Multicenter Postmarket Analysis of the Neuroform Atlas Stent for Stent-Assisted Coil Embolization of Intracranial Aneurysms.

BACKGROUND AND PURPOSE: The Neuroform Atlas is a new microstent to assist coil embolization of intracranial aneurysms that recently gained FDA approval. We present a postmarket multicenter analysis of the Neuroform Atlas stent. MATERIALS AND METHODS: On the basis of retrospective chart review from 11 academic centers, we analyzed patients treated with the Neuroform Atlas after FDA exemption from January 2018 to June 2019. Clinical and radiologic parameters included patient demographics, aneurysm characteristics, stent parameters, complications, and outcomes at discharge and last follow-up. RESULTS: Overall, 128 aneurysms in 128 patients (median age, 62 years) were treated with 138 stents. Risk factors included smoking (59.4%), multiple aneurysms (27.3%), and family history of aneurysms (16.4%). Most patients were treated electively (93.7%), and 8 (6.3%) underwent treatment within 2 weeks of subarachnoid hemorrhage. Previous aneurysm treatment failure was present in 21% of cases. Wide-neck aneurysms (80.5%), small aneurysm size (<7 mm, 76.6%), and bifurcation aneurysm location (basilar apex, 28.9%; anterior communicating artery, 27.3%; and middle cerebral artery bifurcation, 12.5%) were common. A single stent was used in 92.2% of cases, and a single catheter for both stent placement and coiling was used in 59.4% of cases. Technical complications during stent deployment occurred in 4.7% of cases; symptomatic thromboembolic stroke, in 2.3%; and symptomatic hemorrhage, in 0.8%. Favorable Raymond grades (Raymond-Roy occlusion classification) I and II were achieved in 82.9% at discharge and 89.5% at last follow-up. mRS ≤2 was determined in 96.9% of patients at last follow-up. The immediate Raymond-Roy occlusion classification grade correlated with aneurysm location (P < .0001) and rupture status during treatment (P = .03). CONCLUSIONS: This multicenter analysis provides a real-world safety and efficacy profile for the treatment of intracranial aneurysms with the Neuroform Atlas stent.

The interaction between erectile dysfunction complaints and depression in men: a cross-sectional study about sleep, hormones and quality of life.

Depression (DEP) is one of the main disabling diseases and is considered a contributor factor for erectile dysfunction (ED). Both of these conditions may be associated with hormonal changes and sleep disturbances. We aimed to evaluate the interaction between ED complaints and depression symptoms on sleep parameters, hormone levels and quality of life in men. This was a cross-sectional study of 468 men aged 20-80 years. The participants were classified according to the presence of ED and/or DEP in groups of healthy individuals, ED, DEP and DEP with ED (DEP-ED). All participants completed questionnaires about sleep, clinical history and quality of life, and underwent polysomnography with blood collection the following morning. ED participants showed higher frequency of insomnia symptoms (65.5%), whereas DEP group had more complaints of difficulty in falling asleep and early morning awakening. In the polysomnography, all groups showed similar parameters. No differences were found in cortisol and total testosterone levels; however, free testosterone levels and the physiological domain of quality of life were lower in DEP-ED group. ED and DEP, as independent factors, negatively affected subjective sleep parameters. The interaction between these factors led to a low quality of life and was related to a decrease in free testosterone levels.

Computational Modeling of Venous Sinus Stenosis in Idiopathic Intracranial Hypertension.

BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension has been associated with dural venous sinus stenosis in some patients, but the hemodynamic environment of the dural venous sinuses has not been quantitatively described. Here, we present the first such computational fluid dynamics model by using patient-specific blood pressure measurements. MATERIALS AND METHODS: Six patients with idiopathic intracranial hypertension and at least 1 stenosis or atresia at the transverse/sigmoid sinus junction underwent MR venography followed by cerebral venography and manometry throughout the dural venous sinuses. Patient-specific computational fluid dynamics models were created by using MR venography anatomy, with venous pressure measurements as boundary conditions. Blood flow and wall shear stress were calculated for each patient. RESULTS: Computational models of the dural venous sinuses were successfully reconstructed in all 6 patients with patient-specific boundary conditions. Three patients demonstrated a pathologic pressure gradient (≥8 mm Hg) across 4 dural venous sinus stenoses. Small sample size precludes statistical comparisons, but average overall flow throughout the dural venous sinuses of patients with pathologic pressure gradients was higher than in those without them (1041.00 ± 506.52 mL/min versus 358.00 ± 190.95 mL/min). Wall shear stress was also higher across stenoses in patients with pathologic pressure gradients (37.66 ± 48.39 Pa versus 7.02 ± 13.60 Pa). CONCLUSIONS: The hemodynamic environment of the dural venous sinuses can be computationally modeled by using patient-specific anatomy and physiologic measurements in patients with idiopathic intracranial hypertension. There was substantially higher blood flow and wall shear stress in patients with pathologic pressure gradients.

