Interactions between integrin α9ß1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT.

ABSTRACT: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.

Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

BACKGROUND: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. CLINICAL TRIAL REGISTRATION: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838 .

Enhancing axonal myelination: Clemastine attenuates cognitive impairment in a rat model of diffuse traumatic brain injury.

Traumatic brain injury (TBI) has a significant impact on cognitive function, affecting millions of people worldwide. Myelin loss is a prominent pathological feature of TBI, while well-functioning myelin is crucial for memory and cognition. Utilizing drug repurposing to identify effective drug candidates for TBI treatment has gained attention. Notably, recent research has highlighted the potential of clemastine, an FDA-approved allergy medication, as a promising pro-myelinating drug. Therefore, in this study, we aim to investigate whether clemastine can enhance myelination and alleviate cognitive impairment following mild TBI using a clinically relevant rat model of TBI. Mild diffuse TBI was induced using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Animals were treated with either clemastine or an equivalent volume of the vehicle from day 1 to day 14 post-injury. Following treatment, memory-related behavioral tests were conducted, and myelin pathology in the cortex and hippocampus was assessed through immunofluorescence staining and ProteinSimple® capillary-based immunoassay. Our results showed that TBI leads to significant myelin loss, axonal damage, glial activation, and a decrease in mature oligodendrocytes in both the cortex and hippocampus. The TBI animals also exhibited notable deficits in memory-related tests. In contrast, animals treated with clemastine showed an increase in mature oligodendrocytes, enhanced myelination, and improved performance in the behavioral tests. These preliminary findings support the therapeutic value of clemastine in alleviating TBI-induced cognitive impairment, with substantial clinical translational potential. Our findings also underscore the potential of remyelinating therapies for TBI.

Myelin Pathology in Alzheimer's Disease: Potential Therapeutic Opportunities.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by memory loss and cognitive decline. Despite significant efforts over several decades, our understanding of the pathophysiology of this disease is still incomplete. Myelin is a multi-layered membrane structure ensheathing neuronal axons, which is essential for the fast and effective propagation of action potentials along the axons. Recent studies highlight the critical involvement of myelin in memory consolidation and reveal its vulnerability in various pathological conditions. Notably, apart from the classic amyloid hypothesis, myelin degeneration has been proposed as another critical pathophysiological feature of AD, which could occur prior to the development of amyloid pathology. Here, we review recent works supporting the critical role of myelin in cognition and myelin pathology during AD progression, with a focus on the mechanisms underlying myelin degeneration in AD. We also discuss the complex intersections between myelin pathology and typical AD pathophysiology, as well as the therapeutic potential of pro-myelinating approaches for this disease. Overall, these findings implicate myelin degeneration as a critical contributor to AD-related cognitive deficits and support targeting myelin repair as a promising therapeutic strategy for AD.

Pathophysiology, Management, and Therapeutics in Subarachnoid Hemorrhage and Delayed Cerebral Ischemia: An Overview.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke resulting from the rupture of an arterial vessel within the brain. Unlike other stroke types, SAH affects both young adults (mid-40s) and the geriatric population. Patients with SAH often experience significant neurological deficits, leading to a substantial societal burden in terms of lost potential years of life. This review provides a comprehensive overview of SAH, examining its development across different stages (early, intermediate, and late) and highlighting the pathophysiological and pathohistological processes specific to each phase. The clinical management of SAH is also explored, focusing on tailored treatments and interventions to address the unique pathological changes that occur during each stage. Additionally, the paper reviews current treatment modalities and pharmacological interventions based on the evolving guidelines provided by the American Heart Association (AHA). Recent advances in our understanding of SAH will facilitate clinicians' improved management of SAH to reduce the incidence of delayed cerebral ischemia in patients.

Early life adversity as a risk factor for cognitive impairment and Alzheimer's disease.

