A Solution to the Cerebral Perfusion Pressure Transducer Placement Conundrum in Neurointensive Care? The Dual Transducer.

Intracranial pressure is routinely monitored in most intensive care units caring for patients with severe neurological insults and, together with continuous arterial blood pressure measurement, allows for monitoring of cerebral perfusion pressure (CPP). CPP is the driving pressure of blood flow to the brain and is used to guide therapy. However, there is considerable inconsistency in the literature regarding how CPP is technically measured and, more specifically, the appropriate placement of the arterial pressure transducer. Depending on patient positioning and where the arterial pressure transducer is placed, the mean arterial pressure used for CPP calculation can vary widely by up to 15 mm Hg, which is greater than the acceptable variation in target ranges used clinically. Physiologically, the arterial pressure transducer should be placed at the level of the foramen of Monro for CPP measurement, but it is commonly set at the level of the right atrium for systematic measurement. Mean arterial pressure measurement at the level of the right atrium can lead to overestimation and potentially critically low actual CPP levels when the head is elevated, and measurement at the level of the foramen of Monro will underestimate systemic pressures, increasing the risk of excessive and unnecessary use of vasopressors and fluid. At the Karolinska University Hospital neurointensive care unit, we have used a split dual-transducer system, measuring arterial pressure both at the level of the foramen of Monro and at the level of the right atrium from a single arterial source. In doing so, we work with constants and can monitor and target optimum arterial pressures to better secure perfusion to all organs, with potentially less risk of cerebral ischemia or overuse of vasopressors and fluids, which may affect outcome.

Absolute Contusion Expansion Is Superior to Relative Expansion in Predicting Traumatic Brain Injury Outcomes: A Multi-Center Observational Cohort Study.

Contusion expansion (CE) is a potentially treatable outcome predictor in traumatic brain injury (TBI), and a suitable end-point for hemostatic therapy trials. However, there is no consensus on the definition of clinically relevant CE, both in terms of measurement criteria (absolute vs. relative volume increase) and cutoff values. In light of this, the aim of this study was to assess the predictive abilities of different CE definitions on outcome. We performed a multi-center observational cohort study of adults with moderate-to-severe TBI treated in an intensive care unit. The exposure of interest was CE, defined as the absolute and relative volume change between the first and second computed tomography scan. The primary outcome was the Glasgow Outcome Scale (GOS) at 6-12 months post-injury, dichotomized into unfavorable (GOS ≤3) or favorable (GOS ≥4). The secondary outcome was all-cause mortality. In total, 798 patients were included, with a median duration of 7.0 h between the first and second CT scan. The median absolute and relative CE was 1.5 mL (interquartile range [IQR] 0.1-8.3 mL) and 100% (IQR 10-530%), respectively. Both CE forms were independently associated with unfavorable GOS. Absolute CE outperformed relative CE in predicting both unfavorable GOS (area under the curve [AUC]: 0.65 vs. 0.60, p = 0.002) and all-cause mortality (AUC: 0.66 vs. 0.60, p = 0.003). For dichotomized CE, absolute cutoffs of 1-10 mL yielded the best results. We conclude that absolute CE demonstrates stronger outcome correlation than relative CE. In studies focusing on lesion progression in TBI, it may be advantageous to use absolute CE as the primary outcome metric. For dichotomized outcomes, cutoffs between 1 and 10 mL are suggested, depending on the desired sensitivity-specificity balance.

Increased Incidence and Mortality of Civilian Penetrating Traumatic Brain Injury in Sweden: A Single-Center Registry-Based Study.

