PaCO2 Association with Outcomes of Patients with Traumatic Brain Injury at High Altitude: A Prospective Single-Center Cohort Study.

BACKGROUND: Partial pressure of carbon dioxide (PaCO2) is generally known to influence outcome in patients with traumatic brain injury (TBI) at normal altitudes. Less is known about specific relationships of PaCO2 levels and clinical outcomes at high altitudes. METHODS: This is a prospective single-center cohort of consecutive patients with TBI admitted to a trauma center located at 2600 m above sea level. An unfavorable outcome was defined as a Glasgow Outcome Scale-Extended (GOSE) score < 4 at the 6-month follow-up. RESULTS: We had a total of 81 patients with complete data, 80% (65/81) were men, and the median (interquartile range) age was 36 (25-50) years. Median Glasgow Coma Scale (GCS) score on admission was 9 (6-14); 49% (40/81) of patients had severe TBI (GCS 3-8), 32% (26/81) had moderate TBI (GCS 12-9), and 18% (15/81) had mild TBI (GCS 13-15). The median (interquartile range) Abbreviated Injury Score of the head (AISh) was 3 (2-4). The frequency of an unfavorable outcome (GOSE < 4) was 30% (25/81), the median GOSE was 4 (2-5), and the median 6-month mortality rate was 24% (20/81). Comparison between patients with favorable and unfavorable outcomes revealed that those with unfavorable outcome were older, (median age 49 [30-72] vs. 29 [22-41] years, P < 0.01), had lower admission GCS scores (6 [4-8] vs. 13 [8-15], P < 0.01), had higher AISh scores (4 [4-4] vs. 3 [2-4], P < 0.01), had higher Acute Physiology and Chronic Health disease Classification System II scores (17 [15-23] vs. 10 [6-14], P < 0.01), had higher Charlson scores (0 [0-2] vs. 0 [0-0], P < 0.01), and had higher PaCO2 levels (mean 35 ± 8 vs. 32 ± 6 mm Hg, P < 0.01). In a multivariate analysis, age (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.1-1.30, P < 0.01), AISh (OR 4.7, 95% CI 1.55-21.0, P < 0.05), and PaCO2 levels (OR 1.23, 95% CI 1.10-1.53, P < 0.05) were significantly associated with the unfavorable outcomes. When applying the same analysis to the subgroup on mechanical ventilation, AISh (OR 5.4, 95% CI 1.61-28.5, P = 0.017) and PaCO2 levels (OR 1.36, 95% CI 1.13-1.78, P = 0.015) remained significantly associated with the unfavorable outcome. CONCLUSIONS: Higher PaCO2 levels are associated with an unfavorable outcome in ventilated patients with TBI. These results underscore the importance of PaCO2 levels in patients with TBI and whether it should be adjusted for populations living at higher altitudes.

Modulation of beta-hydroxybutyrate in traumatic brain injury.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) is a significant public health concern with substantial morbidity and mortality rates in the United States. Current management strategies primarily focus on symptomatic approaches and prevention of secondary complications. However, recent research highlights the potential role of ketone bodies, particularly beta-hydroxybutyrate (BHB), in modulating cellular processes involved in TBI. This article reviews the metabolism of BHB, its effect in TBI, and its potential therapeutic impact in TBI. RECENT FINDINGS: BHB can be produced endogenously through fasting or administered exogenously through ketogenic diets, and oral or intravenous supplements. Studies suggest that BHB may offer several benefits in TBI, including reducing oxidative stress, inflammation, controlling excitotoxicity, promoting mitochondrial respiration, and supporting brain regeneration. Various strategies to modulate BHB levels are discussed, with exogenous ketone preparations emerging as a rapid and effective option. SUMMARY: BHB offers potential therapeutic advantages in the comprehensive approach to improve outcomes for TBI patients. However, careful consideration of safety and efficacy is essential when incorporating it into TBI treatment protocols. The timing, dosage, and long-term effects of ketone use in TBI patients require further investigation to fully understand its potential benefits and limitations.

Neurological Complications Associated with Hereditary Bleeding Disorders.

PURPOSE OF REVIEW: Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies. RECENT FINDINGS: ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient's pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications-intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.

Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke.

