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Objective Spreading depolarizations (SD) are characterized by breakdown of transmembrane ion gradients and excitotoxicity. Experimentally, N-methyl-d-aspartate receptor (NMDAR) antagonists block a majority of SDs. In many hospitals, the NMDAR antagonist s-ketamine and the GABAA agonist midazolam represent the current second-line combination treatment to sedate patients with devastating cerebral injuries. A pressing clinical question is whether this option should become first-line in sedation-requiring individuals in whom SDs are detected, yet the s-ketamine dose necessary to adequately inhibit SDs is unknown. Moreover, use-dependent tolerance could be a problem for SD inhibition in the clinic. Methods We performed a retrospective cohort study of 66 patients with aneurysmal subarachnoid hemorrhage (aSAH) from a prospectively collected database. Thirty-three of 66 patients received s-ketamine during electrocorticographic neuromonitoring of SDs in neurointensive care. The decision to give s-ketamine was dependent on the need for stronger sedation, so it was expected that patients receiving s-ketamine would have a worse clinical outcome. Results S-ketamine application started 4.2 ± 3.5 days after aSAH. The mean dose was 2.8 ± 1.4 mg/kg body weight (BW)/h and thus higher than the dose recommended for sedation. First, patients were divided according to whether they received s-ketamine at any time or not. No significant difference in SD counts was found between groups (negative binomial model using the SD count per patient as outcome variable, p = 0.288). This most likely resulted from the fact that 368 SDs had already occurred in the s-ketamine group before s-ketamine was given. However, in patients receiving s-ketamine, we found a significant decrease in SD incidence when s-ketamine was started (Poisson model with a random intercept for patient, coefficient − 1.83 (95% confidence intervals − 2.17; − 1.50), p p p p Conclusions These results provide a foundation for a multicenter, neuromonitoring-guided, proof-of-concept trial of ketamine and midazolam as a first-line sedative regime.

Fatigue resulting from shift work and extended hours can compromise patient care and the safety and health of nurses, as well as increasing nursing turnover and health care costs.This research aimed to identify aspects of nurses' work patterns associated with increased risk of reporting fatigue-related outcomes.A national survey of work patterns and fatigue-related outcomes in 6 practice areas expected to have high fatigue risk (child health including neonatology, cardiac care/intensive care, emergency and trauma, in-patient mental health, medical, and surgical nursing).The 5-page online questionnaire included questions addressing: demographics, usual work patterns, work in the previous two weeks, choice about shifts, and four fatigue-related outcomes - having a sleep problem for at least 6 months, sleepiness (Epworth Sleepiness Scale), recalling a fatigue-related error in clinical practice in the last 6 months, and feeling close to falling asleep at the wheel in the last 12 months. The target population was all registered and enrolled nurses employed to work in public hospitals at least 30 h/week in one of the 6 practice areas. Participation was voluntary and anonymous.Respondents (n = 3133) were 89.8% women and 8% Māori (indigenous New Zealanders), median age 40 years, range 21-71 years (response rate 42.6%). Nurses were more likely than New Zealand adults in general to report chronic sleep problems (37.73% vs 25.09%, p 0.0001) and excessive sleepiness (33.75% vs 14.9%, p 0.0001). Fatigue-related error(s) in the last 6 months were recalled by 30.80% and 64.50% reported having felt sleepy at the wheel in the last 12 months. Logistic regression analyses indicated that fatigue-related outcomes were most consistently associated with shift timing and sleep. Risk increased with more night shifts and decreased with more nights with sleep between 11 p.m. and 7 a.m. and on which nurses had enough sleep to feel fully rested. Risk also increased with roster changes and more shift extensions greater than 30 min and decreased with more choice about shifts. Comparisons between intensive care/cardiac care and in-patient mental health nursing highlight that fatigue has different causes and consequences in different practice areas.Findings confirm the need for a more comprehensive and adaptable approach to managing fatigue. We advocate an approach that integrates safety management and scientific principles with nursing and management expertise. It should be data-driven, risk-focused, adaptable, and resilient in the face of changes in the services required, the resources available, and the overall goals of the healthcare system.

Spreading depolarization (SD) is a fundamental pathophysiological mechanism of both pannecrotic and selective neuronal lesions following deprivation of energy. SD with brain injury has been reported including in one patient during an intracranial operation. However, the incidence of SDs in operative resections is unknown. We performed (a) retrospective analysis of intraoperative AC-recordings of 69 patients and (b) a prospective study using intraoperative near-DC recording. All patients had the diagnosis of pharmaco-resistant epilepsy. Both studies were designed to determine the incidence and characteristics of SDs intraoperatively. In the retrospective analysis, we used intraoperative electrocorticography (iECoG) recordings obtained from AC-recording of 69 patients. In the prospective analysis, we used an Octal Bio Amp and Power Lab ECoG recorder with near-DC range. In the retrospective study, we included 69 patients with a mean of 1 h 3 min of iECoG recordings. In the prospective study, we recruited 20 patients with near DC recordings. A total of 35 h 41 min of iECoG recordings with mean of 2 h 32 min/patient were analyzed. We did not find SD in either study. SDs were not detected during intraoperative recordings of epilepsy surgery using AC- or DC-amplifiers.

Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe.A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP).The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions.Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care.

