The evolution of white matter microstructural changes after mild traumatic brain injury: A longitudinal DTI and NODDI study.

Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.

The Future of Neurocritical Care Research: Proceedings and Recommendations from the Fifth Neurocritical Care Research Network Conference.

The Fifth Neurocritical Care Research Network (NCRN) Conference held in Boca Raton, Florida, in September of 2018 was devoted to challenging the current status quo and examining the role of the Neurocritical Care Society (NCS) in driving the science and research of neurocritical care. The aim of this in-person meeting was to set the agenda for the NCS's Neurocritical Care Research Central, which is the overall research arm of the society. Prior to the meeting, all 103 participants received educational content (book and seminar) on the 'Blue Ocean Strategy®,' a concept from the business world which aims to identify undiscovered and uncontested market space, and to brainstorm innovative ideas and methods with which to address current challenges in neurocritical care research. Three five-member working groups met at least four times by teleconference prior to the in-person meeting to prepare answers to a set of questions using the Blue Ocean Strategy concept as a platform. At the Fifth NCRN Conference, these groups presented to a five-member jury and all attendees for open discussion. The jury then developed a set of recommendations for NCS to consider in order to move neurocritical care research forward. We have summarized the topics discussed at the conference and put forward recommendations for the future direction of the NCRN and neurocritical care research in general.

Research priorities in neurocritical care.

This summary of the last session of the First Neurocritical Care Research Conference reviews the discussions about research priorities in neurocritical care. The first presentation reviewed current projects funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and potential models to follow including an independent Neurocritical Care Network or the creation of such a network with the goal of collaborating with already existing ones. Experienced neurointensivists then presented their views on the most common and important research questions that need to be answered and investigated in the field. Finally, utility of clinical registries was discussed emphasizing their importance as hypothesis generators. During the group discussion, interests in comparative effectiveness research, the use of physiological endpoints from monitoring and alternate trial design were expressed.

Clinical trial design in the neurocritical care unit.

Clinical trials provide a robust mechanism to advance science and change clinical practice across the widest possible spectrum. Fundamental in the Neurocritical Care Society's mission is to promote Quality Patient Care by identifying and implementing best medical practices for acute neurological disorders that are consistent with the current scientific knowledge. The next logical step will be to foster rapid growth of our scientific body of evidence, to establish and disseminate these best practices. In this manuscript, five invited experts were impaneled to address questions, identified by the conference organizing committee as fundamental issues for the design of clinical trials in the neurological intensive care unit setting.

Herniography influences the management of patients with suspected occult herniae and patient factors can predict outcome.

PURPOSE: Patients with groin pain and no palpable hernia are a diagnostic challenge for the surgeon. It is recognised that some patients will have an occult hernia and benefit from surgical repair. Herniography remains popular in some units, as it has a high diagnostic sensitivity. METHODS: Presenting symptoms and signs were recorded, along with herniogram findings, management plan and outcome for all patients undergoing herniography between July 2004 and December 2009. Demographic factors and individual symptoms and signs were analysed for their ability to predict a positive herniogram. RESULTS: There were a total of 72 positive and 132 negative herniograms. For positive herniograms, only 41 (59%) patients underwent surgery and six (16%) patients were found not to have a hernia. The most common reasons for not proceeding to surgery were herniogram findings thought to be insignificant and the herniogram being positive on the contralateral side. For negative herniograms, despite a negative herniogram, four (3%) patients underwent surgery and a hernia was confirmed in two patients. Regarding predictive symptoms and signs, history of a groin lump and greater patient age were significantly associated with a positive herniogram and a confirmed hernia at surgery. CONCLUSIONS: After a positive herniogram, less than two-thirds of patients undergo surgery. The majority have improved symptoms on review and we, therefore, suggest a period of watchful waiting prior to herniography. Older patients and a history of a groin lump are associated with a positive herniogram and confirmed hernia at surgery, and could be used to select patients for laparoscopic exploration.