BACKGROUND: Penetrating trauma to the head and neck has increased during the past decade in Sweden. The aim of this study was to characterize these injuries and evaluate the outcomes for patients treated at a tertiary trauma center. METHODS: Swedish trauma registry data were extracted on patients with head and neck injuries admitted to Karolinska University Hospital (Stockholm, Sweden) between 2011 and 2019. Outcome information was extracted from hospital records, with the primary endpoints focusing on the physiological outcome measures and the secondary endpoints on the surgical and radiological outcomes. RESULTS: Of 1436 patients with penetrating trauma, 329 with penetrating head and neck injuries were identified. Of the 329 patients, 66 (20%) had suffered a gunshot wound (GSW), 240 (73%) a stab wound (SW), and 23 (7%) an injury from other trauma mechanisms (OTMs). The median age for the corresponding 3 groups of patients was 25, 33, and 21 years, respectively. Assault was the primary intent, with 54 patients experiencing GSWs (81.8%) and 158 SWs (65.8%). Patients with GSWs had more severe injuries, worse admission Glasgow coma scale, motor, scores, and a higher intubation rate at the injury site. Most GSW patients underwent major surgery (59.1%) as the initial procedure and were more likely to have intracranial hemorrhage (21.2%). The 30-day mortality was 45.5% (n = 30) for GSWs, 5.4% (n = 13) for SWs, and 0% (n = 0) for OTMs. There was an annual increase in the incidence and mortality for GSWs and SWs. CONCLUSIONS: Between 2011 and 2019, an increasing annual trend was found in the incidence and mortality from penetrating head and neck trauma in Stockholm, Sweden. GSW patients experienced more severe injuries and intracranial hemorrhage and underwent more surgical interventions compared with patients with SWs and OTMs.

Extracellular vesicles in plasma and cerebrospinal fluid in patients with COVID-19 and neurological symptoms.

INTRODUCTION: Increased levels of extracellular vesicles (EVs) are associated with haemostatic disturbances in various clinical settings. However, their role in COVID-19 patients is still not fully clear. In the present study we investigated EVs in plasma from patients with COVID-19 and neurological symptoms in relation to the activation of coagulation. METHODS: Nineteen COVID-19 patients with neurological symptoms and twenty-three aged-matched healthy individuals were included. Global coagulation assays were performed and levels of EVs were determined by flow-cytometry in plasma and cerebrospinal fluid (CSF). RESULTS: A procoagulant state characterized by significantly increased overall coagulation- (OCP) and overall haemostatic potential (OHP), diminished overall fibrinolytic potential (OFP) together with a denser fibrin structure was found in patients with COVID-19. Flow cytometry revealed elevated levels of plasma circulating EVs derived from neutrophils (MPO+) and platelets (CD61+), as well as EVs expressing phosphatidylserine (PS+) and complement component C5b-9 (TCC+) in patients with COVID-19 compared with controls. The concentrations of PS+, CD61+ and TCC+ EVs were positively correlated with OCP and OHP in COVID-19 patients. Moreover, we identified CD61+, MPO+ and endothelial cell-derived EVs, as well as EVs exposing PS and TCC in the CSF of patients suffering from neurological symptoms during COVID-19. CONCLUSION: The unique finding in this study was the presence of EVs in the CSF of COVID-19 patients with neurologic manifestations as well as higher expression of complement protein on circulating plasma EVs. EVs may indicate blood-brain barrier damage during SARS-COV-2 infection.

Time-Dependent Changes in the Biofluid Levels of Neural Injury Markers in Severe Traumatic Brain Injury Patients-Cerebrospinal Fluid and Cerebral Microdialysates: A Longitudinal Prospective Pilot Study.

Monitoring protein biomarker levels in the cerebrospinal fluid (CSF) can help assess injury severity and outcome after traumatic brain injury (TBI). Determining injury-induced changes in the proteome of brain extracellular fluid (bECF) can more closely reflect changes in the brain parenchyma, but bECF is not routinely available. The aim of this pilot study was to compare time-dependent changes of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), total Tau, and phosphorylated Tau (p-Tau) levels in matching CSF and bECF samples collected at 1, 3, and 5 days post-injury from severe TBI patients (n = 7; GCS 3-8) using microcapillary-based western analysis. We found that time-dependent changes in CSF and bECF levels were most pronounced for S100B and NSE, but there was substantial patient-to-patient variability. Importantly, the temporal pattern of biomarker changes in CSF and bECF samples showed similar trends. We also detected two different immunoreactive forms of S100B in both CSF and bECF samples, but the contribution of the different immunoreactive forms to total immunoreactivity varied from patient to patient and time point to time point. Our study is limited, but it illustrates the value of both quantitative and qualitative analysis of protein biomarkers and the importance of serial sampling for biofluid analysis after severe TBI.

