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

Brief Summary

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).

Primary Outcomes

Secondary Outcomes

• 30-day mortality(Day 30 after enrollment)
• Hospital length of stay(From date of admission to discharge from the hospital, up to 12 months after enrollment)
• 12-month mortality(12 months after enrollment)
• Major respiratory complications (pneumonia and acute respiratory distress syndrome) within 30 days(Day 30 after enrollment)
• ICU length of stay(From date of admission to discharge from the ICU, up to 12 months after enrollment)
• Time on mechanical ventilation(From initiation of mechanical ventilation to being ventilator-free within 30 days after enrollment)
• Days alive outside the ICU(ICU-free days within 30 days after enrollment)
• Re-intubations(Within 30 days after enrollment)
• Pneumonia post-discharge(From discharge to a maximum of 30 days after enrollment)
• Episode(s) of hypoxemia during intervention (saturation <90%)(During the 8 hours of the oxygen intervention arms)
• Surgical site infections(Within 30 days after enrollment)
• 5-level EQ-5D version (EQ-5D-5L) score(6 and 12 months post-trauma)
• The Glasgow Outcome Scale Extended (GOSE) score(6 and 12 months post-trauma)
• Levels of oxidative stress biomarkers, primarily malondialdehyde (MDA) at hour 24(Hour 0, hour 8, hour 24 and hour 48 after enrollment)
• Days alive without mechanical ventilation(Ventilator-free days within 30 days after enrollment)