Cortical expression of prolactin (PRL), growth hormone (GH) and adrenocorticotrophic hormone (ACTH) is not increased in experimental traumatic brain injury.

BACKGROUND: Cerebral cortical expression of the pituitary hormones prolactin (PRL) and growth hormone (GH) have reported in ischemic damage. Both hormones may be involved in vascular tone regulation and angiogenesis, and growth hormone is thought to be neuroprotective while prolactin stimulates astrogliosis. METHODS: We examined expression of prolactin, growth hormone and adrenocorticotrophic hormone (ACTH) using tissue microarray technology in the controlled cortical impact model of traumatic brain injury (TBI). FINDINGS: No increased expression of these hormones was seen. CONCLUSIONS: Unlike ischemia, traumatic brain injury does not result in up-regulation of the pituitary hormones PRL and GH in cerebral cortex.

Pro-inflammatory and pro-apoptotic elements of the neuroinflammatory response are activated in traumatic brain injury.

BACKGROUND: The inflammatory response may contribute to cerebral edema, increased intracranial pressure and cellular loss in traumatic brain injury (TBI). Cytokines are biomarkers of this inflammatory response and new methods allow simultaneous measurement of multiple cytokines. METHODS: We examined the IL-1beta, IL-6, IL-8 and IL-12, TNFalpha, and IL-10 in arterial and jugular blood as well as cerebrospinal fluid in patients with severe traumatic brain injury. FINDINGS: Multiple cytokines, particularly pro-inflammatory cytokines, are up-regulated following TBI. Cerebrospinal fluid and arteriovenous differences of some of the cytokines suggest production within the central nervous system. Antiinflammatory cytokines are not up-regulated. CONCLUSIONS: Cytokine up-regulation may contribute to the neuroinflammatory reaction that follows traumatic brain injury and may contribute to secondary injury.

Cerebral autoregulation and gas exchange studied using a human cardiopulmonary model.

The goal of this work is to study the cerebral autoregulation, brain gas exchange, and their interaction by means of a mathematical model. We have previously developed a model of the human cardiopulmonary (CP) system, which included the whole body circulatory system, lung and peripheral tissue gas exchange, and the central nervous system control of arterial pressure and ventilation. In this study, we added a more detailed description of cerebral circulation, cerebrospinal fluid (CSF) dynamics, brain gas exchange, and cerebral blood flow (CBF) autoregulation. Two CBF regulatory mechanisms are included: autoregulation and CO(2) reactivity. Central chemoreceptor control of ventilation is also included. We first established nominal operating conditions for the cerebral model in an open-loop configuration using data generated by the CP model as inputs. The cerebral model was then integrated into the larger CP model to form a new integrated CP model, which was subsequently used to study cerebral hemodynamic and gas exchange responses to test protocols commonly used in the assessment of CBF autoregulation (e.g., carotid artery compression and the thigh-cuff deflation test). The model can closely mimic the experimental findings and provide biophysically based insights into the dynamics of cerebral autoregulation and brain tissue gas exchange as well as the mechanisms of their interaction during test protocols, which are aimed at assessing the degree of autoregulation. With further refinement, our CP model may be used on measured data associated with the clinical evaluation of the cerebral autoregulation and brain oxygenation in patients.

Brain tissue PO2: correlation with cerebral blood flow.

This investigation analyzed 22 xenon CT cerebral blood flow (CBF) studies from 18 severely head-injured patients (Glasgow motor score < 6) who underwent xenon CT scanning while brain tissue oxygen tension (PbtO2) was being monitored. CBF was determined both in a localized region of interest around the actual or estimated location of the tip of the PbtO2 probe and in the entire corresponding CT slice. Linear regression analysis was used to examine the relationship between these CBF measurements and PbtO2 values recorded immediately prior to the xenon CT CBF study. PbtO2 varied linearly with both regional CBF (rCBF) and global CBF measurements, but the average global CBF value was significantly higher than the average rCBF value. Very low values were significantly less common for global CBF than for rCBF. Further investigation is necessary to determine how probe placement near contused areas vs. in normal tissue affects our understanding of the relationship between rCBF, global CBF, PbtO2, and cerebral oxygen consumption.