Neurological conditions, including cognitive impairment and Alzheimer's disease (AD), impose a huge burden on society, affecting millions of people globally. In addition to genetic factors, recent studies indicate that environmental and experiential factors may contribute to the pathogenesis of these diseases. Early life adversity (ELA) has a profound impact on brain function and health later in life. In rodent models, exposure to ELA results in specific cognitive deficits and aggravated AD pathology. Extensive concerns have been raised regarding the higher risk of developing cognitive impairments in people with a history of ELA. In this review, we scrutinize findings from human and animal studies focusing on the connection of ELA with cognitive impairment and AD. These discoveries suggest that ELA, especially at early postnatal stages, increases susceptibility to cognitive impairment and AD later in life. In terms of mechanisms, ELA could lead to dysregulation of the hypothalamus-pituitary-adrenal axis, altered gut microbiome, persistent inflammation, oligodendrocyte dysfunction, hypomyelination, and aberrant adult hippocampal neurogenesis. Crosstalks among these events may synergistically contribute to cognitive impairment later in life. Additionally, we discuss several interventions that may alleviate adverse consequences of ELA. Further investigation into this crucial area will help improve ELA management and reduce the burden of related neurological conditions.

PRMT7 can prevent neurovascular uncoupling, blood-brain barrier permeability, and mitochondrial dysfunction in repetitive and mild traumatic brain injury.

Mild traumatic brain injury (TBI) comprises the largest percentage of TBI-related injuries, with pathophysiological and functional deficits that persist in a subset of TBI patients. In our three-hit paradigm of repetitive and mild traumatic brain injury (rmTBI), we observed neurovascular uncoupling via decreased red blood cell velocity, microvessel diameter, and leukocyte rolling velocity 3 days post-rmTBI via intra-vital two-photon laser scanning microscopy. Furthermore, our data suggest increased blood-brain barrier (BBB) permeability (leakage), with corresponding decrease in junctional protein expression post-rmTBI. Mitochondrial oxygen consumption rates (measured via Seahorse XFe24) were also altered 3 days post-rmTBI, along with disrupted mitochondrial dynamics of fission and fusion. Overall, these pathophysiological findings correlated with decreased protein arginine methyltransferase 7 (PRMT7) protein levels and activity post-rmTBI. Here, we increased PRMT7 levels in vivo to assess the role of the neurovasculature and mitochondria post-rmTBI. In vivo overexpression of PRMT7 using a neuronal specific AAV vector led to restoration of neurovascular coupling, prevented BBB leakage, and promoted mitochondrial respiration, altogether to suggest a protective and functional role of PRMT7 in rmTBI.

A role for protein arginine methyltransferase 7 in repetitive and mild traumatic brain injury.

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses revealed excess glutamate production, as well as diffuse axonal injury via Bielschowsky's silver stain kit. Moreover, the heterogeneous nature of rmTBI has made it challenging to identify drug therapies that address rmTBI, therefore we sought to identify novel targets in the concurrent rmTBI pathology. The pathophysiological findings correlated with a time-dependent decrease in protein arginine methyltransferase 7 (PRMT7) protein expression and activity post-rmTBI along with dysregulation of PRMT upstream mediators s-adenosylmethionine and methionine adenosyltransferase 2 (MAT2) in vivo. In addition, inhibition of the upstream mediator MAT2A using the HT22 hippocampal neuronal cell line suggest a mechanistic role for PRMT7 via MAT2A in vitro. Collectively, we have identified PRMT7 as a novel target in rmTBI pathology in vivo and a mechanistic link between PRMT7 and upstream mediator MAT2A in vitro.

Photobiomodulation attenuates oligodendrocyte dysfunction and prevents adverse neurological consequences in a rat model of early life adversity.

