Resonant Acoustic Rheometry to Measure Coagulation Kinetics in Hemophilia A and Healthy Plasma: A Novel Viscoelastic Method.

Compared with conventional coagulation tests and factor-specific assays, viscoelastic hemostatic assays (VHAs) can provide a more thorough evaluation of clot formation and lysis but have several limitations including clot deformation. In this proof-of-concept study, we test a noncontact technique, termed resonant acoustic rheometry (RAR), for measuring the kinetics of human plasma coagulation. Specifically, RAR utilizes a dual-mode ultrasound technique to induce and detect surface oscillation of blood samples without direct physical contact and measures the resonant frequency of the surface oscillation over time, which is reflective of the viscoelasticity of the sample. Analysis of RAR results of normal plasma allowed defining a set of parameters for quantifying coagulation. RAR detected a flat-line tracing of resonant frequency in hemophilia A plasma that was corrected with the addition of tissue factor. Our RAR results captured the kinetics of plasma coagulation and the newly defined RAR parameters correlated with increasing tissue factor concentration in both healthy and hemophilia A plasma. These findings demonstrate the feasibility of RAR as a novel approach for VHA, providing the foundation for future studies to compare RAR parameters to conventional coagulation tests, factor-specific assays, and VHA parameters.

The Choice between Plasma-Based Common Coagulation Tests and Cell-Based Viscoelastic Tests in Monitoring Hemostatic Competence: Not an either-or Proposition.

There has been a significant interest in the last decade in the use of viscoelastic tests (VETs) to determine the hemostatic competence of bleeding patients. Previously, common coagulation tests (CCTs) such as the prothrombin time (PT) and partial thromboplastin time (PTT) were used to assist in the guidance of blood component and hemostatic adjunctive therapy for these patients. However, the experience of decades of VET use in liver failure with transplantation, cardiac surgery, and trauma has now spread to obstetrical hemorrhage and congenital and acquired coagulopathies. Since CCTs measure only 5 to 10% of the lifespan of a clot, these assays have been found to be of limited use for acute surgical and medical conditions, whereby rapid results are required. However, there are medical indications for the PT/PTT that cannot be supplanted by VETs. Therefore, the choice of whether to use a CCT or a VET to guide blood component therapy or hemostatic adjunctive therapy may often require consideration of both methodologies. In this review, we provide examples of the relative indications for CCTs and VETs in monitoring hemostatic competence of bleeding patients.

Relative Hypercoagulopathy of the SARS-CoV-2 Beta and Delta Variants when Compared to the Less Severe Omicron Variants Is Related to TEG Parameters, the Extent of Fibrin Amyloid Microclots, and the Severity of Clinical Illness.

Earlier variants of SARS-CoV-2 have been associated with hypercoagulability and an extensive formation of fibrin amyloid microclots, which are considered to contribute to the pathology of the coronavirus 2019 disease (COVID-19). The newer omicron variants appear to be far more transmissible, but less virulent, even when taking immunity acquired from previous infections or vaccination into account. We here show that while the clotting parameters associated with omicron variants are significantly raised over those of healthy, matched controls, they are raised to levels significantly lower than those seen with more severe variants such as beta and delta. We also observed that individuals infected with omicron variants manifested less extensive microclot formation in platelet-poor plasma compared with those harboring the more virulent variants. The measurement of clotting effects between the different variants acts as a kind of "internal control" that demonstrates the relationship between the extent of coagulopathies and the virulence of the variant of interest. This adds to the evidence that microclots may play an important role in reflecting the severity of symptoms observed in COVID-19.

Cerebrovascular risks with rapid blood pressure lowering in the absence of hypertensive emergency.

STUDY OBJECTIVE: In the Emergency Department (ED) setting, clinicians commonly treat severely elevated blood pressure (BP) despite the absence of evidence supporting this practice. We sought to determine if this rapid reduction of severely elevated BP in the ED has negative cerebrovascular effects. METHODS: This was a prospective quasi-experimental study occurring in an academic emergency department. The study was inclusive of patients with a systolic BP (SBP) > 180 mm Hg for whom the treating clinicians ordered intensive BP lowering with intravenous or short-acting oral agents. We excluded patients with clinical evidence of hypertensive emergency. We assessed cerebrovascular effects with measurements of middle cerebral artery flow velocities and any clinical neurological deterioration. RESULTS: There were 39 patients, predominantly African American (90%) and male (67%) and with a mean age of 50 years. The mean pre-treatment SBP was 210 ±â€¯26 mm Hg. The mean change in SBP was -38 mm Hg (95% CI -49 to -27) mm Hg. The average change in cerebral mean flow velocity was -5 (95% CI -7 to -2) cm/s, representing a -9% (95% CI -14% to -4%) change. Two patients (5.1%, 95% CI 0.52-16.9%) had an adverse neurological event. CONCLUSION: While this small cohort did not find an overall substantial change in cerebral blood flow, it demonstrated adverse cerebrovascular effects from rapid BP reduction in the emergency setting.

Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome.

Background Laminin α5ß2γ1 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity.Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2-/- pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture.Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM.Conclusions These studies show that GBM composition and function can be altered in vivovia vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.

Therapeutic Inertia and Treatment Intensification.

PURPOSE OF REVIEW: This review aims to emphasize how therapeutic inertia, the failure of clinicians to intensify treatment when blood pressure rises or remains above therapeutic goals, contributes to suboptimal blood pressure control in hypertensive populations. RECENT FINDINGS: Studies reveal that the therapeutic inertia is quite common and contributes to suboptimal blood pressure control. Quality improvement programs and standardized approaches to support antihypertensive treatment intensification are ways to combat therapeutic inertia. Furthermore, programs that utilize non-physician medical professionals such as pharmacists and nurses demonstrate promise in mitigating the effects of this important problem. Therapeutic inertia impedes antihypertensive management and requires a broad effort to reduce its effects. There is an ongoing need for renewed focus and research in this area to improve hypertension control.

New Developments in Hypertensive Encephalopathy.

PURPOSE OF REVIEW: This review summarizes the latest science on hypertensive encephalopathy and posterior reversible encephalopathy syndrome (PRES). We review the epidemiology and pathophysiology of these overlapping syndromes and discuss best practices for diagnosis and management. RECENT FINDINGS: Diagnosis of hypertensive encephalopathy largely relies on exclusion of other neurological emergencies. We review the extensive causes of PRES and its imaging characteristics. Management strategies have not changed substantially in the past decade, though newer calcium channel blockers simplify the approach to blood pressure reduction. While this alone may be sufficient for treatment of hypertensive encephalopathy in most cases, management of PRES also depends on modification of other precipitating factors. Hypertensive encephalopathy and PRES are overlapping disorders for which intensive blood pressure lowering is critical. Further research is indicated to both in diagnosis and additional management strategies for these critical conditions.

Change in Lactate Levels After Hemodialysis in Patients With End-Stage Renal Disease.

STUDY OBJECTIVE: Patients with end-stage renal disease commonly visit the emergency department (ED). The purpose of this investigation is to examine the prevalence of baseline abnormal lactate levels and to evaluate the effects of hemodialysis on serum lactate levels. METHODS: This was a prospective observational cohort study performed at an outpatient dialysis facility at an urban tertiary care hospital. The study consisted of 226 patients with end-stage renal disease who were receiving long-term hemodialysis and were enrolled during a 2-day period at the beginning of December 2015. Blood drawn for lactate levels was immediately analyzed before and after hemodialysis sessions. All patients completed their hemodialysis sessions. RESULTS: The prevalence of an abnormal lactate level (greater than 1.8 mmol/L) before hemodialysis was 17.7% (n=40). Overall, lactate levels decreased by 27% (SD 35%) after hemodialysis, with a decrease of 37% (SD 31%) for subgroups with a lactate level of 1.9 to 2.4 mmol/L, and 62% (SD 14%) with a lactate of 2.5 to 3.9 mmol/L. CONCLUSION: The data presented help providers understand the prevalence of abnormal lactate values in an outpatient end-stage renal disease population. After hemodialysis, lactate levels decreased significantly. This information may help medical providers interpret lactate values when patients with end-stage renal disease present to the ED.

Challenge of intravascular volume assessment in acute ischemic stroke.

INTRODUCTION: Retrospective data indicates that dehydration in acute ischemic stroke patients may be common, even though these patients frequently have elevated blood pressure. We sought to evaluate clinical and laboratory measures of intravascular volume status compared to more objective measures using ultrasound measurements of the inferior vena cava (IVC). METHODS: This was a prospective observation study of acute ischemic stroke patients in the emergency department. Patients with NIH stroke scale ≥4 within 12 h of symptom onset were included. A trained ultrasonographer performed bi-dimensional imaging of the IVC with passive respiration to determine the percent inspiratory collapse and maximum diameter. We defined low intravascular volume as >50% IVC collapse and a maximal diameter < 2.1 cm. Analysis was limited to patients with confirmed ischemic stroke. RESULTS: There were 42 patients, of whom 31 had confirmed acute ischemic stroke. The mean age was 65 ±â€¯15 years, 52% were female, and 71% were hypertensive. The median NIH stroke scale score was 7 (IQR 5-15). Based on IVC ultrasound, low intravascular volume was present in 63% (95% CI 44-80%) of patients. A higher proportion of hypertensive patients had low intrasvascular volume (72% vs. 33%). There was poor correlation between IVC assessment of intrasvascular volume and blinded clinician assessment or laboratory markers of dehydration. CONCLUSION: The majority of ED acute ischemic stroke patients in this sample were hypertensive and demonstrated low intravascular volume based on IVC ultrasound.

