Cardiovascular adverse events in patients with hepatocellular carcinoma receiving vascular endothelial growth factor inhibitors.

BACKGROUND: Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs) and anti-angiogenics, are first-line therapies for advanced and metastatic hepatocellular carcinoma. Although TKIs have a greater potential for off-target adverse effects compared with bevacizumab (anti-angiogenics), a direct comparison of the risk of cardiovascular adverse events between these two types of therapies has not been performed. OBJECTIVE: To compare the incidence of and characterize cardiovascular adverse events in patients with hepatocellular carcinoma receiving TKIs versus bevacizumab. METHODS: This cohort study included adult patients with hepatocellular carcinoma who received first-line TKIs (sorafenib or lenvatinib) or bevacizumab at two academic medical centers and one community cancer center from September 2018 to August 2021. The primary outcome was risk of cardiovascular adverse events. Major secondary outcomes included the incidence of individual types of cardiovascular adverse events and risk factors associated with major adverse cardiovascular events (MACE). RESULTS: The study included 221 patients (159 TKI patients; 62 bevacizumab patients). At a median follow-up of 5 months, the probability of cardiovascular adverse events was not significantly different between the two groups (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.58-1.24; p = 0.390). The cumulative incidence of cardiovascular events was highest in patients receiving lenvatinib (sub-distribution hazard ratio [SHR]: 1.53; 95% CI: 1.02-2.30) compared with those receiving sorafenib (reference) or bevacizumab (SHR: 1.05; 95% CI: 0.68-1.64) after adjustment for comorbidities, liver transplant status, and presence of portal vein thrombosis at baseline. Cardiovascular adverse events were observed in 151 (68%) patients, and MACE were observed in 27 (12%) patients. Risk factors associated with MACE were hypertension (SHR: 3.5; 95% CI: 0.9087-15.83; p = 0.086), prior history of MACE (SHR: 2.01; 95% CI: 0.83-4.87; p = 0.124), and tobacco use (SHR: 2.85; 95% CI: 0.90-8.97; p = 0.074). CONCLUSIONS: Cardiovascular risk was not significantly different between TKIs and bevacizumab. Lenvatinib appears to have the highest risk of cardiovascular adverse events among these first-line VEGF inhibitors.

Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and Are Blocked by Lanthanides.

Canonical inflammasome activation induces a caspase-1/gasdermin D (Gsdmd)-dependent lytic cell death called pyroptosis that promotes antimicrobial host defense but may contribute to sepsis. The nature of the caspase-1-dependent change in plasma membrane (PM) permeability during pyroptotic progression remains incompletely defined. We assayed propidium(2+) (Pro(2+)) influx kinetics during NLRP3 or Pyrin inflammasome activation in murine bone marrow-derived macrophages (BMDMs) as an indicator of this PM permeabilization. BMDMs were characterized by rapid Pro(2+) influx after initiation of NLRP3 or Pyrin inflammasomes by nigericin (NG) or Clostridium difficile toxin B (TcdB), respectively. No Pro(2+) uptake in response to NG or TcdB was observed in Casp1(-/-) or Asc(-/-) BMDMs. The cytoprotectant glycine profoundly suppressed NG and TcdB-induced lysis but not Pro(2+) influx. The absence of Gsdmd expression resulted in suppression of NG-stimulated Pro(2+) influx and pyroptotic lysis. Extracellular La(3+) and Gd(3+) rapidly and reversibly blocked the induced Pro(2+) influx and markedly delayed pyroptotic lysis without limiting upstream inflammasome assembly and caspase-1 activation. Thus, caspase-1-driven pyroptosis requires induction of initial prelytic pores in the PM that are dependent on Gsdmd expression. These PM pores also facilitated the efflux of cytosolic ATP and influx of extracellular Ca(2+) Although lanthanides and Gsdmd deletion both suppressed PM pore activity and pyroptotic lysis, robust IL-1ß release was observed in lanthanide-treated BMDMs but not in Gsdmd-deficient cells. This suggests roles for Gsdmd in both passive IL-1ß release secondary to pyroptotic lysis and in nonlytic/nonclassical IL-1ß export.

NLRP3 inflammasome signaling is activated by low-level lysosome disruption but inhibited by extensive lysosome disruption: roles for K+ efflux and Ca2+ influx.

Nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) is a cytosolic protein that nucleates assembly of inflammasome signaling platforms, which facilitate caspase-1-mediated IL-1ß release and other inflammatory responses in myeloid leukocytes. NLRP3 inflammasomes are assembled in response to multiple pathogen- or environmental stress-induced changes in basic cell physiology, including the destabilization of lysosome integrity and activation of K(+)-permeable channels/transporters in the plasma membrane (PM). However, the quantitative relationships between lysosome membrane permeabilization (LMP), induction of increased PM K(+) permeability, and activation of NLRP3 signaling are incompletely characterized. We used Leu-Leu-O-methyl ester (LLME), a soluble lysosomotropic agent, to quantitatively track the kinetics and extent of LMP in relation to NLRP3 inflammasome signaling responses (ASC oligomerization, caspase-1 activation, IL-1ß release) and PM cation fluxes in murine bone marrow-derived dendritic cells (BMDCs). Treatment of BMDCs with submillimolar (≤1 mM) LLME induced slower and partial increases in LMP that correlated with robust NLRP3 inflammasome activation and K(+) efflux. In contrast, supramillimolar (≥2 mM) LLME elicited extremely rapid and complete collapse of lysosome integrity that was correlated with suppression of inflammasome signaling. Supramillimolar LLME also induced dominant negative effects on inflammasome activation by the canonical NLRP3 agonist nigericin; this inhibition correlated with an increase in NLRP3 ubiquitination. LMP elicited rapid BMDC death by both inflammasome-dependent pyroptosis and inflammasome-independent necrosis. LMP also triggered Ca(2+) influx, which attenuated LLME-stimulated NLRP3 inflammasome signaling but potentiated LLME-induced necrosis. Taken together, these studies reveal a previously unappreciated signaling network that defines the coupling between LMP, changes in PM cation fluxes, cell death, and NLRP3 inflammasome activation.

Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1ß secretion in response to ATP.

Although extracellular ATP is abundant at sites of inflammation, its role in activating inflammasome signalling in neutrophils is not well characterized. In the current study, we demonstrate that human and murine neutrophils express functional cell-surface P2X7R, which leads to ATP-induced loss of intracellular K(+), NLRP3 inflammasome activation and IL-1ß secretion. ATP-induced P2X7R activation caused a sustained increase in intracellular [Ca(2+)], which is indicative of P2X7R channel opening. Although there are multiple polymorphic variants of P2X7R, we found that neutrophils from multiple donors express P2X7R, but with differential efficacies in ATP-induced increase in cytosolic [Ca(2+)]. Neutrophils were also the predominant P2X7R-expressing cells during Streptococcus pneumoniae corneal infection, and P2X7R was required for bacterial clearance. Given the ubiquitous presence of neutrophils and extracellular ATP in multiple inflammatory conditions, ATP-induced P2X7R activation and IL-1ß secretion by neutrophils likely has a significant, wide ranging clinical impact.

K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling.

Perturbation of intracellular ion homeostasis is a major cellular stress signal for activation of NLRP3 inflammasome signaling that results in caspase-1-mediated production of IL-1ß and pyroptosis. However, the relative contributions of decreased cytosolic K(+) concentration versus increased cytosolic Ca(2+) concentration ([Ca(2+)]) remain disputed and incompletely defined. We investigated roles for elevated cytosolic [Ca(2+)] in NLRP3 activation and downstream inflammasome signaling responses in primary murine dendritic cells and macrophages in response to two canonical NLRP3 agonists (ATP and nigericin) that facilitate primary K(+) efflux by mechanistically distinct pathways or the lysosome-destabilizing agonist Leu-Leu-O-methyl ester. The study provides three major findings relevant to this unresolved area of NLRP3 regulation. First, increased cytosolic [Ca(2+)] was neither a necessary nor sufficient signal for the NLRP3 inflammasome cascade during activation by endogenous ATP-gated P2X7 receptor channels, the exogenous bacterial ionophore nigericin, or the lysosomotropic agent Leu-Leu-O-methyl ester. Second, agonists for three Ca(2+)-mobilizing G protein-coupled receptors (formyl peptide receptor, P2Y2 purinergic receptor, and calcium-sensing receptor) expressed in murine dendritic cells were ineffective as activators of rapidly induced NLRP3 signaling when directly compared with the K(+) efflux agonists. Third, the intracellular Ca(2+) buffer, BAPTA, and the channel blocker, 2-aminoethoxydiphenyl borate, widely used reagents for disruption of Ca(2+)-dependent signaling pathways, strongly suppressed nigericin-induced NLRP3 inflammasome signaling via mechanisms dissociated from their canonical or expected effects on Ca(2+) homeostasis. The results indicate that the ability of K(+) efflux agonists to activate NLRP3 inflammasome signaling can be dissociated from changes in cytosolic [Ca(2+)] as a necessary or sufficient signal.