[Treatment of traumatic brain injury in the acute setting - An overview]. / Modern handläggning minimerar följder av traumatisk hjärnskada.

Traumatic brain injury (TBI) is the leading cause of death among the young, and has an increasing incidence among the elderly. In Sweden there are 20 000 new TBI cases each year, of which most are mild. The primary impact can lead to different types of brain hemorrhages, fractures and diffuse axonal injuries. The level of consciousness is used to define injury severity. Of all TBIs,  4-5 percent require surgical intervention. The primary impact initiates injury processes exacerbating the initial brain injury, and the goal of the acute management and neurointensive care treatment is to prevent these secondary insults. Among unconscious TBI patients, monitoring of intracranial pressure and cerebral perfusion pressure (CPP, defined as the difference between the mean arterial pressure and intracranial pressure) is routine. In this article we present an overview on different types of TBI, and describe the treatment of patients in the acute setting.

Time Course and Clinical Significance of Hematoma Expansion in Moderate-to-Severe Traumatic Brain Injury: An Observational Cohort Study.

BACKGROUND: Preventing intracranial hematoma expansion has been advertised as a possible treatment opportunity in traumatic brain injury (TBI). However, the time course of hematoma expansion, and whether the expansion affects outcome, remains poorly understood. In light of this, the aim of this study was to use 3D volume rendering to determine how traumatic intracranial hematomas expand over time and evaluate its impact on outcome. METHODS: Single-center, population-based, observational cohort study of adults with moderate-to-severe TBI. Hematoma expansion was defined as the change in hematoma volume from the baseline computed tomography scan until the lesion had stopped progressing. Volumes were calculated by using semiautomated volumetric segmentation. Functional outcome was measured by using the 12 month Glasgow outcome scale (GOS). RESULTS: In total, 643 patients were included. The mean baseline hematoma volume was 4.2 ml, and the subsequent mean hematoma expansion was 3.8 ml. Overall, 33% of hematomas had stopped progressing within 3 h, and 94% of hematomas had stopped progressing within 24 h of injury. Contusions expanded significantly more, and for a longer period of time, than extra-axial hematomas. There was a significant dose-response relationship between hematoma expansion and 12 month GOS, even after adjusting for known outcome predictors, with every 1-ml increase in hematoma volume associated with a 6% increased risk of 1-point GOS deduction. CONCLUSIONS: Hematoma expansion is a driver of unfavorable outcome in TBI, with small changes in hematoma volume also impacting functional outcome. This study also proposes a wider window of opportunity to prevent lesion progression than what has previously been suggested.

A prospective clinical study on the mechanisms underlying critical illness myopathy-A time-course approach.

BACKGROUND: Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive. METHODS: Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. RESULTS: (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma. CONCLUSIONS: The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

Clinical Significance of Vascular Occlusive Events following Moderate-to-Severe Traumatic Brain Injury: An Observational Cohort Study.

Preventing hemorrhage progression is a potential therapeutic opportunity in traumatic brain injury (TBI) management, but its use has been limited by fear of provoking vascular occlusive events (VOEs). However, it is currently unclear whether VOE actually affects outcome in these patients. The aim of this study was to determine incidence, risk factors, and clinical significance of VOE in patients with moderate-to-severe TBI. A retrospective observational cohort study of adults (≥15 years) with moderate-to-severe TBI was performed. The presence of a VOE during hospitalization was noted from hospital charts and radiological reports. Functional outcome, using the Glasgow Outcome Scale (GOS), was assessed at 12 months posttrauma. Univariate and multivariate logistic regressions were used for endpoint assessment. In total, 848 patients were included, with a median admission Glasgow Coma Scale of 7. A VOE was detected in 54 (6.4%) patients, of which cerebral venous thrombosis was the most common (3.2%), followed by pulmonary embolism (1.7%) and deep vein thrombosis (1.3%). Length of ICU stay (p < 0.001), body weight (p = 0.002), and skull fracture (p = 0.004) were independent predictors of VOE. VOE development did not significantly impact 12-month GOS, even after adjusting for potential confounders using propensity score matching. In conclusion, VOE in moderate-to-severe TBI patients was relatively uncommon, and did not affect 12-month GOS. This suggests that the potential benefit of treating bleeding progression might outweigh the risks of VOE.

