Integrating, Harmonizing, and Curating Studies With High-Frequency and Hourly Physiological Data: Proof of Concept from Seven Traumatic Brain Injury Data Sets.

Research in severe traumatic brain injury (TBI) has historically been limited by studies with relatively small sample sizes that result in low power to detect small, yet clinically meaningful outcomes. Data sharing and integration from existing sources hold promise to yield larger more robust sample sizes that improve the potential signal and generalizability of important research questions. However, curation and harmonization of data of different types and of disparate provenance is challenging. We report our approach and experience integrating multiple TBI data sets containing collected physiological data, including both expected and unexpected challenges encountered in the integration process. Our harmonized data set included data on 1536 patients from the Citicoline Brain Injury Treatment Trial (COBRIT), Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial (EPO Severe TBI), BEST-TRIP, Progesterone for the Treatment of Traumatic Brain Injury III Clinical Trial (ProTECT III), Transforming Research and Clinical Knowledge in Traumatic brain Injury (TRACK-TBI), Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II (BOOST-2), and Ben Taub General Hospital (BTGH) Research Database studies. We conclude with process recommendations for data acquisition for future prospective studies to aid integration of these data with existing studies. These recommendations include using common data elements whenever possible, a standardized recording system for labeling and timing of high-frequency physiological data, and secondary use of studies in systems such as Federal Interagency Traumatic Brain Injury Research Informatics System (FITBIR), to engage investigators who collected the original data.

HMG-CoA Reductase Inhibitors for Traumatic Brain Injury.

Traumatic brain injuries (TBIs) are associated with high morbidity and mortality due to both the original insult as well as the destructive biological response that follows. Medical management aims to slow or even halt secondary neurological injury while simultaneously laying the groundwork for recovery. Statins are one class of medications that is showing increased promise in the management of TBI. Used extensively in cardiovascular disease, these drugs were originally developed as competitive inhibitors within the cholesterol production pipeline. They are now used in diverse disease states due to their pleiotropic effects on other biological processes such as inflammation and angiogenesis. Preclinical studies, retrospective reviews, and randomized clinical trials have shown a variety of benefits in the management of TBI, but to date, no large-scale randomized clinical trial has been performed. Despite this limitation, statins' early promise and well-tolerated side effect profile make them a promising new tool in the management of TBIs. More bench and clinical studies are needed to delineate proper treatment regimens as well as understand their true potential.

Overview of Hypothermia, Its Role in Neuroprotection, and the Application of Prophylactic Hypothermia in Traumatic Brain Injury.

The current standard of practice is to maintain normothermia in traumatic brain injury (TBI) patients despite the theoretical benefits of hypothermia and numerous animal studies with promising results. While targeted temperature management or induced hypothermia to support neurological function is recommended for a select patient population postcardiac arrest, similar guidelines have not been instituted for TBI. In this review, we will examine the pathophysiology of TBI and discuss the benefits and risks of induced hypothermia in this patient population. In addition, we provide an overview of the largest randomized controlled trials testing-induced hypothermia. Our literature review on hypothermia returned a myriad of studies and trials, many of which have inconclusive results. The aim of this review was to recognize the effects of hypothermia, summarize the latest trials, address the inconsistencies, and discuss future directions for the study of hypothermia in TBI.

Cerebral microdialysis and glucopenia in traumatic brain injury: A review.

Traditionally, intracranial pressure (ICP) and partial brain tissue oxygenation (PbtO2) have been the primary invasive intracranial measurements used to guide management in patients with severe traumatic brain injury (TBI). After injury however, the brain develops an increased metabolic demand which may require an increment in the oxidative metabolism of glucose. Simultaneously, metabolic, and electrical dysfunction can lead to an inability to meet these demands, even in the absence of ischemia or increased intracranial pressure. Cerebral microdialysis provides the ability to accurately measure local concentrations of various solutes including lactate, pyruvate, glycerol and glucose. Experimental and clinical data demonstrate that such measurements of cellular metabolism can yield critical missing information about a patient's physiologic state and help limit secondary damage. Glucose management in traumatic brain injury is still an unresolved question. As cerebral glucose metabolism may be uncoupled from systemic glucose levels due to the metabolic dysfunction, measurement of cerebral extracellular glucose concentrations could provide more predictive information and prove to be a better biomarker to avoid secondary injury of at-risk brain tissue. Based on data obtained from cerebral microdialysis, specific interventions such as ICP-directed therapy, blood glucose increment, seizure control, and/or brain oxygen optimization can be instituted to minimize or prevent secondary insults. Thus, microdialysis measurements of parenchymal metabolic function provides clinically valuable information that cannot be obtained by other monitoring adjuncts in the standard ICU setting.