Funder: Projekt DEAL, The ability of photoacoustic imaging to measure functional tissue properties, such as blood oxygenation sO[Formula: see text], enables a wide variety of possible applications. sO[Formula: see text] can be computed from the ratio of oxyhemoglobin HbO[Formula: see text] and deoxyhemoglobin Hb, which can be distuinguished by multispectral photoacoustic imaging due to their distinct wavelength-dependent absorption. However, current methods for estimating sO[Formula: see text] yield inaccurate results in realistic settings, due to the unknown and wavelength-dependent influence of the light fluence on the signal. In this work, we propose learned spectral decoloring to enable blood oxygenation measurements to be inferred from multispectral photoacoustic imaging. The method computes sO[Formula: see text] pixel-wise, directly from initial pressure spectra [Formula: see text], which represent initial pressure values at a fixed spatial location [Formula: see text] over all recorded wavelengths [Formula: see text]. The method is compared to linear unmixing approaches, as well as pO[Formula: see text] and blood gas analysis reference measurements. Experimental results suggest that the proposed method is able to obtain sO[Formula: see text] estimates from multispectral photoacoustic measurements in silico, in vitro, and in vivo.

Contains fulltext : 238746.pdf (Publisher’s version ) (Closed access) Recent biomarker innovations hold potential for transforming diagnosis, prognostic modeling, and precision therapeutic targeting of traumatic brain injury (TBI). However, many biomarkers, including brain imaging, genomics, and proteomics, involve vast quantities of high-throughput and high-content data. Management, curation, analysis, and evidence synthesis of these data are not trivial tasks. In this review, we discuss data management concepts and statistical and data sharing strategies when dealing with biomarker data in the context of TBI research. We propose that application of biomarkers involves three distinct steps-discovery, evaluation, and evidence synthesis. First, complex/big data has to be reduced to useful data elements at the stage of biomarker discovery. Second, inferential statistical approaches must be applied to these biomarker data elements for assessment of biomarker clinical utility and validity. Last, synthesis of relevant research is required to support practice guidelines and enable health decisions informed by the highest quality, up-to-date evidence available. We focus our discussion around recent experiences from the International Traumatic Brain Injury Research (InTBIR) initiative, with a specific focus on four major clinical projects (Transforming Research and Clinical Knowledge in TBI, Collaborative European NeuroTrauma Effectiveness Research in TBI, Collaborative Research on Acute Traumatic Brain Injury in Intensive Care Medicine in Europe, and Approaches and Decisions in Acute Pediatric TBI Trial), which are currently enrolling subjects in North America and Europe. We discuss common data elements, data collection efforts, data-sharing opportunities, and challenges, as well as examine the statistical techniques required to realize successful adoption and use of biomarkers in the clinic as a foundation for precision medicine in TBI.

COVID-19 is characterized by acute respiratory distress syndrome progression, which ranges from mild to severe. A percentage of critically ill patients will require endotracheal intubation and mechanical ventilation; therefore, Mexican engineers from different places have had the initiative of creating mechanical ventilators. Although artificial ventilator is one of the last resources for the most severely ill patients, there are patients who are on the verge of not meeting the criteria for intubation; if they are directly intubated, the opportunity for them to overcome the severe phase with high concentration supplemental oxygen would be be missed. Intubation per se induces lung damage, increases the risk of superinfection, and the number of days of ICU stay. Furthermore, non-selective use of artificial ventilators decreases the opportunity for patients who require a ventilator to survive and increases institutional care costs of both human and material resources.

Microbiological testing represents a significant expenditure for producers. Two new double sampling plans employing a compressed limit in the first stage of inspection were proposed to reduce the testing costs. These plans were designed for sanitary characteristics where the bacterial count generally fits a Poisson or a mixed-Poisson distribution. Both plans showed improved consumer protection with substantially smaller average sample size. The application of the new plans was validated using an empirical dataset of aerobic plate counts observed in milk powder samples. The new plans enabled a sample size reduction of between 20 and 75% compared to the actual sampling procedures.

In the recently published article, “Heterogeneous incidence and propagation of spreading depolarizations,” it is shown, in vivo and in vitro, how KCl-induced spreading depolarizations in mouse and rat brains can be highly variable, and that they are not limited, as once thought, to a concentric, isotropic, or homogenous depolarization wave in space or in time. The reported results serve as a link between the different species, and this paper contributes to changing the way in which SD expansion is viewed in the lissencephalic brain. Here, we discuss their results with our previous observations made in the gyrencephalic swine brain, in computer simulations, and in the human brain.

The main objective of this study was to generate a hemodynamically stable swine model to detect spreading depolarizations (SDs) using electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging and laser speckle flowmetry (LSF) after a 30-h middle cerebral artery (MCA) occlusion (MCAo) in German Landrace Swine. A total of 21 swine were used. The study comprised a training group (group 1, n = 7), a group that underwent bilateral craniectomy and MCAo (group 2, n = 10) and a group used for 2,3,5-triphenyltetrazolium (TTC) staining (group 3, n = 5). In group 2, nine animals that underwent MCAo survived for 30 h, and one animal survived for 12 h. We detected MCA variants with 2 to 4 vessels. In all cases, all of the MCAs were occluded. The intensity changes exhibited by IOS and LSF after clipping were closely correlated and indicated a lower blood volume and reduced blood flow in the middle cerebral artery territory. Using IOS, we detected a mean of 2.37 ± (STD) 2.35 SDs/h. Using ECoG, we detected a mean of 0.29 ± (STD) 0.53 SDs/h. Infarctions were diagnosed using histological analysis. TTC staining in group 3 confirmed that the MCA territory was compromised and that the anterior and posterior cerebral arteries were preserved. We confirm the reliability of performing live monitoring of cerebral infarctions using our MCAo protocol to detect SDs.

