Computational modelling for the embolization of brain arteriovenous malformations

Treatment of arteriovenous malformations (AVMs) of the brain often requires the injection of a liquid embolic material to reduce blood flow through the malformation. The type of the liquid and the location of injection have to be carefully planned in a pre-operative manner. We introduce a new model of the interaction of liquid embolic materials with blood for the simulation of their propagation and solidification in the AVM. Solidification is mimicked by an increase of the material's viscosity. Propagation is modelled by using the concept of two-fluids modelling and that of scalar transport. The method is tested on digital phantoms and on one anatomically derived patient AVM case. Simulations showed that intuitive behaviour of the two-fluid system can be confirmed and that two types of glue propagation through the malformation can be reproduced. Distinction between the two types of propagation could be used to identify fistulous and plexiform compartments composing the AVM and to characterize the solidification of the embolic material in them.     

Pulmonary arteriovenous malformations. Physiologic observations and results of therapeutic balloon embolization

Pulmonary arteriovenous malformations can result in severe hypoxemia and dyspnea. We measured pulmonary function, arterial blood gases, and hemodynamics in 10 patients with such malformations. Pulmonary-function tests were normal, but hypoxemia was associated with chronic hyperventilation at rest (mean, 12 liters per minute; mean carbon dioxide tension, 28 mm Hg). With exercise, ventilation increased more than expected for the level of carbon dioxide production. Balloon embolization of 58 of the 71 visible vascular malformations in the 10 patients resulted in an increase in arterial oxygen tension (43 vs. 64 mm Hg; P less than 0.001) and hemoglobin saturation (79 vs. 92 per cent; P less than 0.001). Nine patients had improved exercise tolerance. Forty-eight to 72 hours after correction of the hypoxemia, resting ventilation had decreased but was still above normal (mean, 9.3 liters per minutes; mean carbon dioxide tension, 29 mm Hg). We conclude that ventilatory responses in these patients are similar to those of people from sea-level areas who are acclimated to high altitudes and that dyspnea is due to inappropriately high levels of ventilation for a given workload under hypoxic conditions.     

颅内动静脉畸形患儿血管内栓塞术后出血的危险因素分析

目的探究颅内动静脉畸形(cAVM)行血管栓塞治疗术后出血发生率及相关危险因素。方法选取2013年8月至2018年8月于我院脑外科行血管内栓塞治疗的cAVM患者180例为研究对象,观察其术后1周颅内出血发生情况,比较出血及未出血患者临床资料及畸形血管团特点,采用Logistic回归分析法探究cAVM栓塞术后出血的危险因素。结果cAVM栓塞术后出血发生率为17.78%,多于术后3 d内发生,以脑实质出血最常见。单因素分析显示,高血压史、出血史、畸形血管直径、深静脉引流、合并动脉瘤、栓塞体积、引流静脉栓塞及术后血压未达标与术后出血有关(P<0.05),而性别、年龄、癫痫史、畸形血管位置、S-M分级、栓塞时间及术后使用脱水剂与术后出血无关(P>0.05);多因素分析显示,出血史、深静脉引流及引流静脉栓塞是血管内栓塞术后颅内出血的独立性危险因素(P<0.05)。结论出血史、深静脉引流及引流静脉栓塞是cAVM栓塞术后出血的独立性危险因素,正确认识并在手术过程中采取相应的防范措施有利于降低栓塞出血并发症的发病率。     

Effect of heparin reversal and fresh platelet transfusion on platelet emboli post-cardiopulmonary bypass in a pig model