A Precision Medicine Agenda in Traumatic Brain Injury.

Traumatic brain injury remains a leading cause of death and disability across the globe. Substantial uncertainty in outcome prediction continues to be the rule notwithstanding the existing prediction models. Additionally, despite very promising preclinical data, randomized clinical trials (RCTs) of neuroprotective strategies in moderate and severe TBI have failed to demonstrate significant treatment effects. Better predictive models are needed, as the existing validated ones are more useful in prognosticating poor outcome and do not include biomarkers, genomics, proteonomics, metabolomics, etc. Invasive neuromonitoring long believed to be a "game changer" in the care of TBI patients have shown mixed results, and the level of evidence to support its widespread use remains insufficient. This is due in part to the extremely heterogenous nature of the disease regarding its etiology, pathology and severity. Currently, the diagnosis of traumatic brain injury (TBI) in the acute setting is centered on neurological examination and neuroimaging tools such as CT scanning and MRI, and its treatment has been largely confronted using a "one-size-fits-all" approach, that has left us with many unanswered questions. Precision medicine is an innovative approach for TBI treatment that considers individual variability in genes, environment, and lifestyle and has expanded across the medical fields. In this article, we briefly explore the field of precision medicine in TBI including biomarkers for therapeutic decision-making, multimodal neuromonitoring, and genomics.

Physiological Signatures of Brain Death Uncovered by Intracranial Multimodal Neuromonitoring.

BACKGROUND: The physiological and neurochemical changes that accompany brain death are not well described. MATERIALS AND METHODS: A retrospective observational study of patients with acute brain injury who underwent intracranial multimodality neuromonitoring between October 2015 and June 2018. Patients were included for analysis either if brain death was diagnosed or refractory intracranial hypertension with persistent equalization of intracranial pressure (ICP) and mean arterial pressure (MAP) developed. RESULTS: Of 114 patients who underwent invasive neuromonitoring, 11 cases with MAP/ICP equalization were identified. Of those, 9 were declared brain dead based on accepted national and institutional criteria. An additional 2 cases with MAP/ICP equalization who died after withdrawal of life-sustaining therapies were identified. Of the 11 identified patients, 10 had continuous monitoring data available for analysis. Cerebral microdialysis data were available for 4 patients.In the 10 cases with available continuous data, ICP/MAP equalization was associated with marked reduction of cerebral blood flow and brain tissue oxygen tension to near zero levels as well as a significant decrease in brain temperature compared with body temperature. In the 4 patients with microdialysis monitoring, ICP/MAP equalization resulted in a near complete depletion of cerebral glucose and pyruvate, as well as a marked rise in cerebral glycerol. Finally, ICP/MAP equalization was accompanied by complete loss of cerebrovascular pressure reactivity, decrease in intracranial pulse pressure, and a paradoxical improvement of ICP waveform morphology. CONCLUSIONS: A characteristic set of changes in cerebrovascular physiology and neurochemistry occurs during brain death. These changes can be identified by intracranial neuromonitoring.

Defining a Taxonomy of Intracranial Hypertension: Is ICP More Than Just a Number?

