Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.

Python-Embedded Plugin Implementation in ICM+: Novel Tools for Neuromonitoring Time Series Analysis with Examples Using CENTER-TBI Datasets.

With the appearance of publicly available, high-resolution, physiological datasets in neurocritical care, like Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI), there is a growing need for tools that could be used by clinical researchers to interrogate this information-rich data. The ICM+ software is widely used for processing data acquired from bedside monitors. Considering the growing popularity of scripting simple-syntax programming languages like Python, particularly among clinical researchers, we have developed an interface in ICM+ that provides a streamlined way of adding Python scripting functionality to the ICM+ calculation engine. The new interface imposes certain requirements on the scripts and needs an accompanying descriptor file that tells ICM+ about the functions implemented, so that they become available to the end user in the same way as native ICM+ functions. ICM+ also now includes a tool that eases the creation of Python functions to be imported. The Python extension works very efficiently, and any user with some degree of experience in scripting can use it to enrich capabilities of ICM+. Depending on the data analysed and calculations performed, Python functions are 15-60% slower than built-in ICM+ functions, which is a more-than-acceptable trade-off for empowering ICM+ with the unlimited analytical freedom offered by extensive Python libraries.

Cellular infiltration in traumatic brain injury.

Traumatic brain injury leads to cellular damage which in turn results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These in turn rapidly recruit neutrophils, which assist in limiting the spread of injury and removing cellular debris. Microglia continuously survey the CNS (central nervous system) compartment and identify structural abnormalities in neurons contributing to the response. After some days, when neutrophil numbers start to decline, activated microglia and astrocytes assemble at the injury site-segregating injured tissue from healthy tissue and facilitating restorative processes. Monocytes infiltrate the injury site to produce chemokines that recruit astrocytes which successively extend their processes towards monocytes during the recovery phase. In this fashion, monocytes infiltration serves to help repair the injured brain. Neurons and astrocytes also moderate brain inflammation via downregulation of cytotoxic inflammation. Depending on the severity of the brain injury, T and B cells can also be recruited to the brain pathology sites at later time points.

Continuous Near-infrared Spectroscopy Monitoring in Adult Traumatic Brain Injury: A Systematic Review.

Near-infrared spectroscopy (NIRS) may provide a noninvasive way to monitor cerebral oxygenation in patients with traumatic brain injury, therein allowing for timely intervention aimed at reversing regional brain tissue hypoxia. We conducted a systematic review of NIRS-based oximetry measurements and their association with (A) patient functional outcome (B) other neurophysiological parameters. We searched MEDLINE, EMBASE, SCOPUS, BIOSIS, GlobalHealth and Cochrane Databases from inception to December 2018 and relevant conference proceedings published over the last 5 years. A total of 42 studies meeting our inclusion criteria were found (37 prospective observational, 5 retrospective designs). Seven studies reporting on the association between NIRS-based cerebral oxygenated hemoglobin measurements, mortality, modified Rankin Scale, Glasgow Outcome Scale, or Extended Glasgow Outcome Scale were identified. Forty-two studies exploring associations with neurophysiological parameters were included. Notwithstanding significant gaps in the currently available literature, our analysis suggests a link between NIRS-detected cerebral hypoxia during the acute phase of traumatic brain injury and poor functional outcome. NIRS measurements appear to reflect changes in intracranial pressure, invasively monitored brain tissue oxygen tension and various cerebrovascular reactivity indices although low quality contradicting data exist. More importantly, our review highlights the need for more prospective work before routine integration of NIRS-based techniques into multimodality monitoring regimen.

Recent advances in traumatic brain injury.

Traumatic brain injury (TBI) is the most common cause of death and disability in those aged under 40 years in the UK. Higher rates of morbidity and mortality are seen in low-income and middle-income countries making it a global health challenge. There has been a secular trend towards reduced incidence of severe TBI in the first world, driven by public health interventions such as seatbelt legislation, helmet use, and workplace health and safety regulations. This has paralleled improved outcomes following TBI delivered in a large part by the widespread establishment of specialised neurointensive care. This update will focus on three key areas of advances in TBI management and research in moderate and severe TBI: refining neurointensive care protocolized therapies, the recent evidence base for decompressive craniectomy and novel pharmacological therapies. In each section, we review the developing evidence base as well as exploring future trajectories of TBI research.

Continuous Thermal Diffusion-Based Cerebral Blood Flow Monitoring in Adult Traumatic Brain Injury: A Scoping Systematic Review.

Thermal diffusion flowmetry (TDF) is an appealing candidate for monitoring of cerebral blood flow (CBF) in neurocritical-care patients as it provides absolute measurements with a high temporal resolution, potentially allowing for bedside intervention that could mitigate secondary injury. We performed a systematic review of TDF-regional(r)CBF measurements and their association with (1) patient functional outcome, (2) other neurophysiological parameters, and (3) imaging-based tissue outcomes. We searched MEDLINE, EMBASE, SCOPUS, BIOSIS, GlobalHealth, and the Cochrane Databases from inception to October 2018 and relevant conference proceedings published over the last 5 years. Nine articles that explored the relationship between TDF-rCBF, mortality, and Glasgow Outcome Scale (GOS) or GOS-Extended (GOS-E) at various intervals were included. Despite being based on an overall weak body of evidence, our analysis suggests a link between sustained low or high CBF and poor functional outcome. Twenty-five studies reporting associations with neurophysiological parameters were included. The available data also point to an association between low or high TDF-rCBF and intracranial hypertension. TDF-rCBF appears to correlate well with regional brain tissue oxygenation measurements. We found no studies reporting on imaging-based tissue outcome in relation to TDF. In conclusion, despite being based on a relatively weak body of evidence, the available literature suggests a link between consistently abnormal TDF-rCBF values, intracranial hypertension, and poor functional outcome. TDF-rCBF also appears to correlate well with regional measurements of brain tissue oxygenation. Currently, such monitoring should be considered experimental, requiring much further evaluation prior to widespread adoption.