Neutrophil IL-1ß processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux.

Although neutrophils are the most abundant cells in acute infection and inflammation, relatively little attention has been paid to their role in inflammasome formation and IL-1ß processing. In the present study, we investigated the mechanism by which neutrophils process IL-1ß in response to Streptococcus pneumoniae. Using a murine model of S. pneumoniae corneal infection, we demonstrated a requirement for IL-1ß in bacterial clearance, and we showed that Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 are essential for IL-1ß production and bacterial killing in the cornea. Neutrophils in infected corneas had multiple specks with enzymatically active caspase-1 (YVAD-FLICA 660), and bone marrow neutrophils stimulated with heat-killed S. pneumoniae (signal 1) and pneumolysin (signal 2) exhibited multiple specks when stained for NLRP3, ASC, or Caspase-1. High-molecular mass ASC complexes were also detected, consistent with oligomer formation. Pneumolysin induced K(+) efflux in neutrophils, and blocking K(+) efflux inhibited caspase-1 activation and IL-1ß processing; however, neutrophils did not undergo pyroptosis, indicating that K(+) efflux and IL-1ß processing is not a consequence of cell death. There was also no role for lysosomal destabilization or neutrophil elastase in pneumolysin-mediated IL-1ß processing in neutrophils. Taken together, these findings demonstrate an essential role for neutrophil-derived IL-1ß in S. pneumoniae infection, and they elucidate the role of the NLRP3 inflammasome in cleavage and secretion of IL-1ß in neutrophils. Given the ubiquitous presence of neutrophils in acute bacterial and fungal infections, these findings will have implications for other microbial diseases.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

Prevalence of vertebral artery origin stenosis and occlusion in outpatient extracranial ultrasonography.

BACKGROUND AND PURPOSE: Most data on the prevalence of vertebral artery origin (VAo) disease is derived from hospital-based studies of patients with posterior circulation strokes and TIA. The prevalence of VAo disease in patients without posterior circulation symptoms or asymptomatic patients is poorly characterized. Our objective was to examine the prevalence of VAo stenosis and occlusion in consecutive patients, presenting for extracranial ultrasonography to an outpatient laboratory. METHODS: We retrospectively identified 2490 consecutive extracranial duplex studies performed in an ambulatory neurovascular ultrasound laboratory. All studies were reviewed for the presence of >50% VAo stenosis, defined as a PSV > 114 cm/s, and VA occlusion. We also reviewed the prevalence of >50% carotid stenosis, defined as a PSV > 120 cm/s, in the same population, to draw comparisons with VAo stenosis prevalence. RESULTS: We identified right VAo stenosis in 52/1955 (2.7%) and occlusion in 74/1955 (3.9%) and left-sided VAo stenosis in 45/1973 (2.5%) and occlusion in 64/1973 (3.6%). The prevalence of having any (either right or left) VAo stenosis or occlusion was 8.2% and 1.4% had bilateral VAo stenosis or occlusion. Right carotid stenosis and occlusion was found in 236/2399 (9.8%) and 53/2399 (2.2%) and left carotid stenosis and occlusion in 236/2397 (9.8%) and 45/2397 (1.9%), respectively. Any carotid disease, either right or left, was present in 18.9% and 4.7% had bilateral carotid disease. CONCLUSION: Although less prevalent than cervical carotid disease, we found that approximately 8% of patients who presented to an ambulatory ultrasound laboratory had >50% VAo disease.

Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

OBJECTIVE: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. METHODS: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. RESULTS: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). CONCLUSION: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

Prevalence of vertebral artery origin stenosis and occlusion in outpatient extracranial ultrasonography.