Extended Analysis of Axonal Injuries Detected Using Magnetic Resonance Imaging in Critically Ill Traumatic Brain Injury Patients.

Studies show conflicting results regarding the prognostic significance of traumatic axonal injuries (TAI) in patients with traumatic brain injury (TBI). Therefore, we documented the presence of TAI in several brain regions, using different magnetic resonance imaging (MRI) sequences, and assessed their association to patient outcomes using machine learning. Further, we created a novel MRI-based TAI grading system with the goal of improving outcome prediction in TBI. We subsequently evaluated the performance of several TAI grading systems. We used a genetic algorithm to identify TAI that distinguish favorable from unfavorable outcomes. We assessed the discriminatory performance (area under the curve [AUC]) and goodness-of-fit (Nagelkerke pseudo-R2) of the novel Stockholm MRI grading system and the TAI grading systems of Adams and associates, Firsching and coworkers. and Abu Hamdeh and colleagues, using both univariate and multi-variate logistic regression. The dichotomized Glasgow Outcome Scale was considered the primary outcome. We examined the MRI scans of 351 critically ill patients with TBI. The TAI in several brain regions, such as the midbrain tegmentum, were strongly associated with unfavorable outcomes. The Stockholm MRI grading system exhibited the highest AUC (0.72 vs. 0.68-0.69) and Nagelkerke pseudo-R2 (0.21 vs. 0.14-0.15) values of all TAI grading systems. These differences in model performance, however, were not statistically significant (DeLong test, p > 0.05). Further, all included TAI grading systems improved outcome prediction relative to established outcome predictors of TBI, such as the Glasgow Coma Scale (likelihood-ratio test, p < 0.001). Our findings suggest that the detection of TAI using MRI is a valuable addition to prognostication in TBI.

Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood-brain barrier disruption and outcome prediction following severe traumatic brain injury: a prospective, observational study.

BACKGROUND: Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls. METHODS: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6-12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (QA), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort. RESULTS: TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with QA, among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR2 = 7.4%) and complement factor B in serum (p = 0.003, ΔR2 = 9.2%) were independent outcome predictors also following step-down modelling. CONCLUSIONS: This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.

Time Course of Hemostatic Disruptions After Traumatic Brain Injury: A Systematic Review of the Literature.

Almost two-thirds of patients with severe traumatic brain injury (TBI) develop some form of hemostatic disturbance, which contributes to poor outcome. While the initial head injury often leads to impaired clot formation, TBI is also associated with an increased risk of thrombosis. Most likely there is a progression from early bleeding to a later prothrombotic state. In this paper, we systematically review the literature on the time course of hemostatic disruptions following TBI. A MEDLINE search was performed for TBI studies reporting the trajectory of hemostatic assays over time. The search yielded 5,049 articles, of which 4,910 were excluded following duplicate removal as well as title and abstract review. Full-text assessment of the remaining articles yielded 33 studies that were included in the final review. We found that the first hours after TBI are characterized by coagulation cascade dysfunction and hyperfibrinolysis, both of which likely contribute to lesion progression. This is then followed by platelet dysfunction and decreased platelet count, the clinical implication of which remains unclear. Later, a poorly defined prothrombotic state emerges, partly due to fibrinolysis shutdown and hyperactive platelets. In the clinical setting, early administration of the antifibrinolytic agent tranexamic acid has proved effective in reducing head-injury-related mortality in a subgroup of TBI patients. Further studies evaluating the time course of hemostatic disruptions after TBI are warranted in order to identify windows of opportunity for potential treatment options.