Rationale: Adverse experiences in early life including abuse, trauma and neglect, have been linked to poor physical and mental health outcomes. Emerging evidence implies that those who experienced early life adversity (ELA) are more likely to develop cognitive dysfunction and depressive-like symptoms in adulthood. The molecular mechanisms responsible for the negative consequences of ELA, however, remain unclear. In the absence of effective management options, anticipatory guidance is the mainstay of ELA prevention. Furthermore, there is no available treatment that prevents or alleviates the neurologic sequelae of ELA, especially traumatic stress. Hence, the present study aims to investigate the mechanisms for these associations and evaluate whether photobiomodulation (PBM), a non-invasive therapeutic procedure, can prevent the negative cognitive and behavioral manifestations of ELA in later life. Methods: ELA was induced by repeated inescapable electric foot shock of rats from postnatal day 21 to 26. On the day immediately following the last foot shock, 2-min daily PBM treatment was applied transcranially for 7 consecutive days. Cognitive dysfunction and depression-like behaviors were measured by a battery of behavioral tests in adulthood. Subsequently, oligodendrocyte progenitor cells (OPCs) differentiation, the proliferation and apoptosis of oligodendrocyte lineage cells (OLs), mature oligodendrocyte, myelinating oligodendrocyte, the level of oxidative damage, reactive oxygen species (ROS) and total antioxidant capacity were measured and analyzed using immunofluorescence staining, capillary-based immunoassay (ProteinSimple®) and antioxidant assay kit. Results: The rats exposed to ELA exhibited obvious oligodendrocyte dysfunction, including a reduction in OPCs differentiation, diminished generation and survival of OLs, decreased OLs, and decreased matured oligodendrocyte. Furthermore, a deficit in myelinating oligodendrocytes was observed, in conjunction with an imbalance in redox homeostasis and accumulated oxidative damage. These alternations were concomitant with cognitive dysfunction and depression-like behaviors. Importantly, we found that early PBM treatment largely prevented these pathologies and reversed the neurologic sequelae resulting from ELA. Conclusions: Collectively, these findings provide new insights into the mechanism by which ELA affects neurological outcomes. Moreover, our findings support that PBM may be a promising strategy to prevent ELA-induced neurologic sequelae that develops later in life.

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial.

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). Design, Setting, and Participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. Main Outcomes and Measures: Major or clinically relevant nonmajor (CRNM) bleeding. Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). Conclusions and Relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. Trial Registration: ClinicalTrials.gov Identifier: NCT02415400.

Reducing the Reported Mortality Index Within a Neurocritical Care Unit Through Documentation and Coding Accuracy.

BACKGROUND: The mortality index, or the ratio of observed to expected mortality, is a reported quality metric that has been assumed to directly reflect patient care. However, documentation and coding that does not use knowledge of how a reported mortality index is derived could reflect poorly on a hospital or service line. We present our effort at reducing the reported mortality index of neurosurgery and neurology patients within a neurocritical care unit through documentation and coding accuracy with direct incorporation of mortality modeling. METHODS: Using a reported method from Vizient Inc., we generated a spreadsheet tool to enable direct manipulation of the data to identify documentation and coding issues that influenced the reported mortality index in a retrospective set of patients. Subsequently, we implemented the prospective changes to documentation and coding and compared our calculated mortality index to the reported Vizient mortality index. RESULTS: Prospective implementation of the documentation and coding issues identified through our spreadsheet tool resulted in a drastic reduction of both our calculated and the reported Vizient mortality index. CONCLUSIONS: Incorporating knowledge of mortality index modeling into the documentation and coding resulted in impressive reductions in the reported mortality index for our patients, serving as a both an internal benchmark and a method of comparison with other institutions.

Enhanced renal clearance and impact on vancomycin pharmacokinetic parameters in patients with hemorrhagic stroke.

