Restrictive vs. Liberal Oxygen in Trauma (TRAUMOX2)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Wounds and Injuries; Trauma; Oxygen Toxicity
• Intervention / Treatment: Drug: Restrictive oxygen; Drug: Liberal oxygen

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 Type: Interventional
• Enrollment (Estimated): 1420
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jacob Steinmetz, MD, PhD; Phone Number: +4535458434; Email: jacob.steinmetz@regionh.dk
• Study Contact Backup: Name: Tobias Arleth, MD; Phone Number: +4535459502; Email: tobias.arleth@regionh.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet, Copenhagen University Hospital
  • Odense, Denmark, 5000
    • Odense University Hospital
• Netherlands
  • Rotterdam, Netherlands, 3000
    • Erasmus MC, University Medical Center Rotterdam
• Switzerland
  • Bern, Switzerland, 3010
    • InselSpital University Hospital Bern

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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%

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: The Novo Nordic Foundation
• Investigators: Study Director: Jacob Steinmetz, MD, PhD, Consultant; Principal Investigator: Tobias Arleth, MD, Research assistent

Publications and helpful links

General Publications

• 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.

Helpful Links

• The official study website of TRAUMOX2

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2021
• Primary Completion (Actual): October 12, 2023
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: November 30, 2021
• First Submitted That Met QC Criteria: December 4, 2021
• First Posted (Actual): December 7, 2021

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 13, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Trauma; Oxygen
• Additional Relevant MeSH Terms: Wounds and Injuries
• Other Study ID Numbers: 6011; 2021-000556-19 (EudraCT Number); NNF20OC0063985 (Other Grant/Funding Number: Novo Nordisk Fonden)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No