toxicity, Wounds and Injuries

Intervention / Treatment
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* Drug: Restrictive oxygen
* Drug: Liberal oxygen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Restrictive oxygen<br>- 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<br>* Lowest oxygen delivery possible (≥21%) ensuring an SpO2 target = 94%<br>|
| Active Comparator: Liberal oxygen<br>- 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<br>* 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%<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Day 30 after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-day mortality | Assessed in the patient's medical record/register | Day 30 after enrollment | 
| 12-month mortality | Assessed in the patient's medical record/register | 12 months after enrollment | 
| Major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days | Data from the combined primary endpoint assessment | Day 30 after enrollment | 
| Hospital length of stay | Number of days | From date of admission to discharge from the hospital, up to 12 months after enrollment | 
| ICU length of stay | Number of days | From date of admission to discharge from the ICU, up to 12 months after enrollment | 
| Time on mechanical ventilation | Number of hours; only mechanical ventilation in the ICU should be considered | From initiation of mechanical ventilation to being ventilator-free within 30 days after enrollment | 
| Days alive outside the ICU | Number of days | ICU-free days within 30 days after enrollment | 
| Days alive without mechanical ventilation | Number of days; only mechanical ventilation in the ICU should be considered | Ventilator-free days within 30 days after enrollment | 
| Re-intubations | Number of re-intubations; only re-intubations in the ICU should be considered | Within 30 days after enrollment | 
| Pneumonia post-discharge | Number of trial participants; evaluated through medicines prescribed after hospital discharge in countries where this information is available | From discharge to a maximum of 30 days after enrollment | 
| 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 | During the 8 hours of the oxygen intervention arms | 
| Surgical site infections | Defined as per the Centers for Disease Control and Prevention (CDC) criteria for a surgical site infection event | Within 30 days after enrollment | 
| 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) | 6 and 12 months post-trauma | 
| 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 | 6 and 12 months post-trauma | 
| 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 | Hour 0, hour 8, hour 24 and hour 48 after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trauma, Oxygen