Tomoaki Jikuya

Aprotinin Inhibits Plasmin-Induced Platelet Activation During Cardiopulmonary Bypass

BACKGROUND In the past few years, aprotinin has been used in cardiac surgery with impressive results of reducing blood loss, but several adverse effects of aprotinin also have been reported. One of the most likely mechanisms is the inhibition of plasmin by aprotinin, although this indirect effect has not been reproduced in all experimental studies. METHODS AND RESULTS We evaluated the platelet function and fibrinolytic activity during human cardiac surgery, with or without aprotinin. During cardiopulmonary bypass (CPB) in humans without aprotinin (n=16), decrease of platelet aggregation induced by thrombin, increase of alpha-granule secretion of platelet and microparticle formation, and increase of plasmin/alpha2-antiplasmin complex (PIC) were observed. In contrast, low-dose aprotinin (1.0 x 10(6) KIU), which was administered only into the priming fluid of extracorporeal circuits (n=10), maintained platelet aggregation induced by thrombin and reduced alpha-granule secretion and microparticle formation of platelets during CPB. In vitro, plasmin (0.8 CU/mL) released alpha-granules of washed platelets, and this activation was completely inhibited by aprotinin (10 KIU/mL). CONCLUSIONS Aprotinin has indirect effects to inhibit platelet activation, and this may partly explain the reduction of blood loss during cardiac surgery. To prevent the adverse effects, a single and minimal use of aprotinin is important. The results of in vivo and in vitro studies suggest that platelet preservation was demonstrated by the lower concentration of aprotinin (1.0 x 10(6) KIU per patient or 10 KIU/mL) compared with the concentration that inhibits plasma fibrinolysis.

Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass

OBJECTIVE The heparin-protamine titration method that uses the Hepcon hemostasis management system (Medtronic HemoTec Inc, Englewood, Colo) reduced blood loss in cardiac surgery in previous reports, but the mechanism is not fully understood. This study tests the hypothesis that reduced protamine administration preserves platelet function in human cardiac surgery. METHODS Platelet count, alpha-granule secretion, and aggregation to thrombin before and after cardiopulmonary bypass in human beings were evaluated. In the control group (n = 14), a fixed dose of protamine (3 mg/kg) was administered. In the titration group (n = 20), protamine doses were based on the heparin concentration measured by the Hepcon system. RESULTS Heparin concentrations before protamine administration were higher in the titration group (P =.0012), but protamine doses of patients in the titration group were markedly lower than those of the control group (P <.0001). During protamine infusion at a rate of 0.3 mg. kg(-1). min(-1), the percentage of granule membrane protein-140-positive platelets significantly increased in the control group compared with the titration group (18.8% +/- 8.6% vs 13.0% +/- 5.3%, P =.0188). After protamine administration, aggregation of washed platelets to thrombin recovered almost to the preoperative level in the titration group; however, it remained lower in the control group (20% +/- 20% vs 55% +/- 18%, P =.0009). CONCLUSION Low-dose administration of protamine, based on a heparin-protamine titration method, restores not only the blood coagulation but also the platelet responses to thrombin and attenuates platelet alpha-granule secretion during heparin neutralization. Overdose of protamine activates platelets and may predispose patients to excessive bleeding after cardiac surgery.

SPECIES DIFFERENCES IN ERYTHROCYTE MECHANICAL FRAGILITY : COMPARISON OF HUMAN, BOVINE, AND OVINE CELLS

The erythrocyte destruction rate under constant shear stress was measured to clarify species differences in red blood cell (RBC) mechanical fragility between human, bovine, and ovine cells. Blood was collected from healthy donors by venipuncture. RBC age fractionation was performed by high speed centrifugation (20 min at 12,000 g). Relatively young, middle, and old age RBCs was suspended in Dulbeccos phosphate buffered saline to adjust the hematocrit to 35%. Uniform shear stress was applied to each sample contained in a concavo-convex Couette flow testing machine. Young and old aged samples were exposed to 300 dyne-sec-cm2 for 0 and 15 min. Middle aged samples were exposed to 300 dyne-sec-cm2 for 0, 5, 10 and 15 min. Liberated hemoglobin was estimated by tetramethylbenzidine colorimetric measurement and the erythrocyte destruction rate was calculated. Older samples had a higher hemolysis rate than younger samples in every species. The destruction under constant shear stress is approximately linear in time. Mechanical fragility of ovine and bovine RBCs was 1.8 and 0.5 times as large as human RBCs, respectively. These values could serve as universal standards when extrapolating animal hemolysis data for any blood pump to predict its safety and biocompatibility in human clinical trials.