Neurogenic vs. Myogenic Origin of Acquired Muscle Paralysis in Intensive Care Unit (ICU) Patients: Evaluation of Different Diagnostic Methods.

Introduction. The acquired muscle paralysis associated with modern critical care can be of neurogenic or myogenic origin, yet the distinction between these origins is hampered by the precision of current diagnostic methods. This has resulted in the pooling of all acquired muscle paralyses, independent of their origin, into the term Intensive Care Unit Acquired Muscle Weakness (ICUAW). This is unfortunate since the acquired neuropathy (critical illness polyneuropathy, CIP) has a slower recovery than the myopathy (critical illness myopathy, CIM); therapies need to target underlying mechanisms and every patient deserves as accurate a diagnosis as possible. This study aims at evaluating different diagnostic methods in the diagnosis of CIP and CIM in critically ill, immobilized and mechanically ventilated intensive care unit (ICU) patients. Methods. ICU patients with acquired quadriplegia in response to critical care were included in the study. A total of 142 patients were examined with routine electrophysiological methods, together with biochemical analyses of myosin:actin (M:A) ratios of muscle biopsies. In addition, comparisons of evoked electromyographic (EMG) responses in direct vs. indirect muscle stimulation and histopathological analyses of muscle biopsies were performed in a subset of the patients. Results. ICU patients with quadriplegia were stratified into five groups based on the hallmark of CIM, i.e., preferential myosin loss (myosin:actin ratio, M:A) and classified as severe (M:A < 0.5; n = 12), moderate (0.5 ≤ M:A < 1; n = 40), mildly moderate (1 ≤ M:A < 1.5; n = 49), mild (1.5 ≤ M:A < 1.7; n = 24) and normal (1.7 ≤ M:A; n = 19). Identical M:A ratios were obtained in the small (4-15 mg) muscle samples, using a disposable semiautomatic microbiopsy needle instrument, and the larger (>80 mg) samples, obtained with a conchotome instrument. Compound muscle action potential (CMAP) duration was increased and amplitude decreased in patients with preferential myosin loss, but deviations from this relationship were observed in numerous patients, resulting in only weak correlations between CMAP properties and M:A. Advanced electrophysiological methods measuring refractoriness and comparing CMAP amplitude after indirect nerve vs. direct muscle stimulation are time consuming and did not increase precision compared with conventional electrophysiological measurements in the diagnosis of CIM. Low CMAP amplitude upon indirect vs. direct stimulation strongly suggest a neurogenic lesion, i.e., CIP, but this was rarely observed among the patients in this study. Histopathological diagnosis of CIM/CIP based on enzyme histochemical mATPase stainings were hampered by poor quantitative precision of myosin loss and the impact of pathological findings unrelated to acute quadriplegia. Conclusion. Conventional electrophysiological methods are valuable in identifying the peripheral origin of quadriplegia in ICU patients, but do not reliably separate between neurogenic vs. myogenic origins of paralysis. The hallmark of CIM, preferential myosin loss, can be reliably evaluated in the small samples obtained with the microbiopsy instrument. The major advantage of this method is that it is less invasive than conventional muscle biopsies, reducing the risk of bleeding in ICU patients, who are frequently receiving anticoagulant treatment, and it can be repeated multiple times during follow up for monitoring purposes.

Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review.

Severe acute respiratory syndrome coronavirus 2 is responsible for the current COVID-19 pandemic resulting in an escalating number of cases and fatalities worldwide. Preliminary evidence from these patients, as well as past coronavirus epidemics, indicates that those infected suffer from disproportionate complement activation as well as excessive coagulation, leading to thrombotic complications and poor outcome. In non-coronavirus cohorts, evidence has accumulated of an interaction between the complement and coagulation systems, with one amplifying activation of the other. A pressing question is therefore if COVID-19 associated thrombosis could be caused by overactivation of the complement cascade? In this review, we summarize the literature on thrombotic complications in COVID-19, complement activation in coronavirus infections, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system is able to activate the coagulation cascade and platelets, inhibit fibrinolysis and stimulate endothelial cells. We also describe how these interactions see clinical relevance in several disorders where overactive complement results in a prothrombotic clinical presentation, and how it could be clinically relevant in COVID-19.