BACKGROUND: The majority of patients with hemorrhagic stroke experience enhanced renal clearance or augmented renal clearance (ARC). The purpose of this study was to determine the impact of enhanced renal clearance or ARC on vancomycin pharmacokinetic (PK) parameters. METHODS: This was a post hoc analysis of a prospective study of adult patients with aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH) admitted to the neurosciences intensive care unit who received vancomycin. Creatinine clearance (CrCl) was measured and also estimated using the Cockcroft-Gault equation. Predicted PK parameters were compared with calculated PK parameters using serum peak and trough concentrations. RESULTS: Seventeen hemorrhagic stroke patients met inclusion criteria. All patients experienced enhanced renal clearance on the day that the vancomycin concentrations were obtained, and 12 patients (71%) experienced ARC. The mean calculated elimination rate constant was significantly higher than the predicted value (0.141 ± 0.02 vs. 0.087 ± 0.01 h-1; p = 0.004) and the mean calculated half-life was significantly lower than the predicted half-life (6.5 ± 0.9 vs. 8.7 ± 0.6 h; p = 0.03). CONCLUSIONS: Patients with hemorrhagic stroke and enhanced renal clearance displayed PK alterations favoring an increased elimination of vancomycin than expected. This may result in underexposure to vancomycin, leading to treatment failure.

Stroke in Patients With Peripheral Artery Disease.

Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.

Enhanced Renal Clearance in Patients With Hemorrhagic Stroke.

OBJECTIVES: To evaluate enhanced renal clearance over time in patients with aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage via measured creatinine clearance and to compare measured creatinine clearance to creatinine clearance calculated by the Cockcroft-Gault equation and estimated glomerular filtration rate calculated by the Modification of Diet in Renal Diseases equation. DESIGN: Prospective, observational study. SETTING: Neurosciences ICU in a tertiary care academic medical center. PATIENTS: Study participants had an admission diagnosis of aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage, an expected neurosciences ICU length of stay greater than 48 hours, no evidence of renal dysfunction (admission serum creatinine < 1.5 mg/dL), and no history of chronic kidney disease. INTERVENTIONS: Eight-hour urine collections to measure creatinine clearance were collected daily as the primary method of measuring renal function. Creatinine clearance was also calculated using the Cockcroft-Gault equation and estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation. Enhanced renal clearance was defined as a measured creatinine clearance greater than the calculated creatinine clearance via Cockcroft-Gault and estimated glomerular filtration rate via Modification of Diet in Renal Disease. Augmented renal clearance was defined by a measured creatinine clearance greater than or equal to 130 mL/min/1.73 m. Relevant demographic, clinical, and outcome data were recorded. MEASUREMENTS AND MAIN RESULTS: Fifty aneurysmal subarachnoid hemorrhage patients and 30 intracerebral hemorrhage patients were enrolled, contributing 590 individual measurements. Patients with aneurysmal subarachnoid hemorrhage had a higher mean measured creatinine clearance compared with the mean calculated creatinine clearance based on the Cockcroft-Gault equation (147.9 ± 50.2 vs 109.1 ± 32.7 mL/min/1.73 m; p < 0.0001) and higher mean measured creatinine clearance compared with the mean calculated estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation (147.9 ± 50.2 vs 126.0 ± 41.9 mL/min/1.73 m; p = 0.04). Ninety-four percent of participants with aneurysmal subarachnoid hemorrhage experienced augmented renal clearance on at least 1 day. In patients with intracerebral hemorrhage, there was a higher mean measured creatinine clearance over the study period compared with the mean calculated creatinine clearance (119.5 ± 57.2 vs 77.8 ± 27.6 mL/min/1.73 m; p < 0.0001) and higher mean measured creatinine clearance compared with the mean calculated estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation (119.5 ± 57.2 vs 93.0.0 ± 32.8 mL/min/1.73 m; p = 0.02). Fifty percent of participants with intracerebral hemorrhage experienced augmented renal clearance on at least 1 day. CONCLUSIONS: A substantial group of patients with aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage experienced enhanced renal clearance, which may be otherwise unknown to clinicians. Enhanced renal clearance may lead to increased renal solute elimination over what is expected, resulting in subtherapeutic renally eliminated drug concentrations. This may result in underexposure to critical medications, leading to treatment failure and other medical complications.