The Advanced Reperfusion Era: Implications for Emergency Systems of Ischemic Stroke Care.

Large vessel ischemic stroke is a leading cause of morbidity and mortality throughout the world. Recent advances in endovascular stroke treatment are changing the treatment paradigm for these patients. This concepts article summarizes the time-dependent nature of stroke care and evaluates the recent advancements in endovascular treatment. These advancements have significant implications for out-of-hospital, hospital, and regional systems of stroke care. Emergency medicine clinicians have a central role in implementing these systems that will ensure timely treatment of patients and selection of those who may benefit from endovascular care.

Hemodynamic characteristics of suspected stroke in the emergency department.

BACKGROUND: Systemic hemodynamic characteristics of patients with suspected acute ischemic stroke are poorly described. The objective of this study was to identify baseline hemodynamic characteristics of emergency department (ED) patients with suspected acute stroke. METHODS: This was a planned analysis of the stroke cohort from a multicenter registry of hemodynamic profiling of ED patients. The registry prospectively collected non-invasive hemodynamic measurements of patients with suspicion for acute stroke within 12h of symptom onset. K-means cluster analysis identified hemodynamic phenotypes of all suspected stroke patients, and we performed univariate hemodynamic comparisons based on final diagnoses. RESULTS: There were 72 patients with suspected acute stroke, of whom 38 (53%) had a final diagnosis of ischemic stroke, 10 (14%) had hemorrhagic stroke, and 24 (33%) had transient ischemic attack (TIA). Analysis defined three phenotypic clusters based on low or normal cardiac index (CI) and normal or high systemic vascular resistance index (SVRI). Patients with TIA had lower mean CI (2.3L/min/m2) compared to hemorrhagic or ischemic stroke patients (p<0.01). CONCLUSIONS: The study demonstrates the feasibility of defining hemodynamic phenotypes of ED patients with suspected stroke.

Volume of Plasma Expansion and Functional Outcomes in Stroke.

BACKGROUND: Plasma expansion in acute ischemic stroke has potential to improve cerebral perfusion, but the long-term effects on functional outcome are mixed in prior trials. The goal of this study was to evaluate how the magnitude of plasma expansion affects neurological recovery in acute stroke. METHODS: This was a secondary analysis of data from the Albumin in Acute Stroke Part 2 trial investigating the relationship between the magnitude of overall intravenous volume infusion (crystalloid and colloid) to clinical outcome. The data were inclusive of 841 patients with a mean age of 64 years and a median National Institutes of Health Stroke Scale (NIHSS) of 11. In a multivariable-adjusted logistic regression model, this analysis tested the volume of plasma expansion over the first 48 h of hospitalization as a predictor of favorable outcome, defined as either a modified Rankin Scale score of 0 or 1 or a NIHSS score of 0 or 1 at 90 days. This model included all study patients, irrespective of albumin or isotonic saline treatment. RESULTS: Patients that received higher volumes of plasma expansion more frequently had large vessel ischemic stroke and higher NIHSS scores. The multivariable-adjusted model revealed that there was decreased odds of a favorable outcome for every 250 ml additional volume plasma expansion over the first 48 h (OR 0.91, 95 % CI, 0.88-0.94). CONCLUSIONS: The present study demonstrates an association between greater volume of plasma expansion and worse neurological recovery.

Routine Chest Radiography Is Not Necessary After Ultrasound-Guided Right Internal Jugular Vein Catheterization.