Heparin reversal by protamine and fresh platelet transfusion may decrease bleeding complications post-cardiopulmonary bypass (CPB) and may increase the level of organ trapped platelet emboli. Platelet emboli were quantified in two groups of 12 Yorkshire pigs (30-35 kg), where 111indium labeled autologous platelets (INPLT: 850-1,200 microCi) were injected intravenously before and after CPB (BCPB, ACPB), and the platelet emboli level in intact organs and their samples (brain, heart, kidneys, lung, liver, and spleen) was quantified with an ion chamber and a gamma counter, respectively. All pigs were systemically heparinized (ACT > 400 sec). CPB was carried out at 2.5-3.5 L/min at 28 degrees C using a centrifugal pump, an oxygenator (OX:Bentley Univox 1.8 m2), an arterial filter (AF:0.25 m2), and a cardiotomy reservoir (CR: BMR 250) for 90 min. Heparin was reversed with an equivalent dose of protamine. The percent of INPLT dose (ID%, mean +/- SD) in organs of BCPB and ACPB pigs was calculated. The sequence of platelet emboli on a unit weight basis (ID%/g) had the following order: Spleen > Liver > Lung > Kidneys > Heart > Brain. The presence of significantly higher levels of emboli in brain, heart, and kidneys in the ACPB than the BCPB group suggest that platelet transfusion after heparin reversal with protamine may increase the risk of platelet emboli. However, it is an acceptable risk for patients having bleeding complications post-CPB.     

Iodine-containing cellulose mixed esters as radiopaque polymers for direct embolization of cerebral aneurysms and arteriovenous malformations.

The present study deals with the synthesis and characterization of radiopaque polymers which could, when solubilized in an appropriate water-miscible solvent, be useful embolic materials for the treatment of cerebral aneurysms and arteriovenous malformations. For this purpose cellulose (both microcrystalline and powdered) and partially substituted cellulose acetate (two different viscosity grades) were selected as starting materials to prepare iodine-containing polymers through various synthetic routes. The materials obtained were characterized by IR and NMR spectroscopy, molecular weight, iodine content, radiopacity and solubility in selected injectable organic solvents. The embolic liquids were evaluated for their precipitation behavior in a phosphate buffer solution (pH 7.4) mimicking physiological conditions using an in vitro aneurysm model. A sheep model was also used to assess in vivo the radiopacity and precipitation properties of a highly concentrated solution of a cellulose acetate 2,3,4-triiodobenzoate mixed ester. All materials with 4-iodo- and 2,3,5-triiodobenzoyl groups gave sufficient radiopacity to be regarded as possible embolization materials, whereas iododeoxycellulose and iododeoxycellulose acetate were not radiopaque because of their low iodine content. Esters synthesized using cellulose as starting material were not soluble in the selected organic solvents due to the presence of many residual hydroxyl groups, but could be used for other biomedical applications where insoluble radiopaque materials are used. In contrast, solubility of the materials as well as satisfactory precipitation properties were ensured using cellulose acetate as the starting material. In conclusion, cellulose acetate iodobenzoate mixed esters dissolved in diglyme or dimethyl isosorbide (dimethyl sulfoxide is probably less appropriate because of its toxicity and hemolytic properties) could be useful embolic liquids for the treatment of cerebral aneurysms or arteriovenous malformations.     

Influence of stent expansion states on platelet deposition in an extracorporeal porcine arteriovenous shunt model using a multichannel perfusion chamber

Limited data are available about incomplete stent expansion (SE) on platelet deposition (PD). We examined PD following different SE using an extracorporeal porcine arteriovenous shunt model to which a perfusion chamber with four parallel silastic tubes were connected. Blood flow was set at a 20 and 100 mL/min in 1.8 and 3.1 mm diameter tubes, respectively. P154 stents were deployed completely (Group A, n=15) or incompletely (Group B, n=15) in 1.8 mm (n=13) and 3.1 mm (n=17) tubes. 51Cr-labelled platelet autologous blood was injected 1 hr before the perfusion. After 15 min-perfusion, the testing tubes were assessed for radioactivity counts. In-stent cross sectional area was measured by intravascular ultrasound. There was a significant difference in PD between group A and B regardless of channel size (118+/-18.4 vs 261.4+/-52.1 pits x 10(6)/cm2, p<0.05). With adjusted shear rate and similar stenosis, PD was similar in both tubes. In smaller 1.8 mm tubes, a stenosis as subtle as 10% was associated with a significant PD difference (226.1+/-20 vs 112.9+/-20.5 plts x 10(6)/cm2, p<0.005). This model enabled a repetitive, simultaneous comparison of PD following different SE states. It seems that the quality of SE remains crucial in smaller channels.     