PURPOSE OF REVIEW: This review aims to provide an overview of neuroinflammation in ischemic and hemorrhagic stroke, including recent findings on the mechanisms and cellular players involved in the inflammatory response to brain injury. RECENT FINDINGS: Neuroinflammation is a crucial process following acute ischemic stroke (AIS) and hemorrhagic stroke (HS). In AIS, neuroinflammation is initiated within minutes of the ischemia onset and continues for several days. In HS, neuroinflammation is initiated by blood byproducts in the subarachnoid space and/or brain parenchyma. In both cases, neuroinflammation is characterized by the activation of resident immune cells, such as microglia and astrocytes, and infiltration of peripheral immune cells, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species. These inflammatory mediators contribute to blood-brain barrier disruption, neuronal damage, and cerebral edema, promoting neuronal apoptosis and impairing neuroplasticity, ultimately exacerbating the neurologic deficit. However, neuroinflammation can also have beneficial effects by clearing cellular debris and promoting tissue repair. The role of neuroinflammation in AIS and ICH is complex and multifaceted, and further research is necessary to develop effective therapies that target this process. Intracerebral hemorrhage (ICH) will be the HS subtype addressed in this review. Neuroinflammation is a significant contributor to brain tissue damage following AIS and HS. Understanding the mechanisms and cellular players involved in neuroinflammation is essential for developing effective therapies to reduce secondary injury and improve stroke outcomes. Recent findings have provided new insights into the pathophysiology of neuroinflammation, highlighting the potential for targeting specific cytokines, chemokines, and glial cells as therapeutic strategies.

Imaging biomarkers of cerebral edema automatically extracted from routine CT scans of large vessel occlusion strokes.

BACKGROUND AND PURPOSE: Volumetric and densitometric biomarkers have been proposed to better quantify cerebral edema after stroke, but their relative performance has not been rigorously evaluated. METHODS: Patients with large vessel occlusion stroke from three institutions were analyzed. An automated pipeline extracted brain, cerebrospinal fluid (CSF), and infarct volumes from serial CTs. Several biomarkers were measured: change in global CSF volume from baseline (ΔCSF); ratio of CSF volumes between hemispheres (CSF ratio); and relative density of infarct region compared with mirrored contralateral region (net water uptake [NWU]). These were compared to radiographic standards, midline shift and relative hemispheric volume (RHV) and malignant edema, defined as deterioration resulting in need for osmotic therapy, decompressive surgery, or death. RESULTS: We analyzed 255 patients with 210 baseline CTs, 255 24-hour CTs, and 81 72-hour CTs. Of these, 35 (14%) developed malignant edema and 63 (27%) midline shift. CSF metrics could be calculated for 310 (92%), while NWU could only be obtained from 193 (57%). Peak midline shift was correlated with baseline CSF ratio (ρ = -.22) and with CSF ratio and ΔCSF at 24 hours (ρ = -.55/.63) and 72 hours (ρ = -.66/.69), but not with NWU (ρ = .15/.25). Similarly, CSF ratio was correlated with RHV (ρ = -.69/-.78), while NWU was not. Adjusting for age, National Institutes of Health Stroke Scale, tissue plasminogen activator treatment, and Alberta Stroke Program Early CT Score, CSF ratio (odds ratio [OR]: 1.95 per 0.1, 95% confidence interval [CI]: 1.52-2.59) and ΔCSF at 24 hours (OR: 1.87 per 10%, 95% CI: 1.47-2.49) were associated with malignant edema. CONCLUSION: CSF volumetric biomarkers can be automatically measured from almost all routine CTs and correlate better with standard edema endpoints than net water uptake.

Contemporary Antiplatelet and Anticoagulant Therapies for Secondary Stroke Prevention: A Narrative Review of Current Literature and Guidelines.