Spreading depolarization (SD) is a self-propagating wave of near-complete neuronal depolarization that is abundant in a wide range of neurological conditions, including stroke. SD was only recently documented in humans and is now considered a therapeutic target for brain injury, but the mechanisms related to SD in complex brains are not well understood. While there are numerous approaches to interventional imaging of SD on the exposed brain surface, measuring SD deep in brain is so far only possible with low spatiotemporal resolution and poor contrast. Here, we show that photoacoustic imaging enables the study of SD and its hemodynamics deep in the gyrencephalic brain with high spatiotemporal resolution. As rapid neuronal depolarization causes tissue hypoxia, we achieve this by continuously estimating blood oxygenation with an intraoperative hybrid photoacoustic and ultrasonic imaging system. Due to its high resolution, promising imaging depth and high contrast, this novel approach to SD imaging can yield new insights into SD and thereby lead to advances in stroke, and brain injury research.

Contains fulltext : 206372.pdf (Publisher’s version ) (Closed access) Observer variability in local radiological reading is a major concern in large-scale multi-center traumatic brain injury (TBI) studies. A central review process has been advocated to minimize this variability. The aim of this study is to compare central with local reading of TBI imaging datasets and to investigate the added value of central review. A total of 2050 admission computed tomography (CT) scans from subjects enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed for seven main CT characteristics. Kappa statistics were used to calculate agreement between central and local evaluations and a center-specific analysis was performed. The McNemar test was used to detect whether discordances were significant. Central interobserver and intra-observer agreement was calculated in a subset of patients. Good agreement was found between central and local assessment for the presence or absence of structural pathology (CT+, CT-, kappa = 0.73) and most CT characteristics (kappa = 0.62 to 0.71), except for traumatic axonal injury lesions (kappa = 0.37). Despite good kappa values, discordances were significant in four of seven CT characteristics (i.e., midline shift, contusion, traumatic subarachnoid hemorrhage, and cisternal compression; p = 0.0005). Central reviewers showed substantial to excellent interobserver and intra-observer agreement (kappa = 0.73 to kappa = 0.96), contrasted by considerable variability in local radiological reading. Compared with local evaluation, a central review process offers a more consistent radiological reading of acute CT characteristics in TBI. It generates reliable, reproducible data and should be recommended for use in multi-center TBI studies.

Haemodynamic responses to spreading depolarizations (SDs) have an important role during the development of secondary brain damage. Characterization of the haemodynamic responses in larger brains, however, is difficult due to movement artefacts. Intrinsic optical signal (IOS) imaging, laser speckle flowmetry (LSF) and electrocorticography were performed in different configurations in three groups of in total 18 swine. SDs were elicited by topical application of KCl or occurred spontaneously after middle cerebral artery occlusion. Movement artefacts in IOS were compensated by an elastic registration algorithm during post-processing. Using movement-compensated IOS, we were able to differentiate between four components of optical changes, corresponding closely with haemodynamic variations measured by LSF. Compared with ECoG and LSF, our setup provides higher spatial and temporal resolution, as well as a better signal-to-noise ratio. Using IOS alone, we could identify the different zones of infarction in a large gyrencephalic middle cerebral artery occlusion pig model. We strongly suggest movement-compensated IOS for the investigation of the role of haemodynamic responses to SDs during the development of secondary brain damage and in particular to examine the effect of potential therapeutic interventions in gyrencephalic brains.

The aim was to characterize the effects of magnesium sulfate, using i.v. bolus and local administration, using intrinsic signal imaging, and on electrocorticographic activity during the induction and propagation of spreading depolarizations in the gyrencephalic porcine brain. Local application of magnesium sulfate led to a complete inhibition of spreading depolarizations. One hour after washing out the topical magnesium sulfate, re-incidence of the spreading depolarizations was observed in 50% of the hemispheres. Those spreading depolarizations showed attenuation in hemodynamic characteristics and speed in intrinsic optical signal imaging. The electrical amplitude decreased through electrocorticographic activity. Intravenous magnesium therapy showed no significant effects on spreading depolarization incidence and characteristics.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit.

Objective Spreading depolarization (SD) occurs after traumatic brain injury, subarachnoid hemorrhage, malignant hemispheric stroke and intracranial hemorrhage. SD has been associated with secondary brain injury, which can be reduced by ketamine. In this present study frequency bands of electrocorticographic (ECoG) recordings were investigated with regards to SDs. Methods A total of 43 patients after acute brain injury were included in this retrospective and explorative study. Relative delta 0.5–4Hz, theta 4–8Hz, alpha 8–13Hz and beta 13–40Hz bands were analyzed with regards to SD occurrence and analgesic and sedative administration. Higher frequencies, including gamma 40–70Hz, fast gamma 70–100Hz and high frequency oscillations 100–200Hz were analyzed in a subset of patients with a sampling rate of up to 400Hz. Results A close association of relative beta frequency and SD was found. Relative beta frequency was suppressed up to two hours prior to SD when compared to hours with no SD. This finding was partially explained by administration of ketamine. Even after removal of all patient data during administration of ketamine, SDs occurred predominantly during times with low relative beta frequency in a patient-independent analysis. Conclusion Suppression of beta frequency by ketamine or without ketamine is associated with low SD counts. Significance Alteration of beta frequency might help to predict occurrence of SDs in acutely brain injured patients.