OBJECTIVES: Central venous catheter placement is a common procedure performed on critically ill patients. Routine postprocedure chest radiographs are considered standard practice. We hypothesize that the rate of clinically relevant complications detected on chest radiographs following ultrasound-guided right internal jugular vein catheterization is exceedingly low. DESIGN: Retrospective chart review. SETTING: Adult ICUs, emergency departments, and general practice units at an academic tertiary care hospital system. PATIENTS: All 1,322 ultrasound-guided right internal jugular vein central venous catheter attempts at an academic tertiary care hospital system over a 1-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from standardized procedure notes and postprocedure chest radiographs were extracted and individually reviewed to verify the presence of pneumothorax or misplacement, and any intervention performed for either complication. The overall success rate of ultrasound-guided right internal jugular vein central venous catheter placement was 96.9% with an average of 1.3 attempts. There was only one pneumothorax (0.1% [95% CI, 0-0.4%]), and the rate of catheter misplacement requiring repositioning or replacement was 1.0% (95% CI, 0.6-1.7%). There were no arterial placements found on chest radiographs. Multivariate regression analysis showed no correlation between high-risk patient characteristics and composite complication rate. CONCLUSIONS: In a large teaching hospital system, the overall rate of clinically relevant complications detected on chest radiographs following ultrasound-guided right internal jugular vein catheterization is exceedingly low. Routine chest radiograph after this common procedure is an unnecessary use of resources and may delay resuscitation of critically ill patients.

Therapies to Reduce Blood Pressure Acutely.

Clinicians make frequent treatment decisions regarding acute blood pressure reduction for the critically ill. Key to the decision making process is a balance between reducing arterial wall stress and maintaining perfusion to vital organs. In this article, we review the physiological considerations underlying acute blood pressure management, including the concept of cerebral autoregulation and its adaptations to chronic hypertension. We then discuss available pharmacological interventions suited for reducing blood pressure acutely. We also discuss specific blood pressure targets in common critical illnesses and consider future directions in this therapeutic area.

When to Stop CPR and When to Perform Rhythm Analysis: Potential Confusion Among ACLS Providers.

BACKGROUND: Health care providers nationwide are routinely trained in Advanced Cardiac Life Support (ACLS), an American Heart Association program that teaches cardiac arrest management. Recent changes in the ACLS approach have de-emphasized routine pulse checks in an effort to promote uninterrupted chest compressions. We hypothesized that this new ACLS algorithm may lead to uncertainty regarding the appropriate action following detection of a pulse during a cardiac arrest. METHODS: We conducted an observational study in which a Web-based survey was sent to ACLS-trained medical providers at 4 major urban tertiary care centers in the United States. The survey consisted of 5 multiple-choice, scenario-based ACLS questions, including our question of interest. Adult staff members with a valid ACLS certification were included. RESULTS: A total of 347 surveys were analyzed. The response rate was 28.1%. The majority (53.6%) of responders were between 18 and 32 years old, and 59.9% were female. The majority (54.2%) of responders incorrectly stated that they would continue CPR and possibly administer additional therapies when a team member detects a pulse immediately following defibrillation. Secondarily, only 51.9% of respondents correctly chose to perform a rhythm check following 2 minutes of CPR. The other 3 survey questions were correctly answered an average of 89.1% of the time. CONCLUSION: Confusion exists regarding whether or not CPR and cardiac medications should be continued in the presence of a pulse. Education may be warranted to emphasize avoiding compressions and medications when a palpable pulse is detected.

Endotracheal Intubation in Patients Treated for Prehospital Status Epilepticus.

INTRODUCTION: Limited data describe the frequency, timing, or indications for endotracheal intubation (ETI) in patients with status epilepticus. A better understanding of the characteristics of patients with status epilepticus requiring airway interventions could inform clinical care. We sought to characterize ETI use in patients with prehospital status epilepticus. METHODS: This study was a secondary analysis of the Rapid Anticonvulsant Medication Prior to Arrival Trial, a multi-center, randomized trial comparing intravenous lorazepam to intramuscular midazolam for prehospital status epilepticus treatment. Subjects received ETI in the prehospital, Emergency Department (ED), or inpatient setting at the discretion of caregivers. RESULTS: Of 1023 enrollments, 218 (21 %) received ETI. 204 (93.6 %) of the ETIs were performed in the hospital and 14 (6.4 %) in the prehospital setting. Intubated patients were older (52 vs 41 years, p < 0.001), and men underwent ETI more than women (26 vs 21 %, p = 0.047). Patients with ongoing seizures on ED arrival had a higher rate of ETI (32 vs 16 %, p < 0.001), as did those who received rescue anti-seizure medication (29 vs 20 %, p = 0.004). Mortality was higher for intubated patients (7 vs 0.4 %, p < 0.001). Most ETI (n = 133, 62 %) occurred early (prior to or within 30 min after ED arrival), and late ETI was associated with higher mortality (14 vs 3 %, p = 0.002) than early ETI. CONCLUSIONS: ETI is common in patients with status epilepticus, particularly among the elderly or those with refractory seizures. Any ETI and late ETI are both associated with higher mortality.