Influence of splenectomy on platelet morphometry and function

Summary Functional and morphometric platelet abnormalities may be influenced by splenectomy and thus contribute to postoperative thrombohaemorrhagic complications, especially in patients with splenomegaly and/or platelet defects. We investigated platelet function, platelet secretion, and platelet morphometry before and one week after splenectomy in seven patients with normal platelet production and normal spleen size (Hodgkin's disease) and five patients with splenomegaly and platelet abnormalities (4 with myeloproliferative disorders and 1 with chronic myelomonocytic leukemia).Severe postoperative thrombohaemorrhagic complications occurred only in patients with myeloproliferative disorders, although platelet count and mean platelet volume increased in almost all patients after splenectomy. Four patients with myeloproliferative disorders had impaired platelet aggregation before splenectomy that improved in only one patient after surgery. Platelet buoyant density in this patient group was decreased before splenectomy and normalised thereafter. Concomitantly, intraplatelet concentrations of-granular proteins increased. Before splenectomy, there was a positive correlation between platelet density and platelet volume in patients with Hodgkin's disease (r=0.59,p<0.001), but not in patients with myeloproliferative disorders. There was no correlation between platelet density and platelet volume after splenectomy in either patient group.In conclusion, morphometric platelet abnormalities were found in all patients after splenectomy. In patients with myeloproliferative/myelodysplastic disorders, decreased platelet buoyant density normalised and intraplatelet concentrations of-granule proteins were elevated after splenectomy. However, platelet function defects in this patient group were not corrected and may have been a major cause of thrombohaemorrhagic complications in the postoperative period.Abbreviations ABVD Adriamycin, bleomycin, vinblastine, dacarbazine - ADP Adenosine diphosphate - Ara-C Cytosine arabinoside - BS Busulfan - CML Chronic myelogenous leukemia - CMML Chronic myelomonocytic leukemia - COPP Cyclophosphamide, vincristine, procarbazine, prednisone - HD Hodgkin's disease - HU Hydroxyurea - MDS Myelodysplastic syndrome - MOPP Nitrogen mustard, vincristine, procarbazine, prednisone - MPD Myeloproliferative disorders - MPV Mean platelet volume - PF4 Platelet factor 4 - PRP Platelet rich plasma - PV Polycythemia vera - TG -thromboglobulin     

Production of monoclonal antibodies specific for platelet activation antigens and their use in evaluating platelet function.

Monoclonal antibodies (MAb) were used to identify platelet membrane molecules that are expressed after platelet activation. Balb/C mice were immunized with fixed thrombin-activated human platelets and their spleen cells were fused with the murine myeloma cell line NS1-Ag4/1. The resulting hybridomas were screened for antibody production against fixed thrombin-activated platelets and fixed resting platelets by flow cytometry. Two MAbs 2C8 (an IgM) and 1E3 (an IgG2a) demonstrated significant binding to fixed thrombin-activated platelets while reacting minimally with fixed resting platelets. The reactivity of 2C8 and 1E3 were compared to MAb's S12 and AC1.2, both of which have known specificity for an alpha-granule membrane protein (GMP-140) expressed on the surface of activated platelets. In radioimmunoprecipitation studies, both 2C8 and 1E3 immunoprecipitated a protein of approximately 140 kDa similar to that precipitated by S12 and AC1.2. Immunodepletion studies, with S12, AC1.2, 1E3, and 2C8 confirm that they all react with the same antigen. 2C8 may recognize the same epitope as S12, whereas 1E3 appears to recognize a different epitope of the same molecule. The use of these MAbs to measure platelet activation in whole blood correlates well with the results of conventional platelet aggregometry.     

Calcium alginate gel: a biocompatible and mechanically stable polymer for endovascular embolization

The development and optimization of calcium alginate for potential use in endovascular occlusion was investigated by testing its in vitro and in vivo mechanical stability and biocompatibility. The compressive resistance, rheology, and polymer yield of reacted alginate, and the polymer viscosity of unreacted alginate, were assessed. Biocompatibility was tested by injecting calcium alginate into the kidney capsule of rats. The reactivity of alginates with various structures and levels of purity were compared visually and histologically. Results suggest that calcium alginate is a biocompatible and mechanically stable gel for endovascular applications. Purified alginates exhibited compressive strength of 22 kPa and above at 40% compression, with no significant loss in elasticity. Purified alginate strength was significantly higher than that of crude alginates (p < 0.08). Purified alginates also exhibited significantly lower tissue reaction than crude alginates (p < 0.05). Of the alginates tested, purified high guluronic acid alginates (PHG) exhibited optimal strength and polymer yield, increased biocompatibility, and decreased viscosity. Clinical embolization treatments may be improved with the development of stable and biocompatible polymers such as calcium alginate. Possible uses of improved endovascular polymers include treating arteriovenous malformations (AVMs), aneurysms, blood flow to tumors, and vascular hemorrhaging.     