BACKGROUND AND PURPOSE: Vertebral artery origin stenosis prevalence. Most data on the prevalence of vertebral artery origin (VAo) disease is derived from hospital-based studies of patients with posterior circulation strokes and TIA. The prevalence of VAo disease in patients without posterior circulation symptoms or asymptomatic patients is poorly characterized. Our objective was to examine the prevalence of VAo stenosis and occlusion in consecutive patients, presenting for extracranial ultrasonography at an outpatient laboratory. METHODS: We retrospectively identified 2490 consecutive extracranial duplex studies performed in an ambulatory neurovascular ultrasound laboratory. All studies were reviewed for the presence of >50% VAo stenosis, defined as a PSV > 114 cm/s, and VA occlusion. We also reviewed the prevalence of >50% carotid stenosis, defined as a PSV > 120 cm/s, in the same population, to draw comparisons with VAo stenosis prevalence. RESULTS: We identified right VAo stenosis in 52/1955 (2.7%) and occlusion in 74/ 1955 (3.9%) and left-sided VAo stenosis in 45/1973 (2.5%) and occlusion in 64/1973 (3.6%). The prevalence of having any (either right or left) VAo stenosis or occlusion was 8.2% and 1.4% had bilateral VAo stenosis or occlusion. Right carotid stenosis and occlusion was found in 236/2399 (9.8%) and 53/2399 (2.2%), and left carotid stenosis and occlusion in 236/2397 (9.8%) and 45/2397 (1.9%), respectively. Any carotid disease, either right or left, was present in 18.9% and 4.7% had bilateral carotid disease. CONCLUSION: Although less prevalent than cervical carotid disease, we found that approximately 8% of patients who reported to an ambulatory ultrasound laboratory had >50% VAo disease.

Racial and ethnic disparities in stroke subtypes: a multiethnic sample of patients with stroke.

Stroke subtypes have been reported to differ by race and ethnic subgroups and have not been adequately explained. We aim to evaluate if the prevalence of vascular risk factors accounts for differences observed in stroke subtypes by race/ethnicity. Patients with acute stroke were prospectively enrolled in the Miami Stroke Registry. Patients' demographic, clinical and radiological characteristics were systematically collected. Stroke subtypes were ascertained using TOAST criteria. The sample was divided into Non-Hispanic Whites (NHW), Hispanics, African Americans (AA), and Non-Hispanic Black Caribbean (NHBC). Univariable and multivariable logistic regression analyses were performed to assess differences among groups. Among 473 stroke patients (mean age 64 ± 14 years; 63.7% were men) of which 52.9% were Hispanic, 22.6% were AA, 13.5% NHBC and 11.0% were NHW. Large artery atherosclerosis was more prevalent in NHBC (OR 1.74, 95% CI 1.02-2.97) than in the other groups. Adjusting for covariates rendered the association not significant (OR 1.71, 95% CI 0.93-3.16). Cardioembolism was more frequent in Hispanics (OR 1.94, 95% CI 1.28-2.96) and NHW (OR 2.66, 95% CI 1.42-4.96) as compared to NHBC and AA combined. Adjusting for covariates, the association was no longer significant for Hispanics but was further strengthened for NHW (OR 3.02, 95% CI 1.42-6.42). Our results suggest that the vascular risk factors prevalence among different racial and ethnic groups partially explains disparities found in the prevalence of some stroke subtypes. Addressing health disparities remains an important public health aspect of stroke prevention.

Effects of remote ischemic preconditioning on the coagulation profile of patients with aneurysmal subarachnoid hemorrhage: a case-control study.

BACKGROUND: Animal studies suggest that ischemic preconditioning prolongs coagulation times. OBJECTIVE: Because coagulation changes could hinder the translation of preconditioning into clinical settings where hemorrhage may be an issue, such as ischemic or hemorrhagic stroke, we evaluated the effects of remote ischemic preconditioning (RIPC) on coagulation in patients undergoing RIPC after aneurysmal subarachnoid hemorrhage (SAH). METHODS: Twenty-one patients with SAH (mean age, 56.3 years) underwent 137 RIPC sessions 2 to 12 days after SAH, each consisting of 3 to 4 cycles of 5 to 10 minutes of lower limb ischemia followed by reperfusion. Partial thromboplastin time (PTT), prothrombin time (PT), and international normalized ratio (INR) were analyzed before and after sessions. Patients were followed for hemorrhagic complications. RESULTS: No immediate effect was identified on PTT (mean pre-RIPC, 27.62 s; post-RIPC, 27.54 s; P = .82), PT (pre-RIPC, 10.77 s; post-RIPC, 10.81 s; P = .59), or INR (pre-RIPC, 1.030; post-RIPC, 1.034; P = .57) after each session. However, statistically significant increases in PT and INR were identified after exposure to at least 4 sessions (mean PT pre-RIPC, 11.33 s; post-RIPC, 12.1 s; P = .01; INR pre-RIPC, 1.02; post-RIPC, 1.09; P = .014, PTT pre-RIPC, 27.4 s; post-RIPC, 27.85 s; P = .092) with a direct correlation between the number of sessions and the degree of increase in PT (Pearson correlation coefficient = 0.59, P = .007) and INR (Pearson correlation coefficient = 0.57, P = .010). Prolonged coagulation times were not observed in controls. No hemorrhagic complications were associated with the procedure. CONCLUSION: RIPC by limb ischemia appears to prolong the PT and INR in human subjects with SAH after at least 4 sessions, correlating with the number of sessions. However, values remained within normal range and there were no hemorrhagic complications.