In vitro validation of endovascular Doppler-derived flow rates in models of the cerebral circulation.

This study presents validation of endovascular Doppler velocimetry-based volumetric flow rate measurements conducted in a pulsatile flow loop simulating conditions in both the internal carotid and basilar artery. In vitro models of cerebral vessels, each containing an aneurysm, were fabricated from patient anatomies extracted from 3D rotational angiography. Flow velocity measurements were collected with three different experimental techniques: an endovascular Doppler wire, Particle Image Velocimetry, and a time-resolved ultrasonic flow meter. Womersley's theory of pulsatile flow in a cylindrical vessel was used to compute time-resolved volumetric flow rates from the endovascular Doppler velocity. The volumetric flow rates computed from the Doppler measurements were compared to those from the Particle Image Velocimetry profile measurements, and the direct measurements from the ultrasonic flow meter. The study establishes confidence intervals for any systematic or random errors associated with the wire-derived flow rates as benchmarked to the other two modalities. There is an approximately 10% random error in the Doppler-derived peak and time-averaged flow rates. There is a measurable uniform bias, about 15% too low, in the time-averaged Doppler-derived flow rates. There is also a small proportional bias in the peak systolic Doppler-derived flow rates. Potential sources of error are also discussed.

Seizures after decompressive hemicraniectomy for ischaemic stroke.

OBJECTIVE: The risk of seizures after malignant middle cerebral artery (MCA) infarction with decompressive hemicraniectomy (DHC) is uncertain. Also unknown is how this complication influences survivors' recovery and quality of life. METHODS: We retrospectively reviewed medical charts of all patients admitted to Harborview Medical Center between 1 January 2002 and 31 June 2011 for space-occupying MCA ischaemic stroke and who underwent DHC. Survivors and their surrogates were invited to participate in a telephone or in-person interview. RESULTS: Fifty-five patients were followed for a median of 311 days (IQR 134-727). Twenty-seven patients (49%) had seizures, 25 (45%) developed epilepsy and 21 (38%) achieved moderate disability or better (modified Rankin Scale score ≤3) by 1 year after stroke onset. The only factor significantly associated with seizure occurrence was male gender. Median time from stroke to first seizure was 222 days, with a cluster of first seizures within weeks after cranioplasty; only two of the first seizures occurred right around the time of stroke onset. Follow-up time was significantly longer for patients with seizures (605 days, IQR 297-882) than for those without (221 days, IQR 104-335). Of the 20 patients interviewed, 12 achieved moderate disability or better, 15 experienced a seizure with 6 indicating the seizure was a major drawback. Regardless, all 20 would have chosen DHC again. CONCLUSIONS: In this case series, patients were at high risk of developing seizures after malignant MCA stroke with DHC, especially after cranioplasty. Assuming these findings are replicated, means should be sought to reduce the occurrence of this complication.

Cerebral aneurysms treated with flow-diverting stents: computational models with intravascular blood flow measurements.

BACKGROUND AND PURPOSE: Computational fluid dynamics modeling is useful in the study of the hemodynamic environment of cerebral aneurysms, but patient-specific measurements of boundary conditions, such as blood flow velocity and pressure, have not been previously applied to the study of flow-diverting stents. We integrated patient-specific intravascular blood flow velocity and pressure measurements into computational models of aneurysms before and after treatment with flow-diverting stents to determine stent effects on aneurysm hemodynamics. MATERIALS AND METHODS: Blood flow velocity and pressure were measured in peri-aneurysmal locations by use of an intravascular dual-sensor pressure and Doppler velocity guidewire before and after flow-diverting stent treatment of 4 unruptured cerebral aneurysms. These measurements defined inflow and outflow boundary conditions for computational models. Intra-aneurysmal flow rates, wall shear stress, and wall shear stress gradient were calculated. RESULTS: Measurements of inflow velocity and outflow pressure were successful in all 4 patients. Computational models incorporating these measurements demonstrated significant reductions in intra-aneurysmal wall shear stress and wall shear stress gradient and a trend in reduced intra-aneurysmal blood flow. CONCLUSIONS: Integration of intravascular dual-sensor guidewire measurements of blood flow velocity and blood pressure provided patient-specific computational models of cerebral aneurysms. Aneurysm treatment with flow-diverting stents reduces blood flow and hemodynamic shear stress in the aneurysm dome.