BACKGROUND: Disease progression and delayed neurological complications are common after aneurysmal subarachnoid hemorrhage (aSAH). We explored the potential of quantitative blood-brain barrier (BBB) imaging to predict disease progression and neurological outcome. METHODS: Data were collected as part of the Co-Operative Studies of Brain Injury Depolarizations (COSBID). We analyzed retrospectively, blinded and semi-automatically magnetic resonance images from 124 aSAH patients scanned at 4 time points (24–48 h, 6–8 days, 12–15 days and 6–12 months) after the initial hemorrhage. Volume of brain with apparent pathology and/or BBB dysfunction (BBBD), subarachnoid space and lateral ventricles were measured. Neurological status on admission was assessed using the World Federation of Neurosurgical Societies and Rosen-Macdonald scores. Outcome at ≥6 months was assessed using the extended Glasgow outcome scale and disease course (progressive or non-progressive based on imaging-detected loss of normal brain tissue in consecutive scans). Logistic regression was used to define biomarkers that best predict outcomes. Receiver operating characteristic analysis was performed to assess accuracy of outcome prediction models. FINDINGS: In the present cohort, 63% of patients had progressive and 37% non-progressive disease course. Progressive course was associated with worse outcome at ≥6 months (sensitivity of 98% and specificity of 97%). Brain volume with BBBD was significantly larger in patients with progressive course already 24–48 h after admission (2.23 (1.23–3.17) folds, median with 95%CI), and persisted at all time points. The highest probability of a BBB-disrupted voxel to become pathological was found at a distance of ≤1 cm from the brain with apparent pathology (0·284 (0·122–0·594), p

Spreading depolarization (SD) occurs alongside brain injuries and it can lead to neuronal damage. Therefore, pharmacological modulation of SD can constitute a therapeutic approach to reduce its detrimental effects and to improve the clinical outcome of patients. The major objective of this article was to produce a systematic review of all the drugs that have been tested against SD. Of the substances that have been examined, most have been shown to modulate certain SD characteristics. Only a few have succeeded in significantly inhibiting SD. We present a variety of strategies that have been proposed to overcome the notorious harmfulness and pharmacoresistance of SD. Information on clinically used anesthetic, sedative, hypnotic agents, anti-migraine drugs, anticonvulsants and various other substances have been compiled and reviewed with respect to the efficacy against SD, in order to answer the question of whether a drug at safe doses could be of therapeutic use against SD in humans.

ObjectiveTo investigate whether spreading depolarization (SD)-related variables at 2 different time windows (days 1–4 and 5–8) after aneurysmal subarachnoid hemorrhage (aSAH) correlate with the stereologically determined volume of early focal brain injury on the preinterventional CT scan.MethodsIn this observational multicenter study of 54 patients, volumes of unaffected brain tissue, ventricles, cerebellum, aSAH, intracerebral hemorrhage, and focal parenchymal hypodensity were stereologically estimated. Patients were electrocorticographically monitored using subdural electrodes for 81.8 hours (median) (interquartile range: 70.6–90.5) during days 1–4 (n = 54) and for 75.9 (59.5–88.7) hours during days 5–8 (n = 51). Peak total SD-induced depression duration of a recording day (PTDDD) and peak numbers of (1) SDs, (2) isoelectric SDs, and (3) spreading depressions of a recording day were determined following the recommendations of the Co-Operative Studies on Brain Injury Depolarizations.ResultsThirty-three of 37 patients with early focal brain injury (intracerebral hemorrhage and/or hypodensity) in contrast to 7 of 17 without displayed SDs during days 1–4 (sensitivity: 89% [95% confidence interval, CI: 75%–97%], specificity: 59% [CI: 33%–82%], positive predictive value: 83% [CI: 67%–93%], negative predictive value: 71% [CI: 42%–92%], Fisher exact test, p < 0.001). All 4 SD-related variables during days 1–4 significantly correlated with the volume of early focal brain injury (Spearman rank order correlations). A multiple ordinal regression analysis identified the PTDDD as the most important predictor.ConclusionsOur findings suggest that early focal brain injury after aSAH is associated with early SDs and further support the notion that SDs are a biomarker of focal brain lesions.

Background General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. Methods We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. Results The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36–40 mmHg (4.8–5.3 kPa) in case of controlled intracranial pressure (ICP)

Background: Disease progression and delayed neurological complications are common after aneurysmal subarachnoid hemorrhage (aSAH). We explored the potential of quantitative blood-brain barrier (BBB) imaging to predict disease progression and neurological outcome. Methods: Data were collected as part of the Co-Operative Studies of Brain Injury Depolarizations (COSBID). We analyzed retrospectively, blindly and semi-automatically magnetic resonance images from 124 aSAH patients scanned at 4 time points (24-48 h, 6-8 days, 12-15 days and 6-12 months) after the initial hemorrhage. Volume of brain with apparent pathology and BBB dysfunction (BBBD), subarachnoid space and lateral ventricles were measured. Neurological status on admission was assessed using the Fisher grades, World Federation of Neurosurgical Societies and Rosen-Macdonald (RMS) scores. Clinical outcome at 6 months or later was assessed using the extended Glasgow outcome scale. Findings: Based on repeated volumetric measures of pathological brain tissue and CSF, patients were categorized as having either progressive (increased pathology; 64%) or nonprogressive (36%) disease course. No differences were found between the two groups in aneurysm locations, neurological status on admission, initial brain pathology or treatment (coiling or clipping). Females were older and more likely to have a non-progressive course compared to males (p=0·01). Progressive course was associated with worse outcome at ≥6 months. A substantial brain volume with BBBD was found already 24-48 h after admission, and persisted at all time points. Brain volume with BBBD was significantly larger in patients with progressive course. BBBD increased the likelihood of a normal brain tissue to become pathological (p