Effects of marathon running on platelet activation markers : direct evidence for in vivo platelet activation

We used the ADVIA 2120 Hematology System (Bayer HealthCare, Diagnostics Division, Tarrytown, NY) to study the effects of vigorous exercise on CBC count, WBC differential, RBC fragmentation, and platelet activation parameters in 32 healthy participants in a 26.2-mile (42.2-km) marathon. The runners demonstrated increases in hematocrit and platelet count consistent with dehydration and leukocytosis indicative of demargination of neutrophils or inflammation secondary to tissue destruction (eg, rhabdomyolysis). The number of RBC fragments was increased after the race (P = .008), consistent with exercise-induced hemolysis. The mean platelet component, a measure of platelet granularity, was decreased (P < .0001), and the number of platelet clumps was increased (P = .0026), providing evidence for in vivo platelet activation during the marathon. By using direct measurement of platelet granularity, our study confirms the in vivo activation of platelets by vigorous exercise and establishes the usefulness of automated cell counters for the assessment of platelet activation and of RBC fragmentation in this setting.     

Dose calculation of 142Pr microspheres as a potential treatment for arteriovenous malformations

Arteriovenous malformation (AVM), especially cryptic AVM, can cause highly variable cerebral neurological defects. Injection of 142Pr microspheres into arteries feeding an AVM in order to simulate radio-embolism has been proposed as a novel treatment method. To investigate optimization of radiation dose to the clinically important arterial wall area, preliminary dosimetric studies have been performed. Monte Carlo calculations were performed for simulated arteries filled with microspheres packed by random packing. Arterial radii from 0.05 mm to 3 mm and microsphere radii from 0.01 mm to 0.7 mm were used in the simulation. For constant arterial size, dose varied significantly with microspheres radius. Inter-arterial effect was also simulated using simplified geometry. For the inter-arterial sites, the dose rate was calculated between two arteries of the same size parallel to each other. The dose increased significantly for large arteries (>1 mm radius) filled with large microspheres (>0.3 mm radius). The dose increase between small arteries (<0.3 mm radius) was not as significant as that between large arteries. Overall results indicate that arterial size and microsphere size significantly affect the dose profile. This factor should be taken into account in future clinical applications.     

急诊颅脑手术合并心脏支架术后动态监测血小板功能1例报告

重型颅脑创伤患者病情危重,病情进展极快,后期并发症多,治疗颇为复杂,病死率高。对于颅脑损伤合并冠心病支架术后长期服用双抗药物的患者,围手术期密切监测血小板聚集试验以平衡预防出血与心脏事件之间的矛盾极为关键。现报告动态监测血小板功能应用于急诊颅脑手术合并心脏支架术后患者1例。     

Monitoring of heparin therapy and establishment of an optimal therapy scheme for thrombosis prophylaxis in a pig model for human catheter interventions

This study aims to investigate variables suitable for monitoring of unfractionated heparin (UFH) therapy and establishment of an optimal therapy scheme in pigs. This is a prospective study of 32 pigs undergoing catheterization for endovascular embolization of experimentally induced arteriovenous malformation. Pigs were assigned to four groups receiving different UFH treatment during catheter intervention. In groups?1 and 2, UFH was applied as a bolus of either 100?IU/kg (n?=?6) and 200?IU/kg (n?=?6). Groups?3 and 4 received a continuous infusion of 66?IU/kg/h?UFH (n?=?10) and 100?IU/kg/h (n?=?10), respectively, which was applied 20?min after an initial bolus of 100?IU/kg. Blood samples were taken 0, 10, 20, 40, 60, 100, and 140?min after starting catheterization (groups?1?+?2) and after 0, 10, 20, 30, 40, 50, 60, 80, 100, 120, and 140?min, respectively (groups 3?+?4). High/low range activated coagulation time (LR-ACT), activated partial thromboplastin time (aPTT), prothrombin time, fibrinogen, and anti-FactorXa activity (FXa) activity were assessed. Based on anti-FXa activity, bolus injection of 100 and 200?IU/kg UFH had a mean half-life of 28.43?±?8.85 and 57.05?±?12.42?min, however, an aPTT exceeding 999?s was present in four of seven pigs in group?2. In group?3, aPTT increased from baseline 15?±?2?s to a steady state ranging from 30 to 33?s. In group?4, there was an increase of aPTT to 58?±?23?s 140?min after initiation of treatment. Suitable variables for monitoring UFH therapy included anti-FXa activity, aPTT, and LR-ACT. An initial bolus of 100?IU/kg?followed by a continuous UFH infusion of 66?IU?UFH/kg/h can be recommended as antithrombotic therapy during catheterization.     

