The osmotic removal of water from blood by use of semipermeable membranes and a small amount of concentrated solution (CS) was investigated. The amount of water removed by this method, employing the cellulose acetate osmotic membrane with 55% acetic acid combined, can be controlled with the concentration of CS, regardless of transmembrane pressure. For example, when the CS of 3mol/l; CaCl2 solution was used, the mean hourly water flux from blood side was approximately 4ml/min·m2 and notable differences between in vitro and in vivo experiments were not observed. The amount of solute transfered from CS to blood was negligible small. Biochemical data in dog experiments did not show marked variation, while decreases of platelet and leucocyte were same as the usual hemodialysis treatments. We concluded that this method is useful to remove excess water from blood, applicable for treatment of hyponatremia and further it is possible to develope a miniature artificial kidney combined with other adsorbents.
One of the problems in hemodialysis is the occurrence of disequilibrium syndrome such as headache and vomitting during the treatment. The increase in the difference of osmotic pressures between intra- and extra-cellular fluids due to the rapid reduction in blood osmosis after starting hemodialysis has been considered as the major cause. For combating this problem, various means have been employed: short and frequent hemodialysis for the patients in the dialysis introductory stage; reduced blood and dialysate flows; and minimization of the difference in osmotic pressures by decreasing removal rates of end-products of metabolism by means of a recirculating system. Presently, the equipment in which time-course change in the osmotic pressure of dialysate as well as the volume of fluid removal can be controlled was developed. The controller was aimed for lessoning disequilibrium syndrome by decreasing the difference in the osmotic pressures between intra-and extra-cellular fluids. It enables us to control changes in the blood osmotic pressure of hemodialysis patients by the regulation of dialysate osmotic pressure. In addition, the volume of fluid removal can be controlled and a pre-determined volume can be eliminated at the end of dialysis. With this equipment, the dialyzer can be prescribed according to the purpose of therapy, as the troublesome requirement for the regulation of pressure at the time of dialyzer exchange was omitted
The ultimate object of the artificial kidney is to become on inplantable component. As on approch to the inplantable artificial kidney, we devised the hemofiltrate-intestine-injection system. The purpose of this system was to re-absorb moisture and nourishment into the intestine. In basic experiments on this system, we devised Duodenocystostomy, Jejunocystostomy, Ileocystostomy and Cecocystostomy in dogs. Only dogs with Cecocystostomy performed upon them lived for a long term, those other-wise all died with uremia. As a result of basic experiments, we finally decided to inject hemofiltrate into the caecum. A dog having been operated on, caecum was injected, using the hemofiltrate-intestine-injection system, at an injection rate of 150ml/hr over a period of 128 hours, and survived. there upon the serum urea nitrogen and creatinine were increased to 200mg/dl and 9mg/dl. In consequence ofexperimental in to change injection rate per hour, we proved that increasing of serum urea nitrogen and creatinine were short of injection rate.
Many kidns of extracorporeal equipment have been developed remarkably up to the present, but there is no apparatus which has multifanction for various treatment by itself. Therefone we have designed and multi-purpose artificial kidney apparatus, which is available for various treatment clinically, e. q. Hemofiltration, Hemodialysis, Hemodiafiltration, Plasma exchange. Plusma Cross circulation, Ascites Treatment, Direct hemoperfusion, Presevation of Organs. In vitro and in vivo experiments, it is confirmed that this apparatus has fine characteristic of pump and Accurate volume control system.
Jak-2, a wearable artificial Kidney functioning on the blood purification principle of Orally Diluting Hemofiltration was reported. Improvements have been made and functions have been confirmed as follows: 1) Blood pump. A bellows is made of Teflon and valve sittings are precisely designed. Pumping is very constant at a wide range of flow rate for longer than 10 hours. 2) Hemofilter. New EVA hollow fibers are spun for special use of JAK-2. Filtration rate of the hemofilter more than 2L/hour with comparable protein loss to peritoneal dialysis. 3) Monitor-Controler. Filtration pressure is monitored with a strain gauge type sensor, and a mercury column sensor is abandoned.
We have developed a simple wearable artificial kidney system. In case of designing this system, the main problem is weight and size, therefore the large pressure drop in adsorbent column should be avoided possibly. In view of these consideration, Zirconium phosphate and α-Al2O3 have been evaluated and the cassette tyep adsorbents column, which is able to be exchange at one touch when adsorbents become really saturated, has been made. Using this apparatus, evaluation of the adsorption system were studied, and results obtained in vivo experiments suggest that this system has the possibility of clinical trial.