OBJECT The pressure reactivity index (PRx) correlates with outcome after traumatic brain injury (TBI) and is used to calculate optimal cerebral perfusion pressure (CPPopt). The PRx is a correlation coefficient between slow, spontaneous changes (0.003–0.05 Hz) in intracranial pressure (ICP) and arterial blood pressure (ABP). A novel index—the so-called long PRx (L-PRx)—that considers ABP and ICP changes (0.0008–0.008 Hz) was proposed. METHODS The authors compared PRx and L-PRx for 6-month outcome prediction and CPPopt calculation in 307 patients with TBI. The PRx- and L-PRx–based CPPopt were determined and the predictive power and discriminant abilities were compared. RESULTS The PRx and L-PRx correlation was good (R = 0.7, p < 0.00001; Spearman test). The PRx, age, CPP, and Glasgow Coma Scale score but not L-PRx were significant fatal outcome predictors (death and persistent vegetative state). There was a significant difference between the areas under the receiver operating characteristic curves calculated for PRx and L-PRx (0.61 ± 0.04 vs 0.51 ± 0.04; z-statistic = −3.26, p = 0.011), which indicates a better ability by PRx than L-PRx to predict fatal outcome. The CPPopt was higher for L-PRx than for PRx, without a statistical difference (median CPPopt for L-PRx: 76.9 mm Hg, interquartile range [IQR] ± 10.1 mm Hg; median CPPopt for PRx: 74.7 mm Hg, IQR ± 8.2 mm Hg). Death was associated with CPP below CPPopt for PRx (χ2 = 30.6, p < 0.00001), and severe disability was associated with CPP above CPPopt for PRx (χ2 = 7.8, p = 0.005). These relationships were not statistically significant for CPPopt for L-PRx. CONCLUSIONS The PRx is superior to the L-PRx for TBI outcome prediction. Individual CPPopt for L-PRx and PRx are not statistically different. Deviations between CPP and CPPopt for PRx are relevant for outcome prediction; those between CPP and CPPopt for L-PRx are not. The PRx uses the entire B-wave spectrum for index calculation, whereas the L-PRX covers only one-third of it. This may explain the performance discrepancy.

Objectives The detection of the hemodynamic and propagation patterns of spreading depolarizations (SDs) in the gyrencephalic brain using intrinsic optical signal imaging (IOS). Methods The convexity of the brain surface was surgically exposed in fourteen male swine. Within the boundaries of this window, brains were immersed and preconditioned with an elevated K+ concentration (7 mmol/l) in the standard Ringer lactate solution for 30–40 min. SDs were triggered using 3–5 μl of 1 mol/l KCl solution. Changes in tissue absorbency or reflection were registered with a CCD camera at a wavelength of 564 nm (14 nm FWHM), which was mounted 25 cm above the exposed cortex. Additional monitoring by electrocorticography and laser-Doppler was used in a subset of animals (n = 7) to validate the detection of SD. Results Of 198 SDs quantified in all of the experiments, 187 SDs appeared as radial waves that developed semi-planar fronts. The morphology was affected by the surface of the gyri, the sulci and the pial vessels. Other SD patterns such as spirals and reverberating waves, which have not been described before in gyrencephalic brains, were also observed. Diffusion gradients created in the cortex surface (i.e., KCl concentrations), sulci, vessels and SD–SD interactions make the gyrencephalic brain prone to the appearance of irregular SD waves. Conclusion The gyrencephalic brain is capable of irregular SD propagation patterns. The irregularities of the gyrencephalic brain cortex may promote the presence of re-entrance waves, such as spirals and reverberating waves.

La despolarizacion cortical extendida (cortical spreading depolarization en ingles) es una onda de despolarizacion casi completa de las celulas neuronales y de la glia acoplada a una respuesta de vasoconstriccion y dilatacion vascular que ocurre en la migrana con aura, la hemorragia subaracnoidea, la hemorragia intracerebral, el traumatismo craneoencefalico y el ictus isquemico. Estas ondas de despolarizacion se caracterizan por un cambio de potencial negativo con una amplitud de entre -10 a -30 mV, una duracion de ~1 min y cambios en la homeostasis ionica cerebral intracelular y extracelular. Bajo situaciones patologicas de hipoperfusion estas ondas despolarizantes pueden conducir a estres oxidativo, agravamiento de estados hipoxicos y muerte neuronal debido a vasoconstriccion arterial intensa causada por una repuesta hemodinamica inversa, fenomeno denominado isquemia extendida (spreading ischemia). En los ultimos anos se ha podido confirmar electrofisiologicamente la presencia de estas ondas despolarizantes propagandose en el cerebro humano y se ha visto una asociacion entre su incidencia y el deterioro neurologico. Actualmente se esta recogiendo evidencia clinica que apoya no solo su coexistencia con el dano neuronal, sino su causalidad. Existen medidas terapeuticas probadas en laboratorio que podrian reducir los efectos de este elemento fisiopatologico en el dano cerebral