Incidence of microemboli and correlation with platelet inhibition in aneurysmal flow diversion.

Flow-diverting stents have been associated with embolic and hemorrhagic complications, but the rate of procedure-related microemboli is unknown. Using transcranial Doppler sonography, we measured the rate of microemboli in 23 patients treated with flow-diverting stents. Patients received preprocedural dual antiplatelet medications and intraprocedural heparinization. Point-of-care platelet reactivity testing was performed before the procedure, and nonresponders (>213 P2Y12/ADP receptor reactivity units) received additional thienopyridine. Transcranial Doppler sonography was performed within 12-24 hours. Microemboli were detected in 3 patients (13%), 2 of whom were initially nonresponders. There was no association between the presence of microemboli and procedural or neurologic complications, aneurysm size, number of stents, or procedure time. Eight procedures (34.8%) required additional thienopyridine for inadequate platelet inhibition, and 3 required further treatment for persistent nonresponse to point-of-care platelet reactivity testing. There were 6 technical and 2 postoperative complications; none were associated with inadequate platelet inhibition or microemboli. The combination of routine point-of-care platelet reactivity testing and postprocedural microembolic monitoring may help identify patients at risk for thromboembolic complications after flow-diverting stents.

Endovascular management of cerebral bypass graft problems: an analysis of technique and results.

BACKGROUND AND PURPOSE: Cerebral bypass grafts may develop generalized graft narrowing or focal stenosis during the perioperative period or later. Endovascular techniques such as PTA and stent placement of graft vessels are potential treatment options. Our objective was to review the safety, indications, technique, and results of endovascular management of graft problems. MATERIALS AND METHODS: All patients with cerebral bypass procedures by using graft vessels from 2005 to 2009 were identified from a prospective registry and were studied retrospectively. Patient characteristics, bypass procedures, indications for endovascular interventions, graft patency, and clinical outcomes were reviewed from medical charts and imaging records. RESULTS: A total of 79 patients underwent bypass procedures by using graft vessels. Seven patients of this group underwent endovascular interventions for the treatment of graft narrowing. Four of the 7 patients were treated for graft narrowing in the perioperative period (<1 month) with PTA; and 3 of the 7 patients, for late stenosis, 2 with PTA alone and 1 with PTA followed by stent placement. All procedures were immediately successful in improving flow through the graft. In late stenosis, PTA alone provided temporary improvement followed by recurrence, whereas PTA with a stent procedure was effective in the 1 patient long term. CONCLUSIONS: PTA is safe and effective in the management of graft spasm in the perioperative period. For late graft stenosis, PTA alone provides only temporary respite, while PTA with stent placement may be an effective solution.

Transcranial access using fluoroscopic flat panel detector CT navigation.

FPCT and navigation software on contemporary fluoroscopic units perform imaging of a quality comparable with conventional CT. They can accurately guide percutaneous procedures, providing live instrument visualization and the capability to re-image without patient transfer. FPCT navigation was used in the placement of a ventricular drain in a 62-year-old woman for subarachnoid-related hydrocephalus by using an otherwise standard bedside technique. Ventriculostomy catheter placement was technically successful without complication with a catheter at the foramen of Monro.

Intraoperative angiography for hunterian ligation of a recurrent basilar aneurysm.

Cerebral aneurysms often recur after selective endovascular treatment with detachable coils and are usually treated by recoiling. Sometimes, however, surgical treatment is required, and application of the clip can be difficult. Evacuation of embolic material risks injuring eloquent structures or perforators, especially in the posterior circulation. In such cases parent vessel occlusion for reversal of flow might be an option. If collateral flow is adequate, an additional bypass is not required. When using this technique, known as Hunterian ligation, intraoperative monitoring such as electrophysiological monitoring and intraoperative angiography can be of great help and are advisable. We describe this procedure and related intraoperative considerations in one case report.

Spontaneous ventriculostomy in a patient with obstructive hydrocephalus.