PURPOSE OF REVIEW: Stroke is a leading cause of death and disability worldwide. The annual incidence of new or recurrent stroke is approximately 795,000 cases per year in the United States, of which 87% are ischemic in nature. In addition to the management of modifiable high-risk factors to reduce the risk of recurrent stroke, antithrombotic agents (antiplatelets and anticoagulants) play an important role in secondary stroke prevention. This review will discuss the published literature on the use of antiplatelets and anticoagulants in secondary prevention of acute ischemic stroke and transient ischemic attack (TIA), including their pharmacology, efficacy, and adverse effects. We will also highlight the role of dual antiplatelet therapy (DAPT) in secondary stroke prevention, along with supporting literature. RECENT FINDINGS: Single antiplatelet therapy (SAPT) with aspirin or clopidogrel reduces the risk of recurrent ischemic stroke in patients with non-cardioembolic ischemic stroke or TIA. However, as shown in recent trials, short-term DAPT with aspirin and clopidogrel or ticagrelor for 21-30 days is more effective than SAPT in patients with minor acute non-cardioembolic stroke or high-risk TIA. Although short-term DAPT is highly effective in preventing recurrent stroke, a more prolonged course can increase bleeding risks without additional benefit. DAPT for 90 days, followed by aspirin monotherapy for patients with large vessel intracranial atherosclerotic disease, is suitable for secondary stroke prevention. However, patients need to be monitored for both minor (e.g., bruising) and major (e.g., intracranial) bleeding complications. Conversely, oral warfarin and newer direct oral anticoagulant (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban are the agents of choice for secondary stroke prevention in patients with non-valvular cardioembolic strokes. DOACs may be preferred over warfarin due to decreased bleeding risks, including ICH, lack of need for international normalized ratio monitoring, no dietary restrictions, and limited drug-drug interactions. The choice between different antiplatelets and anticoagulants for prevention of ischemic stroke depends on the underlying stroke mechanism, cytochrome P450 2C19 polymorphisms, bleeding risk profile, compliance, drug tolerance, and drug resistance. Physicians must carefully weigh each patient's relative benefits and bleeding risks before initiating an antiplatelet/anticoagulant treatment regimen. Further studies are warranted to study the optimal duration of DAPT in symptomatic intracranial atherosclerosis since the benefit is most pronounced in the short term while the bleeding risk remains high during the extended duration of therapy.

Pathophysiology of Early Brain Injury and Its Association with Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Review of Current Literature.

Background: Delayed cerebral ischemia (DCI) is a common and serious complication of aneurysmal subarachnoid hemorrhage (aSAH). Though many clinical trials have looked at therapies for DCI and vasospasm in aSAH, along with reducing rebleeding risks, none have led to improving outcomes in this patient population. We present an up-to-date review of the pathophysiology of DCI and its association with early brain injury (EBI). Recent Findings: Recent studies have demonstrated that EBI, as opposed to delayed brain injury, is the main contributor to downstream pathophysiological mechanisms that play a role in the development of DCI. New predictive models, including advanced monitoring and neuroimaging techniques, can help detect EBI and improve the clinical management of aSAH patients. Summary: EBI, the severity of subarachnoid hemorrhage, and physiological/imaging markers can serve as indicators for potential early therapeutics in aSAH. The microcellular milieu and hemodynamic pathomechanisms should remain a focus of researchers and clinicians. With the advancement in understanding the pathophysiology of DCI, we are hopeful that we will make strides toward better outcomes for this unique patient population.

Automated Measurement of Net Water Uptake From Baseline and Follow-Up CTs in Patients With Large Vessel Occlusion Stroke.

Quantifying the extent and evolution of cerebral edema developing after stroke is an important but challenging goal. Lesional net water uptake (NWU) is a promising CT-based biomarker of edema, but its measurement requires manually delineating infarcted tissue and mirrored regions in the contralateral hemisphere. We implement an imaging pipeline capable of automatically segmenting the infarct region and calculating NWU from both baseline and follow-up CTs of large-vessel occlusion (LVO) patients. Infarct core is extracted from CT perfusion images using a deconvolution algorithm while infarcts on follow-up CTs were segmented from non-contrast CT (NCCT) using a deep-learning algorithm. These infarct masks were flipped along the brain midline to generate mirrored regions in the contralateral hemisphere of NCCT; NWU was calculated as one minus the ratio of densities between regions, removing voxels segmented as CSF and with HU outside thresholds of 20-80 (normal hemisphere and baseline CT) and 0-40 (infarct region on follow-up). Automated results were compared with those obtained using manually-drawn infarcts and an ASPECTS region-of-interest based method that samples densities within the infarct and normal hemisphere, using intraclass correlation coefficient (ρ). This was tested on serial CTs from 55 patients with anterior circulation LVO (including 66 follow-up CTs). Baseline NWU using automated core was 4.3% (IQR 2.6-7.3) and correlated with manual measurement (ρ = 0.80, p < 0.0001) and ASPECTS (r = -0.60, p = 0.0001). Automatically segmented infarct volumes (median 110-ml) correlated to manually-drawn volumes (ρ = 0.96, p < 0.0001) with median Dice similarity coefficient of 0.83 (IQR 0.72-0.90). Automated NWU was 24.6% (IQR 20-27) and highly correlated to NWU from manually-drawn infarcts (ρ = 0.98) and the sampling-based method (ρ = 0.68, both p < 0.0001). We conclude that this automated imaging pipeline is able to accurately quantify region of infarction and NWU from serial CTs and could be leveraged to study the evolution and impact of edema in large cohorts of stroke patients.