To evaluate an intraparenchymal probe for intracranial pressure (ICP) and temperature (TEMP) monitoring as well as determination of cerebral hemodynamics using a near-infrared spectroscopy (NIRS) and indocyanine green (ICG) dye dilution method (NIRS-ICP probe).The NIRS-ICP probe was applied after aneurysmal subarachnoid hemorrhage if multimodal monitoring was established due to poor neurological condition. ICP and TEMP values were obtained from ventricular catheters and systemic temperature sensors. Repeated NIRS-ICG measurements (2 injections within 30 min) were performed daily for determination of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time of ICG (mttICG). Secondary neurologic dysfunction was defined as brain tissue oxygen tension20 mmHg and/or lactate/pyruvate ratio35 obtained from cerebral probing.A total of 128 NIRS-ICG measurements were performed in ten patients. The correlation coefficients between ICP and TEMP values obtained with the NIRS-ICP probe and values from routine monitoring were r = 0.72 and r = 0.96, respectively. The mean values were 30.3 ± 13.6 ml/100 g/min for CBF, 3.3 ± 1.2 ml/100 g for CBV, and 6.8 ± 1.6 s for mttICG. The coefficients of variation from repeated NIRS-ICG measurements were 10.9 % for CBF, 11.7 % for CBV, and 3.8 % for mttICG. The sensitivity for detection of secondary neurologic dysfunction was 85 % and the specificity 83 % using a CBF-threshold of 25 ml/100 g/min.Multimodal monitoring using the NIRS-ICP probe is feasible with high reproducibility of measurement values and the ability to detect secondary neurologic dysfunction. No safety concerns exist for the routine clinical use of the NIRS-ICP probe.

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

This study investigates the outcome prediction and calculation of optimal cerebral perfusion pressure (CPPopt) in 307 patients after severe traumatic brain injury (TBI) based on cerebrovascular reactivity calculation of a moving correlation correlation coefficient, named PRx, between mean arterial pressure (ABP) and intracranial pressure (ICP). The correlation coefficient was calculated from simultaneously recorded data using different frequencies. PRx was calculated from oscillations between 0.008 and 0.05Hz and the longPRx (L-PRx) was calculated from oscillations between 0.0008 and 0.016 Hz. PRx was a significant mortality predictor, whereas L-PRx was not. CPPopt for pooled data was higher for L-PRx than for PRx, with no statistical difference. Mortality was associated with mean CPP below CPPopt. Severe disability was associated with CPP above CPPopt (PRx). These relationships were not statistically significant for CPPopt (L-PRx). We conclude that PRx and L-PRx cannot be used interchangeably.

Cerebral autoregulation and, consequently, cerebrovascular pressure reactivity, can be disturbed after traumatic brain injury (TBI). Continuous monitoring of autoregulation has shown its clinical importance as an independent predictor of neurological outcome. The cerebral pressure reactivity index (PRx) reflects that changes in seconds of cerebrovascular reactivity have prognostic significance. Using an alternative algorithm similar to PRx, we investigate whether the utilization of lower-frequency changes of the order of minutes of mean arterial blood pressure (MAP) and intracranial pressure (ICP) could have a prognostic value in TBI patients.Head-injured patients requiring continued advanced multimodal monitoring, including hemodynamic, ICP and microdialysis (MD) monitoring, were analyzed retrospectively. A low-frequency sample pressure reactivity index (L-PRx) was calculated, using 20-min averages of MAP and ICP data as a linear Pearson's correlation. The mean values per patient were correlated to outcome at 6 months after injury. Differences of monitoring parameters between non-survivors and survivors were compared.A total of 29 patients (mean age 37.2 years, 26 males) suffering from TBI were monitored for a mean of 109.6 h (16-236 h, SD ± 60.4). Mean L-PRx was found to be of 0.1 (-0.2 to 0.6, SD ± 0.20), six patients presented impaired (0.2) values. The averaged L-PRx correlated significantly with ICP (r = 0.467, p = 0.011) and 6-month outcome (r = -0.556, p = 0.002). Significant statistical differences were found in L-PRx, cerebral perfusion pressure (CPP), lactate, and lactate-pyruvate ratio when comparing patients who died (n = 5) and patients who survived.L-PRx correlates with the 6-month outcome in TBI patients. Very slow changes of MAP and ICP may contain important autoregulation information. L-PRx may be an alternative algorithm for the estimation of cerebral autoregulation and clinical prognosis.

Introduction Cortical spreading depressions (CSDs) are waves of near-complete cellular depolarization that spread slowly across the cortical surface (2–5 mm/min) and result in transient loss of cell signaling capabilities. CSDs is a biomarker of neuronal damage described in several clinical hypoxic-ischemic conditions However, only has been found in one patient operated for Giant pituitary adenoma. Methods This is a prospective study that included adult patients undergoing elective craniotomy for epileptogenic supratentorial lesions lasting >2 h. Electrocorticographic recordings were obtained from time of dural opening through the time of dural closure, using a standard 1 × 8 silver electrode coupled with a full-spectrum DC amplifier (0–45 Hz, Notch: 60 Hz). We analyzed the clinical and socio-demographic characteristics. The data were processed using the COSBID research group methodology to evaluate for slow potential changes coupled with suppression of high-frequency ECoG propagating across the electrodes. Describe statistics were used. Results We included 16 patients, mean age 37 (19–75) years-old, 50% male, underwent 4 callosotomies and 12 temporal lesionectomies (3 cortical dysplasia, 2 cavernomas, 5 gliomas and 2 dermoid cystic). All the patients had history of symptomatic epilepsy and none had postsurgical complications and only 2 patients post-callosotomy continued with seizures at 6 months of follow-up. We didn’t find any CSD during these neurosurgeries. Conclusion CSDs were absent during lesional epilepsy surgery. Future studies are needed to confirm these findings.