BACKGROUND: Spontaneous ventriculostomy related to progressive obstructive hydrocephalus is rare. Radiologic demonstration of such a phenomenon can be delineated with magnetic resonance imaging (MRI) and cine MRI. CASE PRESENTATION: A 59-year-old woman with a known tectal glioma and symptoms of chronic hydrocephalus developed progressively worsening headaches. During follow-up, she noted spontaneous relief of her headaches. Follow-up cine MRI demonstrated a spontaneous ventriculostomy via the floor of the third ventricle. INTERPRETATION: Clinicians should be aware of spontaneous ventriculostomy demonstrable on cine MRI because it may obviate the need for a CSF diversion procedure.

Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke.

Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg/kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- and AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.

Human Taf(II)130 is a coactivator for NFATp.

NFATp is one member of a family of transcriptional activators that regulate the expression of cytokine genes. To study mechanisms of NFATp transcriptional activation, we established a reconstituted transcription system consisting of human components that is responsive to activation by full-length NFATp. The TATA-associated factor (TAF(II)) subunits of the TFIID complex were required for NFATp-mediated activation in this transcription system, since TATA-binding protein (TBP) alone was insufficient in supporting activated transcription. In vitro interaction assays revealed that human TAF(II)130 (hTAF(II)130) and its Drosophila melanogaster homolog dTAF(II)110 bound specifically and reproducibly to immobilized NFATp. Sequences contained in the C-terminal domain of NFATp (amino acids 688 to 921) were necessary and sufficient for hTAF(II)130 binding. A partial TFIID complex assembled from recombinant hTBP, hTAF(II)250, and hTAF(II)130 supported NFATp-activated transcription, demonstrating the ability of hTAF(II)130 to serve as a coactivator for NFATp in vitro. Overexpression of hTAF(II)130 in Cos-1 cells inhibited NFATp activation of a luciferase reporter. These studies demonstrate that hTAF(II)130 is a coactivator for NFATp and represent the first biochemical characterization of the mechanism of transcriptional activation by the NFAT family of activators.

Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke.

BACKGROUND AND PURPOSE: Although the deleterious role of several proinflammatory mediators, including P-selectin, in reperfused stroke is well established, the role of E-selectin has not been fully characterized. METHODS: E-selectin mRNA expression was studied at 4, 10, and 24 hours after reperfusion with reverse transcription and polymerase chain reaction in mice (n=18) subjected to transient intraluminal middle cerebral artery occlusion (MCAO). Mice received intravenous injection with anti-E-selectin monoclonal antibody (10, 35, or 50 microg), nonimmune IgG, or vehicle immediately before MCAO and 90 minutes later (n=85). Others received anti-E-selectin antibody 3 or 6 hours after MCAO (n=32). Myeloperoxidase activity was measured in sham-operated mice and after 10 hours of reperfusion in saline-, nonimmune IgG-, or anti-E-selectin IgG-treated cohorts (n=17). Serial cerebral blood flow was measured with laser-Doppler flowmetry, and outcomes were assessed by neurological deficits and infarct volumes with the use of planimetric analysis of triphenyltetrazolium chloride-stained sections. RESULTS: Upregulated E-selectin expression occurred in the ischemic cerebral vasculature within 4 hours of reperfusion and persisted for 24 hours. Anti-E-selectin antibody increased ischemic cortical cerebral blood flow up to 2.6-fold (P:<0.05). In addition to dose-dependent reductions in neurological deficits (P:<0.05), mortality, and infarct volumes (P:<0.01 for 35 and 50 microg), anti-E-selectin treatment reduced cerebral neutrophil accumulation (P:<0.05) and was neuroprotective even if delayed until 3 hours after ischemia (P:<0. 05). CONCLUSIONS: These findings establish a functional role for E-selectin in the pathogenesis of tissue injury after cerebral ischemia and reperfusion and suggest that E-selectin blockade may be clinically useful in the treatment of reperfused stroke.

Lumbar sympathetic block for sympathetically maintained pain: changes in cutaneous temperatures and pain perception.