The Impact of Capping Creatinine Clearance on Achieving Therapeutic Vancomycin Concentrations in Neurocritically Ill Patients with Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is associated with secondary complications, including infection, and patients with TBI often exhibit augmented renal clearance (ARC). This phenomenon has been associated with subtherapeutic levels of renally cleared drugs such as vancomycin, which is dosed based on body weight and creatinine clearance (CrCl). Many clinicians, however, cap CrCl at 120 mL/min/1.73 m2 when calculating vancomycin dosing regimens. We hypothesize that capping patient CrCl, as opposed to utilizing the non-capped CrCl, when determining vancomycin dosing schemes results in subtherapeutic serum trough concentrations in patients with TBI. METHODS: This was a retrospective study of adult patients with TBI admitted between April 2014 and December 2015 who received vancomycin. Population-based pharmacokinetic (PK) parameters using non-capped calculated CrCl and capped CrCl were compared with patient-specific PK parameters based on serum trough concentrations. RESULTS: Thirty-two patients with TBI were included in the study. ARC was suspected in 24 (75%) patients due to a median estimated CrCl at serum trough concentration of 167.3 (127.7-197.7) mL/min. The mean dosing regimen was 17.1 (13.2-19.2) mg/kg every 8 (8-8) h. There was no difference between the median measured trough concentration and predicted value using non-capped CrCl [10.4 (7.1-15.0) vs. 11.5 (7.8-13.7) mcg/mL; p = 0.7986]. The median measured trough concentration was significantly lower than the predicted trough concentration when calculated based on capping the CrCl at 120 mL/min/1.73 m2 [16.3 (15.3-22.0) vs. 11.5 (7.8-13.7) mcg/mL; p < 0.0001]. CONCLUSIONS: Patients with traumatic brain injury appeared to exhibit augmented renal clearance, leading to subtherapeutic vancomycin serum trough concentrations when doses were calculated using the traditional method of capping creatinine clearance at 120 mL/min/1.73 m2. Instead, utilizing patients' non-capped creatinine clearance when determining a vancomycin dosing regimen is more accurate and provides a better estimation of vancomycin pharmacokinetics and could be applied to other renally excreted medications.

Energy Expenditure in Critically Ill Adult Patients With Acute Brain Injury: Indirect Calorimetry vs. Predictive Equations.

Introduction: Predictive equations (PE) are used in lieu of indirect calorimetry (IC) due to cost and limited resources; however, these equations may not be as accurate as IC in estimating resting energy expenditure (REE) in critically ill patients, putting them at risk of malnutrition. The purpose of this study is to compare predicted and measured energy expenditure (MEE) in critically ill adults with acute brain injury. Materials and Methods: This was a retrospective review of adult patients admitted to the Neurosciences ICU with acute brain injury between May 1st, 2014 and April 1st, 2016 who had IC performed. The Harris Benedict (HBE), Penn State University, and Mifflin St Jeor (MSJ) PE were used in comparison to IC results. Subgroup analyses stratified patients based on BMI and type of acute brain injury. Results: One hundred and forty-four patients met inclusion criteria. Comparing predicted and MEE found no significant difference (p = 0.1). High degrees of interpatient variability were discovered, with standard deviations ranging from 17 to 29% of each PE. Pearson's correlations indicated weak associations when HBE, Penn State, and MSJ were individually compared to MEE (r = 0.372, 0.409, and 0.372, respectively). A significant difference was found between predicted and MEE in patients with a BMI < 30 kg/m2 (p < 0.01) and in those with aneurysmal subarachnoid hemorrhage (p < 0.01). Discussion: Due to interpatient variability that exists among REE of critically ill patients with acute brain injury, IC should be used when feasible.

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study.

BACKGROUND: More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI. METHODS: This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9-15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT. FINDINGS: Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (<1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931-0·995) and an NPV of 0·996 (0·987-0·999). In three (<1%) of 1959 patients, the CT scan was positive when the test was negative. INTERPRETATION: These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted. FUNDING: Banyan Biomarkers and US Army Medical Research and Materiel Command.

Correction to: Influence of Single-Dose Antibiotic Prophylaxis for Early-Onset Pneumonia in High-Risk Intubated Patients.