Microdialysate nitrate/nitrite levels following severe head injury.

Nitric oxide (NO) has important regulatory functions within the central nervous system. The purpose of this study was to measure the concentration of nitric oxide in the brain after severe traumatic brain injury. NO is oxidized in vivo to nitrate and nitrite. Measurement of these products gives an index of NO production. Laboratory studies have shown a good correlation between NO measured directly with an electrode, and indirectly by microdialysis nitrate/nitrite. Using chemiluminescence method we measured nitrate/nitrite levels in 2024 microdialysate samples obtained from 24 patients during the first five days following severe head injury. We used CMA 70 probe (AB Microdialysis, Sweden) perfused by normal saline at a rate of 2 microliters/min. The median values of nitrate/nitrite for the whole group were highest on day 1 and gradually decreased over the 5 day monitoring period (day 1-19.2 mumol/l, day 5-12.7 mumol/l). Average values were lowest in the patients that died of their injury (14.3 mumol/l), and highest in patients who recovered by 3 months after injury with a moderate or severe disability (25.8 mumol/l or 31.9 mumol/l). In addition, there was a strong interaction between the severity of neurological injury and the change in dialysate nitrate/nitrite over time. The results suggest that nitric oxide may have a role in secondary injury mechanisms, but that this role is complex and varies as the injury evolves over time.

Measurement of the nitric oxide metabolites nitrate and nitrite in the human brain by microdialysis.

To examine the feasibility of measuring the nitric oxide (NO) metabolites nitrate and nitrite in microdialysate samples from the human brain, microdialysis probes were placed in normal appearing cerebral cortex of severely head injured patients in the Neurosurgical Intensive Care Unit at Ben Taub General Hospital. Nitrate/nitrite analysis was performed using NO chemiluminescence. Low micromolar levels of NO metabolites were consistently and easily detected. These levels seen are comparable to levels reported in CSF but tissue tortuosity and probe recovery considerations suggest that the absolute concentrations at the probe site are probably ten fold higher. Microdialysis with measurement of nitric oxide metabolites is technically feasible and may provide valuable insights into both normal neurochemistry and neurochemical derangements in disease.

Comparison of microdialysate arginine and glutamate levels in severely head-injured patient.

L-arginine concentrations in the brain are of interest following TBI because L-arginine is the immediate precursor of nitric oxide (NO). In addition, in vitro studies suggest that glutamate, which is a mediator of secondary injury after TBI, may stimulate release of arginine from glial cells. This study examines arginine concentrations in brain tissue using the microdialysis technique after human TBI. From 78 TBI patients, a total of 1739 microdialysate samples were collected using a CMA-70 probe perfused with normal saline at 2 microliters/min and concentrations of amino acids in microdialysate were determined. Amino acid concentrations for each patient were averaged for 8-hour periods during the first 3 days after injury, and daily for postinjury days 4 and 5. Following an initial rapid decrease in arginine, the dialysate arginine concentrations were low on days 1-3 and then increased over the days 4-5 after injury. In contrast, the microdialysate glutamate levels decreased slowly over the first 48 hours after TBI and thereafter remained low. Thirty-five episodes of jugular venous desaturation (SjvO2 < 50%) occurred during monitoring. Arginine and glutamate levels simultaneously doubled during desaturation and decreased as the clinical episode resolved. The low concentrations of arginine during the first 3 days after TBI may indicate that substrate unavailability could contribute to the decreased NO concentrations that have been observed after TBI. The simultaneous increase in glutamate and arginine during ischemic events is consistent with experimental data which has observed that glutamate induces release of arginine.

Adult respiratory distress syndrome: a complication of induced hypertension after severe head injury.