Transcranial Doppler velocities in a large, healthy population.

BACKGROUND: Transcranial Doppler (TCD) ultrasonography has been extensively used in the evaluation and management of patients with cerebrovascular disease since the clinical application was first described in 1982 by Aaslid and colleagues TCD is a painless, safe, and noninvasive diagnostic technique that measures blood flow velocity in various cerebral arteries. Numerous commercially available TCD devices are currently approved for use worldwide, and TCD is recognized to have an established clinical value for a variety of clinical indications and settings. Although many studies have reported normal values, there have been few recently, and none to include a large cohort of healthy subjects across age, race, and gender. As more objective, automated processes are being developed to assist with the performance and interpretation of TCD studies, and with the potential to easily compare results against a reference population, it is important to define stable normal values and variances across age, race, and gender, with clear understanding of variability of the measurements, as well as the yield from various anatomic segments. METHODS: To define normal TCD values in a healthy population, we enrolled 364 healthy subjects, ages 18-80 years, to have a complete, nonimaging TCD examination. Subjects with known or suspected cerebrovascular disorders, systemic disorders with cerebrovascular effects, as well as those with known hypertension, diabetes, stroke, coronary artery disease, or myocardial infarction, were excluded. Self-reported ethnicity, handedness, BP, and BMI were recorded. A complete TCD examination was performed by a single experienced sonographer, using a single gate nonimaging TCD device, and a standardized protocol to interrogate up to 23 arterial segments. Individual Doppler spectra were saved for each segment, with velocity and pulsatility index (PI) values calculated using the instrument's automated waveform tracking function. Descriptive analysis was done to determine the mean velocities and PI, and all data were analyzed for changes by decade of age, sex race, handedness, BMI, and BP. RESULTS: Among the key intracranial segments, mean blood flow velocities (MBFV) were highest in the MCA and lowest in the PCA across all ages, sexes, and ethnic groups. There was no difference in the MBFVs between left and right side segments of the Circle of Willis, with the exception of the distal M1 (P = .022) and the C1 (P < .0001), both slightly higher on the left. MBFV were higher among women than men in all segments except for the OA. MBFV decreased with advancing age in both men and women, but this was specific to Caucasian subjects. There were lower velocities in the OA for non-Caucasians. The PI was lower in the left VA (P < .0001), and for most segments was lower in women than men. The PI increased with age in all segments for women, but only in some segments for men, and this finding was also specific to Caucasian subjects. The yield of usable data ranged from 99.7% for the VA and BA, to 88.2% for C2. CONCLUSION: Our study provides normal, reference TCD values for a large cohort of healthy subjects across a wide range of age, sex, and race groups. We observed decreased MBFV and increased PI with aging, and higher MBFV in women. There were few differences in MBFV related to side or ethnicity, but the MFBV and PI changes with age were specific to Caucasians. We provide means and standard deviations of MBFVs across various demographic groups in key intracranial arteries. Such normal TCD values across age, gender, and ethnic groups in healthy subjects represent a useful reference tool for detecting individuals with TCD values outside normal limits and at increased vascular risk. TCD studies in large multiethnic populations are still required to determine differences in brain hemodynamics across various ethnic groups.

Moderate correlation between breath-holding and CO(2) inhalation/hyperventilation methods for transcranial doppler evaluation of cerebral vasoreactivity.