Due to an error introduced during the production process, J. Dedrick Jordan's name was improperly tagged in the original publication of this article. It is tagged correctly here.

Influence of Single-Dose Antibiotic Prophylaxis for Early-Onset Pneumonia in High-Risk Intubated Patients.

BACKGROUND: Early-onset pneumonia (EOP) after endotracheal intubation is common among critically ill patients with a neurologic injury and is associated with worse clinical outcomes. METHODS: This retrospective cohort study observed outcomes pre- and post-implementation of an EOP prophylaxis protocol which involved the administration of a single dose of ceftriaxone 2 g around the time of intubation. The study included patients ≥ 18 years who were admitted to the University of North Carolina Medical Center (UNCMC) neuroscience intensive care unit (NSICU) between April 1, 2014, and October 26, 2016, and intubated for ≥ 72 h. RESULTS: Among the 172 patients included, use of an EOP prophylaxis protocol resulted in a significant reduction in the rate of microbiologically confirmed EOP compared to those without prophylaxis (7.4 vs 19.8%, p = 0.026). However, EOP prophylaxis did not decrease the combined incidence of microbiologically confirmed or clinically suspected EOP (32.2 vs 37.4%, p = 0.523). No difference in the rate of late-onset pneumonia (34.6 vs 26.4%, p = 0.25) or virulent organism growth (19.8 vs 14.3%, p = 0.416) was observed. No difference was observed in the duration of intubation, duration of intensive care unit (ICU) stay, duration of hospitalization, or ICU antibiotic days within 30 days of intubation. In hospital mortality was found to be higher in those who received EOP prophylaxis compared to those who did not receive prophylaxis (45.7 vs 29.7%, p = 0.04). CONCLUSIONS: The administration of a single antibiotic dose following intubation may reduce the incidence of microbiologically confirmed EOP in patients with neurologic injury who are intubated ≥ 72 h. A prophylaxis strategy does not appear to increase the rate of virulent organism growth or the rate of late-onset pneumonia. However, this practice is not associated with a decrease in days of antibiotic use in the ICU or any clinical outcomes benefit.

Early versus late tracheostomy after decompressive craniectomy for stroke.

Background: Stroke patients requiring decompressive craniectomy are at high risk of prolonged mechanical ventilation and ventilator-associated pneumonia (VAP). Tracheostomy placement may reduce the duration of mechanical ventilation. Predicting which patients will require tracheostomy and the optimal timing of tracheostomy remains a clinical challenge. In this study, the authors compare key outcomes after early versus late tracheostomy and develop a useful pre-operative decision-making tool to predict post-operative tracheostomy dependence. Methods: We performed a retrospective analysis of prospectively collected registry data. We developed a propensity-weighted decision tree analysis to predict tracheostomy requirement using factors present prior to surgical decompression. In addition, outcomes include probability functions for intensive care unit length of stay, hospital length of stay, and mortality, based on data for early (≤ 10 days) versus late (> 10 days) tracheostomy. Results: There were 168 surgical decompressions performed on patients with acute ischemic or spontaneous hemorrhagic stroke between 2010 and 2015. Forty-eight patients (28.5%) required a tracheostomy, 35 (20.8%) developed VAP, and 126 (75%) survived hospitalization. Mean ICU and hospital length of stay were 15.1 and 25.8 days, respectively. Using GCS, SOFA score, and presence of hydrocephalus, our decision tree analysis had 63% sensitivity and 84% specificity for predicting tracheostomy requirement. The early group had fewer ventilator days (7.3 versus 15.2, p < 0.001) and shorter hospital length of stay (28.5 versus 44.4 days, p = 0.014). VAP rates and mortality were similar between the two groups. Withdrawal of treatment interventions shortly post-operatively confounded mortality outcomes. Conclusion: Early tracheostomy shortens duration of mechanical ventilation and length of stay after surgical decompression for stroke, but it did not impact mortality or VAP rates. A decision tree is a practical tool that may be helpful in guiding pre-operative decision-making with patients' families.