Influence of training on markers of platelet activation in response to a bout of heavy resistance exercise

Recent connections between platelet activity and cardiovascular disease have raised questions of whether platelet function varies in exercising individuals. Resistance training has been linked to a possible reduction in hyper-aggregability of platelets, especially following acute strenuous exercise. The present investigation was designed to explore the effects of an acute resistance exercise test on the primary hemostatic system in both resistance-trained (RT) and untrained (UT) individuals. Ten RT (five men and five women; age, 26.0 ± 4.5 years; height, 175.12 ± 8.54 cm; weight, 79.56 ± 13.56 kg) and ten UT (five men and five women; age, 26.4 ± 6.2 years; height, 170.31 ± 7.45 cm; weight 67.88 ± 16.90 kg) individuals performed an Acute Exhaustive Resistance Exercise Test (AERET; six sets of ten repetitions of squats at 80 % of the 1-Repetition Maximum (RM)). Blood samples were obtained before, immediately after, and at 15, 60, and 120 min following the AERET. Blood samples were analyzed for platelet count, von Willebrand factor antigen (vWF:Ag), beta-thromboglobulin (β-TG), and platelet factor 4 (PF4). B-TG showed significant differences (p < 0.05) between RT and UT at +15 and +60 min. Both groups showed a main effect for time in platelet count, vWF, and β-TG following the AERET, whereas PF4 remained unchanged. All blood variables returned to baseline 120 min after exercise. Compared with UT, RT demonstrated reduced platelet activation in response to an acute bout of heavy resistance exercise. Reduced platelet activation may be attributed to training status, as shown by a reduction in plasma concentrations of B-TG in the RT group.     

Leukocyte CD15 expression and platelet activation in the coronary sinus after coronary intervention

Markers associated with coronary restenosis must be identified to develop therapeutic strategies for improving the clinical outcome. We studied whether adhesion proteins on leukocytes and platelets from coronary sinus blood were associated with restenosis after coronary intervention in patients with stable coronary artery disease. Adhesion proteins on platelets and leukocytes were measured by flow cytometry. Pre- and postinterventional leukocyte CD15 expression was significantly higher in patients with restenosis than in those without it. Increased leukocyte CD15 expression during the intervention may contribute to coronary restenosis. Inhibition of leukocyte adhesion may be useful for the prevention of restenosis.     

Pathogenesis of malformations in a rodent model for Smith-Lemli-Opitz syndrome

The fact that Smith-Lemli-Opitz syndrome (SLOS), a syndrome comprising major malformations involving a number of organ systems, results from an abnormality in cholesterol biosynthesis, was discovered only recently. Utilizing a drug (BM 15.766) to inhibit the same step in cholesterol biosynthesis as is abnormal in those affected with SLOS, we have developed a rat model that presents with abnormalities observed as early as gestational day 12 that appear to be consistent with some of those subsequent malformations that comprise the human syndrome. Abnormalities of the brain and face include deficiency in the midline region of the upper face, narrowing of the forebrain hemispheres and of the cerebral aqueduct, and deficiency in the developing lower jaw. Associated pathogenesis, as observed on gestational day 11 in histological sections and with scanning electron microscopy, involves abnormal cell populations at the rim of the developing forebrain and in the alar plate of the lower midbrain and hind-brain. The affected cells appear abnormally rounded up, having apparently lost their normal cell contacts. The potential basis for the selective vulnerability of this cell population and the impact of its vulnerability relative to subsequent dysmorphogenesis is discussed. Am. J. Med. Genet. 68:328–337, 1997. © 1997 Wiley-Liss, Inc.     