BACKGROUND: Both CO(2) inhalation followed by hyperventilation and breath-holding have been utilized to measure cerebral vasomotor reactivity (VMR) but their correlation has been poorly studied and understood. METHODS: A retrospective study was conducted in 143 subjects (62.6 ± 15.8 years old, 64% men) with transcranial Doppler ultrasonography measurement of mean flow velocity (MFV) at baseline, after 30 seconds of breath-holding, and after CO(2) inhalation followed by hyperventilation, in the left and right middle cerebral artery. Breath-holding index (BHI) was calculated as the percentage of MFV increase from baseline per second of apnea. CO(2) inhalation/hyperventilation index (CO(2) /HV) was calculated as the percentage of MFV difference between CO(2) inhalation and hyperventilation. RESULTS: There were 75 carotid arteries with >70% stenosis or occlusion, and 18 middle cerebral arteries with >50% stenosis or occlusion. The mean BHI was 0.93 ± 0.7 and 0.89 ± 0.6, whereas the mean CO(2) /HV was 61 ± 26% and 60 ± 26%, respectively, on the right and left sides. The correlation between BHI and CO(2) /HV was moderate on the right (r = 0.33; p < 0.01) and left sides (r = 0.38; p < 0.01). Multivariate linear regression analysis indicated that age (p = 0.01) and history of stroke (p = 0.007) were associated independently with an impaired VMR on the right as measured by CO(2) /HV. No predictors for impaired VMR by CO(2) /HV on the left and by BHI on either side were found. CONCLUSIONS: CO(2) /HV and BHI are only moderately correlated. Further studies are necessary to determine which method more accurately predicts clinical morbidity. © 2012 Wiley Periodicals, Inc. J Clin Ultrasound 2012; Published online in Wiley Online Library.

Recommendations for management of patients with carotid stenosis.

Stroke is a one of the leading causes of morbidity and mortality in the world. Carotid atherosclerosis is recognized as an important factor in stroke pathophysiology and represents a key target in stroke prevention; multiple treatment modalities have been developed to battle this disease. Multiple randomized trials have shown the efficacy of carotid endarterectomy in secondary stroke prevention. Carotid stenting, a newer treatment option, presents a less invasive alternative to the surgical intervention on carotid arteries. Advances in medical therapy have also enabled further risk reduction in the overall incidence of stroke. Despite numerous trials and decades of clinical research, the optimal management of symptomatic and asymptomatic carotid disease remains controversial. We will attempt to highlight some of the pivotal trials already completed, discuss the current controversies and complexities in the treatment decision-making, and postulate on what likely lies ahead. This paper will highlight the complexities of decision-making optimal treatment recommendations for patients with symptomatic and asymptomatic carotid stenosis.

Are initial radiographic and clinical scales associated with subsequent intracranial pressure and brain oxygen levels after severe traumatic brain injury?

BACKGROUND: Prediction of clinical course and outcome after severe traumatic brain injury (TBI) is important. OBJECTIVE: To examine whether clinical scales (Glasgow Coma Scale [GCS], Injury Severity Score [ISS], and Acute Physiology and Chronic Health Evaluation II [APACHE II]) or radiographic scales based on admission computed tomography (Marshall and Rotterdam) were associated with intensive care unit (ICU) physiology (intracranial pressure [ICP], brain tissue oxygen tension [PbtO2]), and clinical outcome after severe TBI. METHODS: One hundred one patients (median age, 41.0 years; interquartile range [26-55]) with severe TBI who had ICP and PbtO2 monitoring were identified. The relationship between admission GCS, ISS, APACHE II, Marshall and Rotterdam scores and ICP, PbtO2, and outcome was examined by using mixed-effects models and logistic regression. RESULTS: Median (25%-75% interquartile range) admission GCS and APACHE II without GCS scores were 3.0 (3-7) and 11.0 (8-13), respectively. Marshall and Rotterdam scores were 3.0 (3-5) and 4.0 (4-5). Mean ICP and PbtO2 during the patients' ICU course were 15.5 ± 10.7 mm Hg and 29.9 ± 10.8 mm Hg, respectively. Three-month mortality was 37.6%. Admission GCS was not associated with mortality. APACHE II (P = .003), APACHE-non-GCS (P = .004), Marshall (P < .001), and Rotterdam scores (P < .001) were associated with mortality. No relationship between GCS, ISS, Marshall, or Rotterdam scores and subsequent ICP or PbtO2 was observed. The APACHE II score was inversely associated with median PbtO2 (P = .03) and minimum PbtO2 (P = .008) and had a stronger correlation with amount of time of reduced PbtO2. CONCLUSION: Following severe TBI, factors associated with outcome may not always predict a patient's ICU course and, in particular, intracranial physiology.