UNLABELLED: Lumbar sympathetic block (LSB) is used in the management of sympathetically maintained pain states. We characterized cutaneous temperature changes over the lower extremities after LSB. Additionally, we examined the effects of iohexol, a radio-opaque contrast medium, on temperature changes and pain relief. After institutional review board approval and written, informed consent, 28 LSBs were studied in 17 patients. Iohexol or normal saline was injected in a randomized, double-blinded fashion before bupivacaine. Lower extremity cutaneous temperatures were measured. Pain, allodynia, interference with daily function, and perceived pain relief were reported in a subset of 15 LSBs for 1 wk after the block. The distal lower extremity ipsilateral to the LSB had the greatest magnitude (8.7 degrees +/- 0.8 degrees C) and rate (1.1 degrees +/- 0.2 degrees C/min) of temperature change. The great toe temperature was within 3 degrees C of core temperature within 35 min after LSB. There were no differences in temperature change between the groups. The iohexol group had greater relief of pain until the morning of the first postblock day (P = 0.002) and longer perceived relief of pain (P = 0.01). The maximum temperature of the great toe correlated with allodynia relief (P = 0.0007). Thus clinicians should expect ipsilateral toe temperatures to increase to within approximately 3 degrees C of core temperature. Iohexol does not alter the efficacy of LSB and may improve relief of symptoms. The magnitude of temperature change may predict relief of allodynia. IMPLICATIONS: Cutaneous toe temperatures approaching core temperature provide a useful monitor of lumbar sympathetic block and may predict relief of sympathetically maintained pain. Iohexol will not compromise temperature changes or pain relief.

The accuracy and precision of body temperature monitoring methods during regional and general anesthesia.

UNLABELLED: We tested the hypotheses that accuracy and precision of available temperature monitoring methods are different between spinal anesthesia (SA) and general anesthesia (GA), and that patients receiving SA are at equal risk for hypothermia as those receiving GA. Patients scheduled for radical retropubic prostatectomy were enrolled. Either GA (n = 16) or SA (n = 16) was given according to patient and clinician preference. Temperatures were monitored with thermocouple probes at the tympanic membrane, axilla, rectum, and forehead skin surface. Tympanic temperatures were also measured with an infrared device, and forehead skin temperatures were monitored with two brands of liquid crystal thermometer strips. Accuracy and precision of these monitoring methods were determined by using tympanic membrane temperature, measured by thermocouple, as the reference core temperature (T(c)). At the end of surgery, T(c) was similar between SA (35.0 +/- 0.1 degrees C) and GA (35.2 +/- 0.1 degrees C) (P = 0.44). Accuracy and precision of each temperature monitoring method were similar between SA and GA. Rectal temperature monitoring offered the greatest combination of accuracy and precision. All other methods underestimated T(c). These findings suggest that patients receiving SA or GA are at equal and significant risk for hypothermia, and should have their temperatures carefully monitored, recognizing that most monitoring methods underestimate T(c). IMPLICATIONS: Body temperature should be monitored during spinal anesthesia because patients are at significant risk for hypothermia. Rectal temperature is a valid method of measuring core temperature, whereas other methods tend to underestimate true core temperature.

Characterization of DNA binding, transcriptional activation, and regulated nuclear association of recombinant human NFATp.

BACKGROUND: NFATp is one member of a family of transcriptional activators whose nuclear accumulation and hence transcriptional activity is regulated in mammalian cells. Human NFATp exists as a phosphoprotein in the cytoplasm of naive T cells. Upon antigen stimulation, NFATp is dephosphorylated, accumulates in nuclei, and functions to regulate transcription of genes including those encoding cytokines. While the properties of the DNA binding domain of NFATp have been investigated in detail, biochemical studies of the transcriptional activation and regulated association with nuclei have remained unexplored because of a lack of full length, purified recombinant NFATp. RESULTS: We developed methods for expressing and purifying full length recombinant human NFATp that has all of the properties known to be associated with native NFATp. The recombinant NFATp binds DNA on its own and cooperatively with AP-1 proteins, activates transcription in vitro, is phosphorylated, can be dephosphorylated by calcineurin, and exhibits regulated association with nuclei in vitro. Importantly, activation by recombinant NFATp in a reconstituted transcription system required regions of the protein outside of the central DNA binding domain. CONCLUSIONS: We conclude that NFATp is a bona fide transcriptional activator. Moreover, the reagents and methods that we developed will facilitate future studies on the mechanisms of transcriptional activation and nuclear accumulation by NFATp, a member of an important family of transcriptional regulatory proteins.

Safety and efficacy of fixed-dose heparin in carotid endarterectomy.