Gel strength and solution viscosity of temperature-sensitive, in-situ-gelling polymers for endovascular embolization

The goal of this work was to investigate the relationship of the gel strength and stiffness (at 37 degrees C) to solution viscosity (at 25 degrees C) in poly(N-isopropylacrylamide-co-acrylic acid) solutions with regard to acid content, molecular weight and solution concentration. It was hypothesized that the gel strength could be maximized while minimizing the increase in solution viscosity. If so, there would be motivation to investigate these materials for arteriovenous malformation embolization. The co-polymers were synthesized with 0-2 mol% content of acrylic acid (AAc) in benzene, dioxane, THF, 50:50 benzene/dioxane, or 50:50 dioxane/THF to obtain polymers of different molecular weight. The polymers were characterized for molecular weight by GPC/light scattering, for acrylic acid content by acid titration, for lower critical solution temperature by differential scanning calorimetry, and for solution viscosity (at 25 degrees C) and gel strength (at 37 degrees C) by rheometry. Solutions of lower-molecular-weight polymers were shown to have lower viscosities while possessing higher strengths as gels than the highest manageable concentrations of higher-molecular-weight polymers. This work demonstrates that the mechanical properties of poly(N-isopropylacrylamide-co-acrylic acid) can be increased while minimizing the increase in solution viscosity.     

Preparation, characterization, and evaluation of radiopaque hydrogel filaments for endovascular embolization

Radiopaque hydrogel filaments were prepared, characterized, and evaluated for potential use as implants for endovascular embolization of vascular defects. Three hydrogel formulations were prepared by free radical polymerization: (i) poly(ethylene glycol) diacrylate with 2,4,6-triiodophenyl penta-4-enoate (PEG-I), (ii) poly(ethylene glycol) diacrylamide with barium sulfate (PEG-B), and (iii) poly(propylene glycol) diacrylate with barium sulfate (PPG-B). The PEG-B and PPG-B hydrogels exhibited radiopacity comparable with clinically used platinum coils, whereas the PEG-I hydrogel did not. In the dry state, the average ultimate tensile strength and strain of the hydrogels ranged from 37 to 128 gf and 21% to 72%, respectively. The PEG-B hydrogel had significantly higher tensile strength compared with the PEG-I hydrogel. In the hydrated state, the average ultimate tensile strength and strain ranged from 5 to 15 gf and 7% to 30%, respectively. Statistically significant differences in tensile strength were not present when hydrated. Compared with poly(ethylene) after 4-week implantation into the subcutaneous space of rabbits, the PEG-I hydrogel elicited slightly more inflammation, whereas the PEG-B and PPG-B hydrogels elicited less inflammation. All three hydrogel formulations elicited less fibrous encapsulation than poly(ethylene). With further development, these materials have potential as embolization devices.     

An embolic gelling solution based on acrylic copolymers in ethanol for the treatment of arteriovenous malformations

We report the preparation of an embolic agent based on specific association of an acrylic copolymer with dedicated particles formulated in ethanol. The copolymers were synthesized by radical polymerization of tertiobutylacrylamide (tBA) and 2-hydroxypropyl methacrylate (HPMA). Influences of the monomers composition, molecular weight and copolymer concentration have been evaluated on an in vitro model. Introduction of tBA units improves significantly the occlusion properties but these properties are similar whatever the molecular weight of the copolymer. As observed by viscosity studies, it seems necessary to work with a relatively high polymer concentration (C > Ce) to form a cohesive embolus. Addition of solid particles composed by a crosslinked polymer of 2-hydroxyethyl methacrylate (HEMA) and N-trishydroxymethyl methacrylamide (TRIS) in the acrylic copolymer solution has allowed to obtain an embole having an enhanced cohesion and giving a more compact structure. An in vivo evaluation has been performed by injection of this embolic agent in intercostal arteries and renal artery of sheep. There was no fragmentation of the plug during and after injection and a complete arterial occlusion by a cohesive embole. The pathological examination confirmed that there was a complete arterial occlusion by the plug and that the dedicated particles were as expected embedded in the precipitate acrylic copolymer.