OBJECT: The factors involved in the development of adult respiratory distress syndrome (ARDS) after severe head injury were studied. The presence of ARDS complicates the treatment of patients with severe head injury, both because hypoxia causes additional injury to the brain and because therapies that are used to protect the lungs and improve oxygenation in patients with ARDS can reduce cerebral blood flow (CBF) and increase intracranial pressure (ICP). In a recent randomized trial of two head-injury management strategies (ICP-targeted and CBF-targeted), a fivefold increase in the incidence of ARDS was observed in the CBF-targeted group. METHODS: Injury severity, physiological data, and treatment data in 18 patients in whom ARDS had developed were compared with the remaining 171 patients in the randomized trial in whom it had not developed. Logistic regression analysis was used to study the interaction of the factors that were related to the development of ARDS. In the final exact logistic regression model, several factors were found to be significantly associated with an increased risk of ARDS: administration of epinephrine (5.7-fold increased risk), administration of dopamine in a larger than median dose (10.8-fold increased risk), and a history of drug abuse (3.1-fold increased risk). CONCLUSIONS: Although this clinical trial was not designed to study the association of management strategy and the occurrence of ARDS, the data strongly indicated that induced hypertension in this high-risk group of patients is associated with the development of symptomatic ARDS.

Ischemic injury and faulty gene transcripts in the brain.

The brain has the highest metabolic rate of all organs and depends predominantly on oxidative metabolism as a source of energy. Oxidative metabolism generates reactive oxygen species, which can damage all cellular components, including protein, lipids and nucleic acids. The processes of DNA repair normally remove spontaneous gene damage with few errors. However, cerebral ischemia followed by reperfusion leads to elevated oxidative stress and damage to genes in brain tissue despite a functional mechanism of DNA repair. These critical events occur at the same time as the expression of immediate early genes, the products of which trans-activate late effector genes that are important for sustaining neuronal viability. These findings open the possibility of applying genetic tools to identify molecular mechanisms of gene repair and to derive new therapies for stroke and brain injury.

Potentiated endothelium-derived hyperpolarizing factor-mediated dilations in cerebral arteries following mild head injury.

Evidence in the literature suggests that endothelium-derived hyperpolarizing factor (EDHF) may act in a compensatory manner such that during conditions of compromised nitric oxide (NO), EDHF serves as a back-up mechanism. Given that constitutive NO synthase is chronically downregulated after head trauma, we tested the hypothesis that EDHF is potentiated following injury. Male adult rats were subjected to either sham injury (n = 27) or mild controlled cortical impact (CCI) injury (n = 26). Branches of the middle cerebral artery (MCA) directly within the contusion site were harvested either 1 or 24 h later, pressurized to 60 mm Hg in a vessel chamber and allowed to develop spontaneous tone. Relaxation to luminal application of adenosine triphosphate (ATP) was similar in all groups. Relaxation to ATP in the presence of L-NAME (N(G)-nitro-L-arginine methyl ester) and indomethacin was similar in all groups except for vessels isolated at 24 h following mild CCI injury. In this case, L-NAME and indomethacin had no effect on the ATP-mediated dilation. The ATP-mediated dilation in L-NAME and indomethacin-treated MCA branches was inhibited by charybdotoxin, an inhibitor of large conductance Ca2+-sensitive K+ channels. These findings suggest that there is a significant potentiation of the EDHF-mediated dilation to ATP in cerebral arteries isolated at 24 h following mild CCI injury.

Ultrasound is a reliable method for determining jugular bulb dominance.