Study Objective Recent experimental evidence identified GABAergic sedation as a possible cause for deprived neuroregeneration and poor outcome after acute brain injury. Patients with aneurysmal subarachnoid hemorrhage are often sedated, and GABAergic sedation, such as midazolam and propofol, is commonly used. Design Retrospective cohort study based on a prospectively established database. Setting Single-center neurointensive care unit. Patients Twenty-nine patients after subarachnoid hemorrhage. Intervention Noninterventional study. Measurements The relationship between mean GABAergic sedative dose during the acute phase and outcome after 6 months according to the Glasgow Outcome Scale, and initial Glasgow Coma Scale was investigated. Main Results Use of GABAergic sedatives was negatively correlated with Glasgow Outcome Scale ( r 2 =0.267; P =.008). Administration of sedatives was independent of the initial Glasgow Coma Scale. GABAergic sedatives flunitrazepam, midazolam, and propofol were used differently during the first 10 days after ictus. Conclusion Administration of GABAergic sedation was associated with an unfavorable outcome after 6 months. To avoid bias (mainly through the indication to use sedation), additional experimental and comparative clinical investigation of, for example, non-GABAergic sedation, and clinical protocols of no sedation is necessary.

BACKGROUND Disturbed brain metabolism is a signature of primary damage and/or precipitates secondary injury processes after severe brain injury. Sedatives and analgesics target electrophysiological functioning and are as such well-known modulators of brain energy metabolism. Still unclear, however, is how sedatives impact glucose metabolism and whether they differentially influence brain metabolism in normally active, healthy brain and critically impaired, injured brain. We therefore examined and compared the effects of anesthetic drugs under both critical ( 1 mmol/L) extracellular brain glucose levels. METHODS We performed an explorative, retrospective analysis of anesthetic drug administration and brain glucose concentrations, obtained by bedside microdialysis, in 19 brain-injured patients. RESULT Our investigations revealed an inverse linear correlation between brain glucose and both the concentration of extracellular glutamate (Pearson r=-0.58, P=0.01) and the lactate/glucose ratio (Pearson r=-0.55, P=0.01). For noncritical brain glucose levels, we observed a positive linear correlation between midazolam dose and brain glucose (P

Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization that propagates across the cerebral cortex and has been implicated in the pathophysiology of brain injury states and migraine with aura. Analgesics and sedatives seem to have a significant effect on SD modulation. Studies have shown that ketamine, an NMDA receptor blocker, has the capacity to influence SD occurrence. The aim of this study was to analyze the dose-dependent effect of ketamine on SD susceptibility through electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging in a gyrencephalic brain. Ketamine in a low-dose infusion (2 mg/kg/h) decreases SD spread and had an effect on the amplitude of SD deflections, as well as on duration, and speed. Moreover, during ketamine infusion at this dose, there was a sustained decrease in the hyperemic response following SD. However, a high-dose infusion (4 mg/kg/h) of ketamine inhibited SD induction and expansion. Furthermore, a high-dose bolus (4 mg/kg), 1 min after stimulation, blocked SD propagation abruptly within 1-2 min, and hindered SD induction and expansion for the following 15-30 min. The results suggest that ketamine may be therapeutically beneficial in preventing SDs. Nonetheless, an adequate dosage and way of administration should be considered and established for human use.

Background: The role of decompressive craniectomy (DC) in aneurysmal subarachnoid hemorrhage (aSAH) patients is still controversial. In this study we evaluated the effect of DC for aSAH patients. Methods: A matched-pair analysis was performed to compare the outcomes of patients with DC to those of patients without DC. Among 295 consecutive aSAH patients, 56 required DC. Of the remaining group, 56 matched controls were found. The match was conducted on the basis of epidemiological and potential prognostic factors, such as age, gender, World Federation of Neurosurgical Societies (WFNS) grade, Fisher group and occurrence of vasospasm. Results: Fifty-four of 56 (96.4%) patients with DC were dependent or dead at 1 month, compared with 49 of 56 (87.5%) without DC. There was no significant difference between the groups (p = 0.16). One-year outcomes were available for 108 patients (96.4%). Thirty-nine of 54 (72.2%) patients treated with DC were dependent or dead at 1 year, compared with 30 of 54 (55.6%) patients in the control group. There was no significant difference between the groups (p = 0.11). This result was unaffected by age, sex and WFNS grade. Subgroup analyses whether DC was performed primarily or delayed, and whether DC was performed due to spasm, hematoma or vessel occlusion failed to detect any significant difference. Conclusion: There was no significant advantage for patients treated with DC, but more than 25% achieved a good long-term outcome. While the value of DC is deemed uncertain, it may be effective for a very specific subset of aSAH patients. Further comparative studies are needed to resolve this matter.

Objective: The aim of this study was to co-record electrical changes using electrocorticography (ECoG) and blood volume changes using intrinsic optical signal (IOS) imaging during the induction, propagation, and termination of cortical spreading depolarizations (CSDs).

Background and Purpose— We studied the dynamics of extracellular brain tissue concentrations of glucose, lactate, pyruvate, and glutamate during the occurrence of spreading depolarizations (SDs) in patients with aneurysmal subarachnoid hemorrhage. Methods— In this prospective observational study, patients with aneurysmal subarachnoid hemorrhage received multimodal cerebral monitoring, including intracranial pressure, cerebral microdialysis, and subdural electrocorticography. Results— Seven of the 17 recruited patients had intracerebral hemorrhage, acute ischemia and severe brain oedema leading to acute ischemic neurological deficits associated with early disturbance of metabolism at the recording site. They displayed a total of 130 SDs. The remaining 10 patients without acute ischemic neurological deficits exhibited 138 single SDs and 68 SDs in clusters. In patients without acute ischemic neurological deficits, clustered SDs were associated with a significant transient decrease in glucose and increase in lactate compared with baseline during the first 140 minutes after SDs. Moreover, the number of clustered SDs correlated with the outcome ( R =−0.659; P Conclusion— SDs can propagate in nonischemic human brain tissue. Clusters of SDs are related to metabolic changes suggestive of ongoing secondary damage in primarily nonischemic brain tissue.