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol.

Despite improvements in medical triage and tertiary care, traumatic brain injury (TBI) remains associated with significant morbidity and mortality. Almost two-thirds of patients with severe TBI develop some form of hemostatic disturbance, which contributes to poor outcome. In addition, the complement system, which is abundant in the healthy brain, undergoes significant intra- and extracranial amplification following TBI. Previously considered to be structurally similar but separate systems, evidence of an interaction between the complement and coagulation systems in non-TBI cohorts has accumulated, with the activation of one system amplifying the activation of the other, independent of their established pathways. However, it is not known whether this interaction exists in TBI. In this review we summarize the available literature on complement activation following TBI, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system interacts with the coagulation cascade by activating the intrinsic coagulation pathway and by bypassing the initial cascade and directly producing thrombin as well. This crosstalk also effects platelets, where evidence points to a relationship with the complement system on multiple levels, with complement anaphylatoxins being able to induce disproportionate platelet activation and adhesion. The complement system also stimulates thrombosis by inhibiting fibrinolysis and stimulating endothelial cells to release prothrombotic microparticles. These interactions see clinical relevance in several disorders where a deficiency in complement regulation seems to result in a prothrombotic clinical presentation. Finally, based on these observations, we present the outline of an observational cohort study that is currently under preparation and aimed at assessing how complement influences coagulation in patients with isolated TBI.

Influence of Blood-Brain Barrier Integrity on Brain Protein Biomarker Clearance in Severe Traumatic Brain Injury: A Longitudinal Prospective Study.

Brain protein biomarker clearance to blood in traumatic brain injury (TBI) is not fully understood. The aim of this study was to analyze the effect that a disrupted blood-brain barrier (BBB) had on biomarker clearance. Seventeen severe TBI patients admitted to Karolinska University Hospital were prospectively included. Cerebrospinal fluid (CSF) and blood concentrations of S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) were analyzed every 6-12 h for ∼1 week. Blood and CSF albumin were analyzed every 12-24 h, and BBB integrity was assessed using the CSF:blood albumin quotient (QA). We found that time-dependent changes in the CSF and blood levels of the two biomarkers were similar, but that the correlation between the biomarkers and QA was lower for NSE (ρ = 0.444) than for S100B (ρ = 0.668). Because data were longitudinal, we also conducted cross correlation analyses, which indicated a directional flow and lag-time of biomarkers from CSF to blood. For S100B, this lag-time could be ascribed to BBB integrity, whereas for NSE it could not. Upon inferential modelling, using generalized least square estimation (S100B) or linear mixed models (NSE), QA (p = 0.045), time from trauma (p < 0.001), time from trauma2 (p = 0.023), and CSF biomarker levels (p = 0.008) were independent predictors of S100B in blood. In contrast, for NSE, only time from trauma was significant (p < 0.001). These findings are novel and important, but must be carefully interpreted because of different characteristics between the two proteins. Nonetheless, we present the first data that indicate that S100B and NSE are cleared differently from the central nervous system, and that both the disrupted BBB and additional alternative pathways, such as the recently described glymphatic system, may play a role. This is of importance both for clinicians aiming to utilize these biomarkers and for the pathophysiological understanding of brain protein clearance, but warrants further examination.

[Better guidelines needed for mild traumatic brain injury in the primary care setting]. / Behov av bättre riktlinjer vid lätta traumatiska hjärnskador i primärvården - Handläggning uppvisar variation enligt resultat från enkätstudie.

In Sweden, there are currently no consensus guidelines aimed at the management of patients with mild traumatic brain injury (mTBI) in a primary care setting. The aim of this study was to assess the need for such guidelines by a web-based, multiple choice, case-based survey asking primary care physicians how they manage mTBI patients in the early (acute) and late (persistent symptoms) stage. The survey demonstrated a more uniform patient management pattern in the acute stage of mTBI, while it revealed a more heterogenous pattern in the later stage. This illustrates the need for consensus guidelines in the management of this patient category in the primary care setting, which was further substantiated by the request for such guidelines by 85% of the physicians participating in the survey.