Comparative evaluation of a bioactive restorative material with resin modified glass ionomer for calcium-ion release and shear bond strength to dentin of primary teeth-an in vitro study.

OBJECTIVES: This study aimed to evaluate the release of calcium ions from a bioactive restorative material and its shear bond strength (SBS) to primary dentin. STUDY DESIGN: Occlusal surface of extracted non-carious primary molars were flattened, onto which 2 × 2 mm cylinders of ACTIVA™ BioActive Restorative (PULPDENT® Corporation, Watertown MA) or Fuji II LC (GC Corporation, Tokyo, Japan) were prepared using a polypropylene straw mould. SBS of the materials to primary dentin was tested using a universal testing machine. The mode of bond failure was assessed using stereomicroscopy. 10 mm × 2 mm disks of each material were prepared and immersed in Milli-Q water for 1, 7, 14 and 21 days. The released calcium ions in the immersion media were quantified using Atomic Absorption Spectroscopy. RESULTS: ACTIVA™ BioActive Restorative showed a mean SBS of 4.29 ± 0.65 MPa to primary dentin and calcium ion release of 0.76 ± 0.12 ppm over 21 days. CONCLUSION: ACTIVA™ BioActive Restorative showed a significantly higher mean SBS to primary dentin, and significantly higher calcium ion release compared to Fuji II LC.

Current Endovascular Treatment of Acute Ischemic Stroke.

Acute ischemic stroke is one of the leading causes of death and long-term disability in the United States. Intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) has been the mainstay of acute therapy. However, multiple randomized clinical trials have been published that have shown higher rates of recanalization and improved functional outcomes with endovascular therapy compared with intravenous rt-PA in patients with ischemic stroke from large vessel occlusion. This article provides an update and discusses the role of endovascular therapy in management of acute ischemic stroke.

Drug-Eluting Balloon Angioplasty for In-Stent Restenosis Following Carotid Artery Stent Placement.

BACKGROUND AND PURPOSE: Drug-eluting balloons (DEBs) have been proposed as an option for the treatment of in-stent restenosis (ISR) following carotid artery stent placement. We report our experience and review of literature to provide additional data. METHODS: For literature review, PubMed search was conducted to identify studies published between 2005 and 2019, reporting data on management of carotid ISR with DEBs. Two cases with carotid ISR, which were successfully treated with DEB at our facility, were also included in the final compilation of results RESULTS: A total of seven studies demonstrating the use of the DEBs for treatment of carotid ISR were identified. They encompassed 31 patients, 11 (35.5%) of whom presented with symptomatic ISR, with the remaining 20 patients (64.5%) asymptomatic. DEB angioplasty followed by stent placement was performed in 3 patients, whereas DEB alone was utilized in 28 patients. Periprocedural complications included asymptomatic dissection from DEB inflation in 1 patient and transient neurological deficits in another patient. Follow-up period was variable and ranged from 1 month to 5 years. Three patients were noted to develop recurrent asymptomatic stenosis, whereas 1 patient developed an episode of symptomatic restenosis post procedural on follow-up. In our two cases, both patients were noted to have protracted period of hypotension postprocedure without any new or recurrent neurological symptoms. CONCLUSION: The use of DEBs is a promising development and a viable alternative for management of severe and recurrent carotid ISR.

Modern Approaches to Evacuating Intracerebral Hemorrhage.

PURPOSE OF REVIEW: The present review aims to discuss the recent advances in surgical management of spontaneous intracerebral hemorrhage (ICH), safety and efficacy of minimally invasive surgical techniques, and the existing evidence supporting their use. RECENT FINDINGS: Newer surgical techniques, collectively referred to as minimally invasive surgery (MIS), have been evaluated and studied in management of ICH. Stereotactic evacuation of intracerebral hemorrhage using aspiration-irrigation technique has showed significant reductions in the hematoma volume with minimal intra-operative bleeding. Catheter-based evacuation in combination with use of recombinant tissue plasminogen activator (rt-PA) produces lysis and drainage of spontaneous ICH and intraventricular hemorrhage (IVH) rapidly with minimal major adverse events. Recent advances in the management of spontaneous ICH highlights potential advantages including safety and efficacy in clot lysis and reduction in hematoma volume especially with image-guided catheter-based drainage and concurrent use of rt-PA. Controlled trials are required to conclusively establish standard surgical techniques and rt-PA dosage, before incorporating minimally invasive surgery plus rt-PA, as a standard of care in patients with spontaneous ICH.