Subarachnoid hemorrhage (SAH) is a devastating disease associated with death and poor functional outcome. Despite decades of intense research and improvements in clinical management, delayed cerebral ischaemia (DCI) remains the most important cause of morbidity and mortality after SAH. The key role of angiographic cerebral vasospasm, thought to be the main cause of DCI, has been questioned. Emerging evidence suggests that DCI is likely to have a multifactorial etiology. Over the last few years, spreading depolarization (SD) has been identified as a potential pathophysiological mechanism contributing to DCI. The presence of cortical spreading ischaemia, due to an inverse hemodynamic response to SD, offers a possible explanation for DCI and requires more intensive research. Understanding the role of SD as another mechanism inducing DCI and its relationship with other pathological factors could instigate the development of new approaches to the diagnosis and treatment of DCI in order to improve the clinical outcome.

Non-traumatic subarachnoid hemorrhage (SAH) represents about 5 to 6% of the overall incidence of stroke and is associated with high morbidity and mortality. Despite the substantial research and clinical efforts, delayed cerebral ischemia (DCI) is still the major complication after SAH and represents an important factor for severe neurological deficits. Cerebral vasospasm (VSP) has been recognised for a long time as an important underlying pathophysiologic cause of DCI, but it is now clearer that the mechanisms underlying DCI are multifactorial. Among other pathomechanisms proposed, ischemia-producing cortical spreading depolarizations (CSDs) are likely to be involved in DCI development. Understanding the plethora of different pathophysiological derangements after SAH is very important for the development of new therapies, in order to abolish secondary ischemic brain injuries early-on and improve patients’ outcome. In this review, we strive to summarise the mechanisms and therapeutic developments of DCI.

The pathogenesis of delayed cerebral ischemia (DCI) is multifactorial and not completely elucidated. Our objective was to determine if episodes of spreading depolarization (SD) are reflected in compromised levels of extracellular glucose monitored by bedside microdialysis (MD) in aneurysmal subarachnoid hemorrhage (aSAH) patients. Patients with aSAH, prospectively included in the COSBID (CoOperative Study on Brain Injury Depolarisations) protocol (Berlin, Heidelberg), had hourly monitoring of cerebral glucose by MD and in parallel electrocorticographic (ECoG) monitoring for SD detection on day of admission until days 10–14 after aSAH. Cerebral MD probes were placed in the vascular territory at risk for DCI. Twenty-one aSAH patients (53.3 ± 9.1 years; mean ± standard deviation), classified according to the World Federation of Neurosurgical Societies (WFNS) in low (I–III, 11) and high (IV–V, 10) grades, were studied. Of these, 13 patients (62%) presented with DCI. Median glucose was 1.48 (0.00–8.79). Median occurrence of SD was 7 (0–66)/patients. High WFNS grade (WFNS grades IV–V) patients had more SDs (p = 0.027), while the overall glucose level did not differ. In high-grade SAH patients, SDs were more frequent. Individually, the occurrence of SD was not linked to local deviations (neither high nor low) from the LOWESS (locally weighted scatterplot smoothing) trend curve for extracellular glucose concentrations. Rapid-sampling MD techniques and analyses of SD clusters may elucidate more detail of the relationship between SD and brain energy metabolism.

Background: Cortical spreading depolarization (CSD) has been implicated in the pathophysiology of migraine with aura. Patients that suffer from this type of migraine have shown a higher risk of developing an ischaemic stroke. Case: A 42-year-old female exhibited reoccurring migraine attacks for the first time 1 month before suffering an ischaemic infarction. Imaging studies revealed an occlusion in the right middle cerebral artery. Other possible disorders were excluded. It was possible to register 20 CSDs, of which 12 coincided with high levels of glutamate and lactate/pyruvate ratio. Loss of electrocorticographic activity was observed for 89 hours after the 8th depolarization. Conclusions: Migraine with aura symptoms may be induced by CSDs triggered by hypoperfusion states. Our case supports the idea of the migraine with aura–stroke continuum.

Objectives: To evaluate whether cortical spreading depolarizations (CSD) occur in the early stage after cortical intracerebral hemorrhage (ICH).

Objective: We correlated oxygen, flow, and pressure indices of cerebrovascular reactivity (CR) with extracellular cerebral metabolite concentrations in a porcine model of intracerebral hemorrhage (ICH).

The cerebral pressure reactivity index (PRx) correlates with the outcome in intracerebral haemorrhage (ICH) patients and has been used to define an autoregulation-oriented “optimal cerebral perfusion pressure” (CPPopt). PRx has been calculated as a moving correlation coefficient between mean arterial pressure (MAP) and intracranial pressure (ICP) averaged over 5-10 s, using a 2.5- to 5-min moving time window, in order to reflect changes in MAP and ICP within a time frame of 20 s to 2 min. We compared PRx with a different calculation method [low-frequency PRx (L-PRx)], where rapid fluctuations of MAP and ICP are cancelled (waves with frequencies greater than 0.01 Hz). A total of 548.5 h of artefact-free data (sampling frequency 1 Hz) from 18 patients suffering from non-traumatic ICH were included in the analysis. L-PRx was calculated using minute averages, between both MAP and ICP, in 20-min moving correlation windows. CPPopt was calculated based on PRx and on L-PRx. The averaged PRx values for each patient correlated with L-PRx (P = 0.846, p