OBJECTIVE: Although fixed dosage of heparin is frequently used during vascular surgery, there are very few studies that document the appropriateness of this type of dosing. We have undertaken a prospective study to determine the physiological response to a fixed dose of heparin, using a conventional measure of anticoagulation, and have correlated this measure with complications. METHODS: We studied 140 consecutive patients undergoing elective carotid endarterectomy. Serial activated clotting times (ACT values) were obtained in duplicate before administration of heparin, 15 minutes after application of a carotid artery cross-clamp, and 1 hour after administration of 5000 U of heparin by intravenous bolus. Postoperatively, patients were assessed for new neurological deficits (transient ischemic attack and stroke) and neck hematomas. A battery of neuropsychometric tests was performed in 49 patients at baseline and on the day after carotid endarterectomy to identify subtle new neurological deficits. RESULTS: ACT values were found to be highly reproducible, with less than a 1.5% difference between duplicate baseline samples. Although all patients received 5000 U of heparin, the dose received per kilogram of body weight varied considerably (44-116 U/kg), as did ACT values at both 15 minutes (178-423 s) and 1 hour (173-390 s). Nevertheless, there was a significant correlation between heparin dose per kilogram and ACT values at 15 minutes (r = 0.45) and at 1 hour (r = 0.38) postinfusion, as well as ACT ratios (final ACT/initial ACT) at 15 minutes (r = 0.43) and at 1 hour (r = 0.34) after heparin bolus. Eight patients (5.7%) developed postoperative wound hematomas, one of which (0.7%) required reoperation. No patient had a stroke, but one patient had a transient ischemic attack, and 19 (39%) of 49 patients demonstrated significant early postoperative neuropsychometric deficits. Although the incidence of neck hematoma was not influenced by the heparin dose (P = 0.23), the ACT value at 15 minutes (P = 0.71) or 1 hour (P = 0.61), or the ACT ratio (P = 0.68), the only severe hematoma requiring reoperation occurred when the maximal ACT value was more than 400 seconds. Although performance on neuropsychometric tests did not appear to be statistically influenced by heparin dosing, the ACT value, or the degree of ACT elevation, there was a trend for deficits to be associated with lower heparin doses. CONCLUSION: Fixed heparin dosing achieves safe and efficacious anticoagulation in the great majority of patients having carotid endarterectomy, with 5000 U expected to result in 15-minute and 1-hour ACT values of 175 to 425 seconds and 170 to 390 seconds, respectively. Although weight-based heparin dosing may reduce the incidence of subtle complications (hematoma formation or decline on neuropsychometric tests) and may result in more predictable 15-minute and 1-hour ACT values (85 U/kg; 225-375 and 200-340 s, respectively), no statistically compelling clinical advantage could be demonstrated. Therefore, either weight-based or fixed dosing is acceptable, with both obviating the need for routine pre-clamp ACT confirmation, thereby saving operative time and expense.

Targeted inhibition of intrinsic coagulation limits cerebral injury in stroke without increasing intracerebral hemorrhage.

Agents that restore vascular patency in stroke also increase the risk of intracerebral hemorrhage (ICH). As Factor IXa is a key intermediary in the intrinsic pathway of coagulation, targeted inhibition of Factor IXa-dependent coagulation might inhibit microvascular thrombosis in stroke without impairing extrinsic hemostatic mechanisms that limit ICH. A competitive inhibitor of native Factor IXa for assembly into the intrinsic Factor X activation complex, Factor IXai, was prepared by covalent modification of the Factor IXa active site. In a modified cephalin clotting time assay, in vivo administration of Factor IXai caused a dose-dependent increase in time to clot formation (3.6-fold increase at the 300 micrograms/kg dose compared with vehicle-treated control animals, P < 0.05). Mice given Factor IXai and subjected to middle cerebral artery occlusion and reperfusion demonstrated reduced microvascular fibrin accumulation by immunoblotting and immunostaining, reduced 111In-labeled platelet deposition (42% decrease, P < 0.05), increased cerebral perfusion (2.6-fold increase in ipsilateral blood flow by laser doppler, P < 0.05), and smaller cerebral infarcts than vehicle-treated controls (70% reduction, P < 0.05) based on triphenyl tetrazolium chloride staining of serial cerebral sections. At therapeutically effective doses, Factor IXai was not associated with increased ICH, as opposed to tissue plasminogen activator (tPA) or heparin, both of which significantly increased ICH. Factor IXai was cerebroprotective even when given after the onset of stroke, indicating that microvascular thrombosis continues to evolve (and may be inhibited) even after primary occlusion of a major cerebrovascular tributary.