Method of Noninvasive and Continuous Hemolysis/Thrombogenesis Measurement by Laser Photometry During Artificial Heart Development

The purpose of this research is to propose and develop a method to measure hemolysis and thrombogenesis non invasively and continuously to aid in development of an artificial heart. Generally, the optical absorption rate of hemoglobin is influenced by oxygen saturation except at the isosbestic point, which is not influenced by oxygen saturation. The authors, therefore, used an 805 nm laser diode, an optical spectrum analyzer to obtain greater accuracy. An experimental blood circuit system was constructed using a Bio-Pump, Tygon tubing, a soft shell reservoir, and an optical measurement system. Experimental settings for monitoring hemolysis were as follows; blood volume 200 ml, blood flow 6 L/min, and afterload 200 mmHg. Blood was sampled six times (0, 30, 60, 120, 180, and 240 min), and hemolysis in each sampled was measured using a colorimetric method. Comparing continuous laser measurement data with the sample data, an adequate correlation is obtained, proving that the dynamic trend of hemolysis could be continuously measured. Furthermore, to analyze the process of thrombogenesis, simple experiments were performed using blood neutralized by protamine. As a result, the authors could see the process of thrombogenesis as it occurred and could confirm that this method is able to dynamically detect hemolysis and thrombogenesis.

Development of built-in type and noninvasive sensor systems for smart artificial heart.

It is very important to grasp the artificial heart condition and the physiologic conditions for the implantable artificial heart. In our laboratory, a smart artificial heart (SAH) has been proposed and developed. An SAH is an artificial heart with a noninvasive sensor; it is a sensorized and intelligent artificial heart for safe and effective treatment. In this study, the following sensor systems for SAH are described: noninvasive blood temperature sensor system, noninvasive blood pressure sensor system, and noninvasive small blood flow sensor system. These noninvasive sensor systems are integrated and included around the artificial heart to evaluate these sensor systems for SAH by the mockup experiments and the animal experiments. The blood temperature could be measured stably by the temperature sensor system. Aortic Pressure was estimated, and sucking condition was detected by the pressure sensor system. The blood flow was measured by the flow meter system within 10% error. As a result of these experiments, we confirmed the effectiveness of the sensor systems for SAH.

Cerebral metastasis from angiosarcoma of the aortic wall: case report.

BACKGROUND Primary or metastatic cerebral angiosarcoma is extremely rare, and only limited cases have been reported. The authors here describe a case of angiosarcoma, which was initially identified and diagnosed by the cerebral metastatic lesion; later examinations suggested that the primary site was the abdominal aorta. CASE DESCRIPTION A 53-year-old man, who had suffered an abdominal aortic aneurysm 2 months earlier, experienced a sudden onset of left-sided hemifacial convulsion and dysarthric speech. Computed tomography (CT) showed a hemorrhagic mass lesion with perifocal edema in the right frontal lobe. Magnetic resonance imaging (MRI) showed a regionally marked hypointensity in the mass lesion on both T1- and T2-weighted images, which might suggest hemosiderin deposition. The tumor was removed in its entirety. Pathologic examination revealed an old hematoma with a hemosiderin deposit containing markedly atypical tumor cells, and angiosarcoma was diagnosed. Resection of the abdominal aortic aneurysm and iliac bone biopsy were performed and angiosarcoma was recognized in each surgical specimen. Based on clinical and pathologic findings, the primary site was considered to be the abdominal aorta. CONCLUSIONS Clinicians should be aware of this rare histologic type of tumor. Unique MRI findings such as those obtained in our case might be useful for differentiating this condition from other intracranial neoplasms.

Cystic tumor of the atrioventricular nodal region.

We report a case of a 66-year-old female who presented exertional dyspnea and palpitation. Echocardiography, transesophageal echocardiography and computed tomography showed a right atrial cystic mass attached to the interatrial septum. The patient underwent successful excision of the mass. The histopathological findings confirmed the lesion as a cystic tumor of the atrioventricular nodal region. This is the third known case of this condition diagnosed antemortem and treated successfully with surgical excision.