Purifying colloidal nanoparticles through ultracentrifugation with implications for interfaces and materials.

Liquid-phase processing and colloidal self-assembly will be critical to the successful implementation of nanotechnology in the next generation of materials and devices. A key hurdle to realizing this will be the development of efficient methods to purify nanomaterials composed of a variety of shapes, including nanocrystals, nanotubes, and nanoplates. Although density-gradient ultracentrifugation (DGU) has long been appreciated as a valuable tool for separating biological macromolecules and components, the method has recently emerged as an effective way to purify colloidal nanoparticles by size and optical and electronic properties. In this feature article, we review our recent contributions to this growing field, with an emphasis on some of the implications that our results have for interfaces and materials. Through transient or isopycnic DGU performed in both aqueous and organic environments, we demonstrate some explicit examples of how the mechanical, electronic, and optical properties of thin films assembled from two specific colloidal nanomaterials--single-walled carbon nanotubes and silicon nanocrystals--can be modified in response to fractionation.

Phase separation and the 'coffee-ring' effect in polymer-nanocrystal mixtures.

The coupling between the 'coffee-ring' effect and liquid-liquid phase separation is examined for ternary mixtures of solvent, polymer and semiconductor nanocrystal. Specifically, we study mixtures of toluene, polystyrene (PS) and colloidal silicon nanocrystals (SiNCs) using real-space imaging and spectroscopic techniques to resolve the kinetic morphology of the drying front for varied molecular weight of the PS. Our results demonstrate that the size of the polymer has a significant impact on both phase-separation and drying, and we relate these observations to simulations, measured and predicted binodal curves, and the observed shape of the flow field at the contact line. The results inform a deposition process that reduces the influence of drying instabilities for low-molecular-weight polymers while paving the way for more detailed and generic computational descriptions of drying instabilities in complex fluids.

Short-Stay Units vs Routine Admission From the Emergency Department in Patients With Acute Heart Failure: The SSU-AHF Randomized Clinical Trial.

Importance: More than 80% of patients who present to the emergency department (ED) with acute heart failure (AHF) are hospitalized. With more than 1 million annual hospitalizations for AHF in the US, safe and effective alternatives are needed. Care for AHF in short-stay units (SSUs) may be safe and more efficient than hospitalization, especially for lower-risk patients, but randomized clinical trial data are lacking. Objective: To compare the effectiveness of SSU care vs hospitalization in lower-risk patients with AHF. Design, Setting, and Participants: This multicenter randomized clinical trial randomly assigned low-risk patients with AHF 1:1 to SSU or hospital admission from the ED. Patients received follow-up at 30 and 90 days post discharge. The study began December 6, 2017, and was completed on July 22, 2021. The data were analyzed between March 27, 2020, and November 11, 2023. Intervention: Randomized post-ED disposition to less than 24 hours of SSU care vs hospitalization. Main Outcomes and Measures: The study was designed to detect at least 1-day superiority for a primary outcome of days alive and out of hospital (DAOOH) at 30-day follow-up for 534 participants, with an allowance of 10% participant attrition. Due to the COVID-19 pandemic, enrollment was truncated at 194 participants. Before unmasking, the primary outcome was changed from DAOOH to an outcome with adequate statistical power: quality of life as measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). The KCCQ-12 scores range from 0 to 100, with higher scores indicating better quality of life. Results: Of the 193 patients enrolled (1 was found ineligible after randomization), the mean (SD) age was 64.8 (14.8) years, 79 (40.9%) were women, and 114 (59.1%) were men. Baseline characteristics were balanced between arms. The mean (SD) KCCQ-12 summary score between the SSU and hospitalization arms at 30 days was 51.3 (25.7) vs 45.8 (23.8) points, respectively (P = .19). Participants in the SSU arm had 1.6 more DAOOH at 30-day follow-up than those in the hospitalization arm (median [IQR], 26.9 [24.4-28.8] vs 25.4 [22.0-27.7] days; P = .02). Adverse events were uncommon and similar in both arms. Conclusions and Relevance: The findings show that the SSU strategy was no different than hospitalization with regard to KCCQ-12 score, superior for more DAOOH, and safe for lower-risk patients with AHF. These findings of lower health care utilization with the SSU strategy need to be definitively tested in an adequately powered study. Trial Registration: ClinicalTrials.gov Identifier: NCT03302910.

Corrigendum: Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies.

[This corrects the article DOI: 10.3389/fimmu.2023.1230049.].