Infusion-rate-dependent Acute Neuropathic Pain with Duopa in a Patient with Parkinson's Disease and Pre-existing Neuropathy.

The association of peripheral neuropathy (PN) with the cumulative use of levodopa, presumably by vitamin B12 deficiency, has been well-documented in the literature. However, less is known about the L-dopa infusion-rate-dependent precipitation of pre-existing peripheral neuropathy. We report an unusual case of Parkinson's disease in a patient who presented with acute exacerbations of pre-existing peripheral neuropathy on exceeding certain rates of continuous Carbidopa-Levodopa Infusions (CLI). We present a case of a 68-year-old gentleman with a 20-year history of idiopathic Parkinson's disease with bilateral subthalamic nucleus deep brain stimulation who was started on Duopa therapy for worsening dyskinesias. Workup before initiating Duopa was significant for idiopathic sensorimotor axonal polyneuropathy, although the symptoms were well controlled with medications. Subsequently, the patient developed severe neuropathic pain within 24 hours of initiating Duopa characterized by burning and stinging in his feet. Symptoms resolved within four hours of reducing the continuous infusion rates without modifying the bolus doses. The patient was doing well with extra bolus doses to manage off periods with no further recurrence of symptoms. With the support of this case report, we would like to conclude that the acute worsening of neuropathic pain with infusion rate or duration of treatment might limit the clinical benefits of Duopa and adds to the expanding spectrum of neurotoxic side effects associated with this therapy. Further prospective studies are needed to monitor the acute worsening of neuropathic pain in patients with pre-existing PN, after initiating CLI and its association with doses of levodopa/carbidopa.

Predictors of early neurological deterioration in patients with acute ischaemic stroke with special reference to blood urea nitrogen (BUN)/creatinine ratio & urine specific gravity.

BACKGROUND & OBJECTIVES: Early neurological deterioration (END) occurs in about 20 to 40 per cent of patients with acute ischaemic stroke and results in increased mortality and functional disability. In recent studies relative dehydration has been found to be associated with END in patients with acute ischaemic stroke. This study was conducted to identify factors useful for predicting END and to assess the role of blood urea nitrogen/creatinine ratio (BUN/creatinine) and urine specific gravity (USG) as predictors of END in patients with acute ischaemic stroke. METHODS: The present study was an observational prospective study. Various parameters comprising demographic, clinical, laboratory and radiological variables along with stroke severity were assessed and studied as predictors of early neurological deterioration in 114 consecutive patients presenting to the Emergency department during 2012. BUN/creatinine >15 and USG >1.010 were studied as markers of relative dehydration contributing to END. RESULTS: Of the 114 patients enrolled in the study, END was observed in 25 (21.9%) patients. National Institutes Health Stroke Scale score (NIHSS) ≥ 12 at admission was found to be an independent risk factor for END. Amongst markers of relative dehydration, BUN/creatinine >15 at admission was found to be an independent risk factor for END, as also USG >1.010. Also, cerebral oedema and size of hypodensity >1/3 rd of the middle cerebral artery territory on cranial CT were observed to be independent risk factors for END. INTERPRETATION & CONCLUSIONS: Our study findings highlighted a possible association of relative dehydration, as indicated by BUN/creatinine ratio >15, with END along with other parameters like stroke severity at presentation, extent of hypodensity >1/3 rd of the middle cerebral artery (MCA) territory and cerebral oedema. Dehydration being a treatable condition, the use of BUN/creatinine >15 as a marker of relative dehydration, can be helpful in detecting patients with dehydration early and thus play a role in preventing END.

Design of an x-ray / ventilator synchronization system in an integrated clinical environment.

Patients in an ICU may receive daily chest x-rays. These x-rays are taken manually and may be at different phases of respiration, which limits their clinical usefulness. We examine design issues around automatically synchronizing an x-ray and ventilator in an interoperable manner, including requirements on the individual devices and new safety hazards introduced by connecting them into a system.