Influence of bypass grafting to the infarct artery on late potentials in coronary operations

BACKGROUND Late potentials (LPs) after myocardial infarction identify the risk of arrhythmic events and sudden death, and the absence of anterograde flow in the infarct-causing occluded coronary artery frequently is associated with LPs on signal-averaged electrocardiography. The present study was designed to clarify the influence of revascularization of the infarct artery on the LPs in the late course after myocardial infarction. METHODS We studied 21 patients after myocardial infarction with positive LPs who had at least one occluded infarct coronary artery. We investigated the LPs on signal-averaged electrocardiograms on the day of elective coronary artery bypass grafting (CABG) and 1 week after CABG. RESULTS There were 25 infarct arteries in the study patients, 13 of which were grafted. The positive LPs disappeared soon after CABG in 13 patients, 10 of whom had grafts to all of the infarct arteries. The LPs persisted in 8, who received no graft to the infarct artery. One week after CABG, the LPs were still present in 4, all of whom had no graft to the infarct right coronary artery. CONCLUSIONS In patients with positive LPs late after myocardial infarction, grafting to the infarct artery eliminated the LPs soon after CABG.

ONO-6818, a novel, potent neutrophil elastase inhibitor, reduces inflammatory mediators during simulated extracorporeal circulation

BACKGROUND Among the serine proteases, neutrophil elastase is a powerful cytotoxic enzyme and plays a pivotal role in the inflammatory response associated with cardiopulmonary bypass. This study assesses the effects of the specific inhibition of neutrophil elastase by a novel, potent, low-molecular-weight neutrophil elastase inhibitor, ONO-6818. We hypothesized that ONO-6818 reduces inflammatory mediators and modulates adhesion molecules and the deformability of neutrophils during simulated extracorporeal circulation. METHODS Simulated extracorporeal circulation was established by recirculating fresh heparinized (3.75 U/mL) human blood for 120 minutes in a membrane oxygenator and a roller pump with and without 1.0 micromol/L of ONO-6818 (n = 9 for control group, n = 7 for ONO-6818 group). The neutrophil adhesion molecules, CD11b and L-selectin, and the cytoplasmic F-actin of neutrophils were measured by flow cytometry. Neutrophil deformability was evaluated using simulated silicon microcapillaries. Neutrophil elastase, interleukin 8, and C5b-9 were measured using enzyme immunoassay. RESULTS Neutrophil elastase levels were significantly lower in the ONO-6818 group. ONO-6818 significantly reduced interleukin 8 and C5b-9 production. ONO-6818 did not modulate changes of CD11b and L-selectin during recirculation. Cytoplasmic F-actin content and changes of neutrophil deformability did not significantly differ between the groups. CONCLUSIONS Inhibition of neutrophil elastase activity with ONO-6818 reduces further interleukin 8 production and the formation of the complement membrane attack complex, and this results in a reduction of neutrophil elastase levels during simulated extracorporeal circulation. This study suggests that specific neutrophil elastase inhibition with ONO-6818 is a feasible therapeutic option to attenuate the exaggerated inflammatory response associated with cardiopulmonary bypass.

Fluid dynamic characteristics of monopivot magnetic suspension blood pumps.

A monopivot magnetic suspension blood pump is a centrifugal pump under development with a magnetic suspension and a ceramic pivot to support the impeller with minimum contact. The pump size has been reduced by implementing a direct impeller drive mechanism in place of a magnetic coupling and motor. Flow visualization studies revealed that high shear, which seems to be closely related to hemolysis, concentrates in boundary layers near the walls. This implies that fluid dynamic shear can be reduced not by widening the gap, but by reducing the impeller velocity. Therefore, compared with the results of the previous semi-open curved vane impeller model, impeller velocity was reduced by 30% with a closed impeller having radial straight vanes, and smaller impeller/housing gaps. The volute shape around the impeller tip was also changed such that the outflow from the impeller enters along the center plane of the volute. To examine the effect of the improvements, hemolysis testing was conducted and found that the newly developed closed impeller model generated a lower level of hemolysis than the previous semi-open impeller model.