Correction to: Predictors of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation: an observational cohort study.

[This corrects the article DOI: 10.1186/s40560-017-0223-2.].

Comparison of high versus low frequency cerebral physiology for cerebrovascular reactivity assessment in traumatic brain injury: a multi-center pilot study.

Current accepted cerebrovascular reactivity indices suffer from the need of high frequency data capture and export for post-acquisition processing. The role for minute-by-minute data in cerebrovascular reactivity monitoring remains uncertain. The goal was to explore the statistical time-series relationships between intra-cranial pressure (ICP), mean arterial pressure (MAP) and pressure reactivity index (PRx) using both 10-s and minute data update frequency in TBI. Prospective data from 31 patients from 3 centers with moderate/severe TBI and high-frequency archived physiology were reviewed. Both 10-s by 10-s and minute-by-minute mean values were derived for ICP and MAP for each patient. Similarly, PRx was derived using 30 consecutive 10-s data points, updated every minute. While long-PRx (L-PRx) was derived via similar methodology using minute-by-minute data, with L-PRx derived using various window lengths (5, 10, 20, 30, 40, and 60 min; denoted L-PRx_5, etc.). Time-series autoregressive integrative moving average (ARIMA) and vector autoregressive integrative moving average (VARIMA) models were created to analyze the relationship of these parameters over time. ARIMA modelling, Granger causality testing and VARIMA impulse response function (IRF) plotting demonstrated that similar information is carried in minute mean ICP and MAP data, compared to 10-s mean slow-wave ICP and MAP data. Shorter window L-PRx variants, such as L-PRx_5, appear to have a similar ARIMA structure, have a linear association with PRx and display moderate-to-strong correlations (r ~ 0.700, p < 0.0001 for each patient). Thus, these particular L-PRx variants appear closest in nature to standard PRx. ICP and MAP derived via 10-s or minute based averaging display similar statistical time-series structure and co-variance patterns. PRx and L-PRx based on shorter windows also behave similarly over time. These results imply certain L-PRx variants may carry similar information to PRx in TBI.

Prognostic performance of computerized tomography scoring systems in civilian penetrating traumatic brain injury: an observational study.

BACKGROUND: The prognosis of penetrating traumatic brain injury (pTBI) is poor yet highly variable. Current computerized tomography (CT) severity scores are commonly not used for pTBI prognostication but may provide important clinical information in these cohorts. METHODS: All consecutive pTBI patients from two large neurotrauma databases (Helsinki 1999-2015, Stockholm 2005-2014) were included. Outcome measures were 6-month mortality and unfavorable outcome (Glasgow Outcome Scale 1-3). Admission head CT scans were assessed according to the following: Marshall CT classification, Rotterdam CT score, Stockholm CT score, and Helsinki CT score. The discrimination (area under the receiver operating curve, AUC) and explanatory variance (pseudo-R2) of the CT scores were assessed individually and in addition to a base model including age, motor response, and pupil responsiveness. RESULTS: Altogether, 75 patients were included. Overall 6-month mortality and unfavorable outcome were 45% and 61% for all patients, and 31% and 51% for actively treated patients. The CT scores' AUCs and pseudo-R2s varied between 0.77-0.90 and 0.35-0.60 for mortality prediction and between 0.85-0.89 and 0.50-0.57 for unfavorable outcome prediction. The base model showed excellent performance for mortality (AUC 0.94, pseudo-R2 0.71) and unfavorable outcome (AUC 0.89, pseudo-R2 0.53) prediction. None of the CT scores increased the base model's AUC (p > 0.05) yet increased its pseudo-R2 (0.09-0.15) for unfavorable outcome prediction. CONCLUSION: Existing head CT scores demonstrate good-to-excellent performance in 6-month outcome prediction in pTBI patients. However, they do not add independent information to known outcome predictors, indicating that a unique score capturing the intracranial severity in pTBI may be warranted.