Normobaric hyperoxia increases cerebral aerobic metabolism after traumatic brain injury

Objects: Traumatic brain injury (TBI) is associated with depressed aerobic metabolism and mitochondrial dysfunction. Normobaric hyperoxia (NBH) has been suggested as a treatment for TBI but human studies have produced equivocal results. We used brain tissue oxygen tension (PbrO2) measurement, cerebral microdialysis and near infrared spectroscopy to study the effects of NBH after TBI. We investigated the effects on cellular and mitochondrial redox state, measured by brain tissue lactate:pyruvate ratio (LPR) and change in oxidized cytochrome c oxidase concentration (∆[oxCCO]) respectively. Methods: We studied eight adult human patients with TBI within the first 48 hours post injury. Inspired oxygen percentage (FiO2), at nomobaric pressure, was increased from baseline to 60% for 60 minutes and then to 100% for 60 minutes before being returned to baseline for 30 minutes. Results are presented as median (interquartile range). During the 100% FiO2 phase, PbrO2 increased by 7.2 kPa (4.5-9.6) (p<0.0001), microdialysate lactate concentration decreased by 0.26 mmol/l (0.0-0.45) (p=0.01), microdialysate LPR decreased by 1.6 (1.0-2.3) (p=0.02) and ∆[oxCCO] increased by 0.21 μmol/l (0.13-0.38) (p=0.0003). There were no significant changes in intracranial pressure, or arterial, or microdialysate, glucose concentration. ∆ [oxCCO] correlated with changes in PbrO2 (rs=0.57 p=0.005) and change in LPR (rs=0.-52 p=0.006). Conclusions: We have demonstrated oxidation in cerebral cellular and mitochondrial redox state during NBH in adult patients with TBI. These findings are consistent with increased aerobic metabolism and suggest that NBH has the potential to improve outcome after TBI. Further studies are warranted. Introduction Traumatic brain injury (TBI) is responsible for approximately 500,000 hospital admissions and 17,500 deaths in the United States per year and, as it predominantly affects young people, it results in a huge socioeconomic burden. TBI describes a heterogenous set of injury mechanisms and pathologies but there are common metabolic pathways leading to depressed aerobic metabolism, reduced cellular adenosine triphosphate (ATP) production, inability to maintain ionic homeostasis and ultimately cell death 37, 46, . The exact etiology of this cellular energy failure is poorly understood but both reduced substrate delivery and impaired mitochondrial substrate utilization appear to be implicated. Using a cerebral fluid percussion insult in the cat, Alves et al demonstrated that TBI induces cerebral hypoxia despite unchanged arterial oxygen tension and arterial blood pressure suggesting that reduced ATP production after TBI may be in part related to mitochondrial hypoxia. It is well established that hypotension and hypoxemia, are associated with poor functional outcome after TBI and so, within the context of attempting to minimize secondary injury after TBI, it appears vital to ensure adequate oxygen delivery to cerebral mitochondria, particularly in the early stages post TBI when reduced cerebral blood flow (CBF) increases the risk of cerebral hypoxia. Hyperoxia has been investigated as a potential treatment strategy for increasing aerobic metabolism after TBI and hyperbaric hyperoxia (HBH) in particular has shown beneficial effects in both animals and humans 34, . However chambers capable of delivering HBH to critically ill patients are expensive and availability is severely limited. Interest has therefore grown in the use of normobaric hyperoxia (NBH) which is cheap and simple to administer. Studies investigating the use of NBH in adults after TBI have consistently shown increases in brain oxygen tension (PbrO2) and reductions in microdialysis measured brain tissue lactate concentration 28, 43 but interpretation of these findings is controversial. Some investigators conclude that they support a beneficial role for NBH while others suggest that NBH may be detrimental. Cerebral microdialysis is an established technique that allows focal measurement of brain tissue biochemistry and is becoming incorporated into routine multimodality monitoring on the neurointensive care unit (NCU). Raised microdialysate lactate concentration is associated with tissue hypoxia and poor outcome after TBI. However it reflects not only the degree of anaerobic metabolism but also the global glycolytic rate. Lactate:pyruvate ratio (LPR) is considered a superior marker of anaerobic metabolism and is a measure of cellular redox state . However, clinical TBI studies to date have shown no changes in LPR and this has contributed to the controversy surrounding interpretation of the resulting data. Broadband near infrared spectroscopy (NIRS) is a non-invasive technique which measures the attenuation of light by tissue at multiple wavelengths. It exploits the fact that biological tissue is relatively transparent to near infrared (NIR) light between 700-900 nm, allowing interrogation of the cerebral cortex by optodes placed on the scalp. Biological tissue is a highly scattering medium and this complicates the calculation of chromophore concentration. However, if the average pathlength of light through tissue is known, the modified Beer-Lambert law, which assumes constant scattering losses, allows calculation of absolute changes in chromophore concentration. The in vivo use of NIR spectroscopy (NIRS) was first described by Jöbsis in 1977, and has been used in animals and humans to measure change in concentration of oxy-hemoglobin (∆[HbO2]), deoxy-hemoglobin (∆[HHb]), and oxidized cytochrome c oxidase (∆[oxCCO]) 25, 38, 40, . Cytochrome c oxidase (CCO) is the terminal electron acceptor of the mitochondrial electron transfer chain. As electrons pass along the electron transfer chain, protons are pumped out of the mitochondrial matrix and into the intermembrane space against their concentration gradient, thus providing the driving force for ATP synthesis (figure 1). CCO therefore plays a crucial role in the dynamics of cellular oxygen utilization and energy production, with the movement of electrons down the mitochondrial respiratory chain (via redox reactions) to oxygen resulting in >95% of cellular oxygen utilization. CCO contains a unique Cu-Cu dimer (termed CuA) that is a strong NIR absorber at 830nm. If the total concentration of CCO remains constant during a study, changes in the NIRS CCO signal represent changes in the CCO redox state. This reflects the balance between electron donation from cytochrome c and oxygen reduction to water. In animals, broadband NIRS measured cerebral ∆[oxCCO] has been validated as a marker of cellular energy status against magnetic resonance spectroscopy measured reduction in nucleoside triphosphate levels. It has also recently been shown to correlate with estimated change in cerebral oxygen delivery during hypoxemia in healthy adult humans. Animal models indicate that CCO mediated oxidative metabolism is decreased after TBI and that this effect may last up to 10 days post injury. Changes in CCO activity after TBI may therefore have an important effect on the ability of mitochondria to metabolize ATP aerobically and it is possible to investigate these changes non-invasively using NIRS. We hypothesize that NBH will cause oxidation in cerebral cellular and mitochondrial redox state in adult patients in the early period post TBI. Materials and Methods This study was approved by the Joint Research Ethics Committee of the National Hospital for Neurology and Neurosurgery and the Institute of Neurology and, as all patients were unconscious at the time of the study, written assent was obtained from their personal representatives. Inclusion criteria were a diagnosis of TBI requiring sedation and ventilation on the NCU and age>16 years. Exclusion criteria were the expectation of death or weaning of sedation within 24 hours of injury, a baseline FiO2 ≥60% or more than 48 hours elapsing between the time of injury and the start of the study.