Intracranial pressure (ICP) monitoring and control is a cornerstone of neuroanesthesia and neurocritical care. However, because elevated ICP can be due to multiple pathophysiological processes, its interpretation is not straightforward. We propose a formal taxonomy of intracranial hypertension, which defines ICP elevations into 3 major pathophysiological subsets: increased cerebral blood volume, masses and edema, and hydrocephalus. (1) Increased cerebral blood volume increases ICP and arises secondary to arterial or venous hypervolemia. Arterial hypervolemia is produced by autoregulated or dysregulated vasodilation, both of which are importantly and disparately affected by systemic blood pressure. Dysregulated vasodilation tends to be worsened by arterial hypertension. In contrast, autoregulated vasodilation contributes to intracranial hypertension during decreases in cerebral perfusion pressure that occur within the normal range of cerebral autoregulation. Venous hypervolemia is produced by Starling resistor outflow obstruction, venous occlusion, and very high extracranial venous pressure. Starling resistor outflow obstruction tends to arise when cerebrospinal fluid pressure causes venous compression to thus increase tissue pressure and worsen tissue edema (and ICP elevation), producing a positive feedback ICP cycle. (2) Masses and edema are conditions that increase brain tissue volume and ICP, causing both vascular compression and decrease in cerebral perfusion pressure leading to oligemia. Brain edema is either vasogenic or cytotoxic, each with disparate causes and often linked to cerebral blood flow or blood volume abnormalities. Masses may arise from hematoma or neoplasia. (3) Hydrocephalus can also increase ICP, and is either communicating or noncommunicating. Further research is warranted to ascertain whether ICP therapy should be tailored to these physiological subsets of intracranial hypertension.

Endothelial nitric oxide synthase mediates the cerebrovascular effects of erythropoietin in traumatic brain injury.

BACKGROUND: Erythropoietin (Epo) improves post-traumatic cerebral blood flow (CBF), pressure autoregulation, and vascular reactivity to l-arginine. This study examines the dependence of these cerebral hemodynamic effects of Epo on nitric oxide generated by endothelial nitric oxide synthase (eNOS). METHODS: Using laser Doppler flow imaging, CBF was monitored in wild-type (WT) and eNOS-deficient mice undergoing controlled cortical impact followed by administration of Epo (5000 U/kg) or normal saline. RESULTS: Cerebral blood flow decreased in all groups post-injury with the greatest reductions occurring at the impact site. Epo administration resulted in significantly higher CBF in the peri-contusional sites in the WT mice [70.2 ± 3.35% in Epo-treated compared to 53 ± 3.3% of baseline in saline-treated mice (p < 0.0001)], but no effect was seen in the eNOS-deficient mice. No CBF differences were found at the core impact site where CBF dropped to 20-25% of baseline in all groups. CONCLUSION: These differences between eNOS-deficient and WT mice indicate that the Epo mediated improvement in CBF in traumatic brain injury is eNOS dependent.

The 1-piece transbasal approach: operative technique and anatomical study.

OBJECT: The transbasal approach (TBA) is an anterior skull base approach, which provides access to the anterior skull base, sellar-suprasellar region, and clivus. The TBA typically involves a bifrontal craniotomy with orbital bar and/or nasal bone osteotomies performed in 2 separate steps. The authors explored the feasibility of routinely performing this approach in 1 piece with a quantitative cadaveric anatomical study, and present an operative case example of their approach. METHODS: Seven latex-injected cadaveric heads underwent a 1-piece TBA, followed by additional bone removal typical for a traditional 2-piece approach. Six surgical angles relative to the pituitary stalk, as well as the surface area of the orbital roof osteotomy, were measured before and after additional bone removal. The vertical angle from the frontonasal suture to the foramen cecum was measured in all specimens. In addition to an anatomical study, the authors have used this technique in the operating room, and present an illustrative case of resection of an anterior skull base meningioma. RESULTS: Morphometric results were as follows: the vertical angle from the frontonasal suture to the foramen cecum ranged from 17.4° to 29.7° (mean 23.8° ± 4.8°) superiorly. Of the 6 surgical angle measures, only the middle horizontal angle was increased in the 2-piece versus the 1-piece approach (mean 43.4° ± 4.6° vs 43.0° ± 4.3°, respectively; p = 0.049), with a mean increase of 0.4°. The surface area of the orbital osteotomy was increased in the 2-piece versus the 1-piece approach (mean 2467 mm(2) ± 360 mm(2) vs 2045 mm(2) ± 352 mm(2), respectively; p < 0.001). The patient in the illustrative clinical case had a good outcome, both clinically and cosmetically. CONCLUSIONS: The 1-piece TBA provides an alternative to the traditional 2-piece approach. It allows easier reconstruction, potentially decreased operative time, and improved cosmesis. While more of the orbital roof can be removed with the 2-piece approach, this additional bone removal offers only a small increase in 1 of 6 surgical angles that were measured.