Intermediate Normal Versus High Normal Oxygen Levels in the Emergency Department for Severe Traumatic Brain Injury

Study Overview
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Brief Summary
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Despite almost universal usage of supplemental oxygen therapy in patients presenting in the emergency department with traumatic brain injury (TBI), optimal oxygen levels are unclear. The investigators propose a pilot multi-center randomized controlled trial to test the hypothesis that maintaining intermediate normal as opposed to high normal oxygen levels in patients presenting in the emergency department with TBI is feasible, and to obtain preliminary data on the efficacy of the two approaches to oxygen therapy. The aim is that the investigators produce pilot data, which could inform the design of potential subsequent larger clinical trials.

Detailed Description
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Despite the worldwide burden of traumatic brain injury (TBI), medical research on the field as opposed to other health problems is underrepresented. Consequently, there are few data to support commonly used interventions for the management of TBI, especially in the setting of the emergency department. For example, despite almost universal usage of supplemental oxygen therapy, the effects of different oxygenation levels under normobaric conditions on outcomes of patients presenting in the emergency department with TBI are unknown. On the one hand, liberal oxygenation may provide a margin of safety against hypoxemia and may be needed to meet the high oxygen demands of an acutely altered brain physiology. On the other hand, there are increasing concerns that excessive oxygen supplementation may have harmful effects, such as central nervous system toxicity, cerebral vasoconstriction, impaired immunity leading to predisposition to infections (including pneumonia) and acute lung injury/acute respiratory distress syndrome. Such effects could be avoided by intermediate normal oxygen levels. Taken together, the relative merits and risks of the abovementioned two approaches to oxygen therapy (namely, intermediate normal versus high normal oxygen levels) of patients with TBI in terms of important clinical outcomes (namely, development of nosocomial pneumonia, acute respiratory distress syndrome, disability and mortality) remain undefined. This suggests the need for randomized controlled trials. However, randomized controlled trials focusing on patient-centered outcomes should be preceded by pilot randomized controlled trials, which demonstrate a separation in treatment and protocol compliance (feasibility) associated with the studied interventions. Therefore, the investigators propose a pilot multi-center randomized controlled trial to test the hypothesis that maintaining intermediate normal as opposed to high normal oxygen levels in patients presenting in the emergency department with TBI is feasible, and to obtain preliminary data on the efficacy of the two approaches to oxygen therapy.

Official Title
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Impact of Intermediate Normal Compared to High Normal Oxygen Levels on Outcomes of Patients Presenting in the Emergency Department With Severe Traumatic Brain Injury (INACHOS): a Pilot Randomized Controlled Trial

Conditions
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Traumatic Brain Injury, Acute Respiratory Failure, Acute Respiratory Distress Syndrome, Acute Brain Injury

Intervention / Treatment
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* Other: Oxygen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient ≥18 years Glasgow Coma Scale ≤ 8 Non-penetrating traumatic brain injury Intubated patient Exclusion Criteria: Age <18 years Lack of intention to admit to the intensive care unit Moribund patient expected to die within 24 hours Expected need for mechanical ventilation < 24 hours Time interval from intubation to group allocation more than 60 minutes Penetrating traumatic brain injury Pregnancy Lack of equipoise of the treating clinician Lack of informed consent

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: Enrolled patients will be randomly allocated using opaque sealed envelopes to either intermediate normal oxygen or high normal oxygen group. The asymptomatic maximal procedure, with an allocation ratio of 1:1 and a maximum tolerated imbalance of 2 will be used to randomize subjects.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intermediate normal oxygen<br>For the intermediate normal oxygen group, an oxygen saturation by pulse oximetry (SpO2) of 95-97% will be recommended in the light of the Improving Oxygen Therapy in Acute-illness (IOTA) meta-analysis. The acceptable lower limit of PaO2 will be set to 80 mmHg according to a recent consensus of experts endorsed by the European Society of Intensive Care Medicine. The lower-limit and higher-limit monitor alarm for SpO2 will be set at 94% and 98%, respectively. In case that the emergency department of a study site uses ventilators, which allow for only two options of FiO2 titration (namely, air mix and FiO2 of 1.0), then the intermediate normal oxygen group should receive air mix. | Other: Oxygen<br>* Oxygen to achieve assigned SpO2 (or FiO2) targets will be administered to study subjects. The treating clinician can alter oxygenation targets at any time if deemed necessary. The oxygenation goal will be based on SpO2 rather than arterial oxygen saturation (SaO2) or arterial pressure oxygen (PaO2) from arterial blood gases. However, PaO2 can be used instead in situations where the treating clinician considers that peripheral perfusion is poor or SpO2 readings are unreliable. Assigned SpO2 targets will apply to the study subjects for a total duration of 6 hours from intubation or until death or until transfer to the operating theater (whatever comes first).<br>|
| Active Comparator: High normal oxygen<br>For the high normal oxygen group, an oxygen saturation by pulse oximetry (SpO2) of 99-100% will be recommended. The lower-limit monitor alarm for SpO2 will be set at 98%. No upper alarm limit for SpO2 will be set. In case that the emergency department of a study site uses ventilators, which allow for only two options of FiO2 titration (namely, air mix and FiO2 of 1.0), then the high normal oxygen group should receive FiO2 of 1.0. | Other: Oxygen<br>* Oxygen to achieve assigned SpO2 (or FiO2) targets will be administered to study subjects. The treating clinician can alter oxygenation targets at any time if deemed necessary. The oxygenation goal will be based on SpO2 rather than arterial oxygen saturation (SaO2) or arterial pressure oxygen (PaO2) from arterial blood gases. However, PaO2 can be used instead in situations where the treating clinician considers that peripheral perfusion is poor or SpO2 readings are unreliable. Assigned SpO2 targets will apply to the study subjects for a total duration of 6 hours from intubation or until death or until transfer to the operating theater (whatever comes first).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean area-under-curve (AUC) for SpO2 | SpO2 will be recorded each hour for a total duration of 6 hours from intubation. Subsequently, mean area-under-curve (AUC) will be calculated for each group. This will demonstrate the feasibility of the study. | Measurements will be obtained each hour for a total duration of 6 hours from intubation. | 
| Mean area-under-curve (AUC) for FiO2 | FiO2 will be recorded each hour for a total duration of 6 hours from intubation. Subsequently, mean area-under-curve (AUC) will be calculated for each group. This will demonstrate the feasibility of the study. | Measurements will be obtained each hour for a total duration of 6 hours from intubation. | 
| PaO2 | PaO2 will be recorded at least once during 6 hours from intubation. Subsequently, PaO2 values (mmHg) will be calculated for each group. This will demonstrate the feasibility of the study. | Measurements will be obtained at least once during 6 hours from intubation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nosocomial pneumonia | Incidence of nosocomial pneumonia will be recorded for each arm | Within 7 days of subject enrollment | 
| Acute Respiratory Distress Syndrome (ARDS) | Incidence of ARDS will be recorded for each arm | Within 7 days of subject enrollment | 
| All-cause mortality | All-cause mortality will be recorded during ICU stay | Within 28 days of subject enrollment | 
| Extended Glasgow Outcome Score (GOS-E) | A combined outcome of disability and mortality at 6 months using the Extended Glasgow Outcome Score will be assessed | At 6 months following subject enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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emergency care, acute respiratory failure, trauma, oxygen, disability, acute care, critical care, mortality, brain injury, mechanical ventilation