Despite widespread application of jugular oximetry devices, the optimal side to cannulate for monitoring cerebral oxygenation is controversial. For most monitoring strategies, the dominant or larger internal jugular vein gives the most representative values for venous oxygen saturation. However, there is little information on how to best determine the dominant side. The purpose of this study was to compare the results of an ultrasound examination to two other standard methods for determining the dominant internal jugular vein, the jugular vein compression test and the computed tomographic (CT) approach. Seventeen patients with severe head injury (GCS <8) were studied. The ultrasound examination showed the mean internal diameter of the right and the left internal jugular veins to be 1.27 cm (standard deviation [SD] 0.16 cm) and 1.21 cm (SD 0.36 cm), respectively. The right internal jugular vein was larger than the left in 11 (65%) of the patients. The diameter of the dominant or larger internal jugular veins were 1.44 cm (SD = 0.22), compared with 1.04 cm (SD = 0.18) on the opposite side (P < .05). The results of the ultrasound method were in agreement with the CT scan method in 94% of the comparisons and with the jugular vein compression test in 82% of comparisons. These studies demonstrate that the ultrasound method provides useful information about the side of the dominant cerebral venous drainage, comparable to other standard methods, without the need for a CT scan or manipulation of intracranial pressure.

Subarachnoid-pleural fistula treated with noninvasive positive-pressure ventilation. Case report.

The authors describe the case of a 24-year-old man who underwent an L-1 corpectomy for spinal decompression and stabilization following an injury that caused an L-1 burst fracture. Postoperatively, an accumulation of spinal fluid developed in the pleural space, which was refractory to 1 week of thoracostomy tube drainage and lumbar cerebrospinal fluid (CSF) diversion. The authors then initiated a regimen of positive-pressure ventilation in which a bi-level positive airway pressure (PAP) mask was used. After 5 days, the CSF collection in the pleural space resolved. Use of a bi-level PAP mask represents a safe, noninvasive method of reducing the negative intrathoracic pressure that promotes CSF leakage into the pleural cavity and may be a useful adjunct in the treatment of subarachnoid-pleural fistula.

The relation between acute physiological variables and outcome on the Glasgow Outcome Scale and Disability Rating Scale following severe traumatic brain injury.

The relation between outcome and duration of adverse physiological events was studied, using suggested critical physiological values. Subjects were 184 patients with severe traumatic brain injury who received continuous monitoring of intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and jugular venous oxygen saturation. Longer durations of adverse physiological events were significantly related to Glasgow Outcome Scale (GOS) scores and Disability Rating Scale (DRS) scores for all variables at all timepoints postinjury. When analyses excluded patients who died, the relation between adverse physiological events and GOS was nonsignificant; however, duration of ICP, MAP, and CPP still accounted for a significant portion of the variance in DRS scalres. The relative sensitivity of the GOS and DRS is discussed.

Interstitial brain adenosine and xanthine increase during jugular venous oxygen desaturations in humans after traumatic brain injury.

OBJECTIVE: Adenosine decreases the cerebral metabolic rate for oxygen and increases cerebral blood flow, and it may play an important role in cerebrometabolic and cerebrovascular responses to hypoperfusion after traumatic brain injury. Jugular venous oxygen saturation is monitored after traumatic brain injury to assess brain oxygen extraction, and desaturations may reflect secondary brain insults. We hypothesized that brain interstitial adenosine and related purine metabolites would be increased during jugular venous oxygen saturation desaturations (<50%) and determined associations between the purines, lactate, and glucose to assess the role of adenosine during secondary insults in humans. DESIGN: Study of critically ill adults with severe traumatic brain injury. SETTING: Adult neurointensive care unit. PATIENTS: We prospectively defined periods of normal saturation and desaturation in six patients after severe traumatic brain injury. INTERVENTIONS: During these periods, cerebral microdialysis samples of brain interstitial fluid were collected, and adenosine and purine metabolites were measured by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Adenosine increased 3.1-fold and xanthine increased 2.5-fold during desaturation periods (both p <.05 vs. normal saturation period, signed rank). Adenosine, xanthine, hypoxanthine, and cyclic-adenosine monophosphate correlated with lactate over both study periods (r(2) =.32,.14,.31,.07, and.26, respectively, all p <.05, Pearson product moment correlation). CONCLUSION: The marked increases in interstitial brain adenosine that occur during jugular venous oxygen desaturations suggest that adenosine may play an important role during periods of secondary insults after traumatic brain injury. The correlation of these metabolites with lactate further suggests that adenosine is increased during periods of enhanced glycolytic metabolism.