A hemofiltration is used in therapy of uremia. This method is also possible to be used in therapy of hepatic failure. We developed handy type hemofiltration and plasma exchang machine. This machine has two roller pumps; one is a three tubed roller pump, and the other a small one tubed pump. In order to make drainage and return blood flow rate equal, two of the three tubes are used for drainage and return blood pump, and third is used for negative pressure pump. Inlet of substitute is connected between filter and return tube. Therefore, the substitute is infused with a same volume of ultrafiltrate without special device. In order to correct hypervolemia, the small one tubed pump is used in parallel with drainage pump; thus, make a difference of flow rate between drainage and return. Adoption of these methods enable to develop the handy type.
The main disadvantage of artificial kidney is to need large quantity of dialysate. In this paper, a dialyzer packed with agar solutions containing small amount of some materials in the side of dialysate was developed for the sucessful approach to the wearable dialyzer. This dialyzer has a less performance of solute transport than usual one. However, if human is weared with this dialyzer, it may be employed as an alternative to human kidney satisfactorily. Further, the dialyzer packed with other gel solutions or gel solutions containing dispersed enzyme is expected to be applicable to artificial liver, to which many functionality is given.
The feasibility, safety and anticoagulability of continuous blood pH monitoring were studided, using a micro pH electrode. MOS type FET was applied to this pH microelectrode. Both pH electrode and reference electrode were designed to fit for 18G, 13cm or 19G, 6cm teflon needles In most mongrel dogs, successful monitoring of arterial pH was possible for a few hours by administration of 250 to 500U/kg of heparin Na. In two dogs, it was possible to monitor arterial pH for 48 consecutive hours by the continuous administration of 100U/kg/h of heparin Na. In 9 out of 12 patients with hemodialysis arterial pH was monitored successfully by an initial injection of 1, 500 to 2.000U of heparin Na and followed by the continuous administration of 700 to 800U/h. These experimental and clinical data indicate that this pH electrode is useful for the continuous monitoring of the blood pH.
Continuous monitoring system has been developed for determination of Urea-N during hemodialysis or hemofiltration. This system consists of immobilized urease column and ammonia gas electrode. Samples were obtained automatically with a small ultrafiltration apparatus. This system, although the response was rather slow, linearity to Urea-N concentration and reproducibility were good, may be suitable for the clinical monitoring because of its simplicity.
The study of analyzing plasma during hemodialysis is one of the most important things for the clinical evaluation of hemodialysis patients, but the extraction of blood samples is not so good for hemodialysis patients. We thought it then possible to use Ultrafiltrate for analysis instead of plasma, because the concentration of many solutes in plasma related to the concentration of ultrafiltrate, so we developed a new device for continuous sampling of ultrafiltrate. In using this device in our studies, we have been able to analyze many solutes which are difficult to analyze by the plasma method, for example, organic acids, catechol amines, etc. during hemodialysis continuously. To analyze ultrafiltrate has many advantages: for example, 1. no necessity for deproteinization, 2. no effect by the enzymes in the blood, 3. easy to micro-analyze in the blood, etc., so this method would be used in clinical evaluation of hemodialysis.
We produced a measuring monitor of ultrafiltration volume using microscopic low flow meters. We included these 2 flow meters in the entrance of single pass dialyser, and we converted dialysate flow into ultrafiltration volume from the balance of 2 flow meters. Clinical using, this monitor could use at negative pressure over -100mmHg, but it could not use at negative pressure under -100mmHg because its measuring error was larger. In the future we are going to improve this monitor using at negative pressure under -100mmHg.
Recently we have developed a new bubble oxygenator to enlarge “the extracorporeal circulation without the primed blood” for wider age application including infants. Spaced in an oxygenating column of this device is the polyurethane sponge to enhance oxygenating efficiency. The initial study revealed the sponge caused significantly greater hemolysis as well. Our target, therefore, was focussed to how to reduce the hemolysis without sacrificing the good oxygenation. It was achieved by an appropriate setting in the section area and height of the sponge column. The pediatric unit tentatively manufactured on such experimental backgrounds was characterized by lower minimum priming volume (approximately 100cc less than the commercialized), higher oxygenating efficiency and acceptable hemolysis level. The clinical application so far was satisfactory.
A new disposable rotating disc type oxygenator was developed. This oxygenator is consisted of two doubled cylinders. The inner cylinder, in which the rotating discs are installed, is the oxygenator, and the outer cylinder is the heat-exchanger. Every part of this oxygenator is made of plastic material including the discs. Each disc is 8cm in diameter and 0.3mm thick. 120 discs are used for adults and are driven by a D. C. servo-motor. The initial priming blood volume is about 600ml, and through many experimental studies, the oxygenator has been testified as having enough qualities in oxygenating the venous blood.
Numerous studies have demonstrated the superiority of membrane oxygenator over the bubble oxygenators during extracorporeal circulation. Recently a new type of membrane oxygenator with heat exchanger was developed and 20 cases of cardiac surgery in infants and children were performed with this oxygenator. The purpose of this report is to describe our clinical experiences in cardiac surgery with the use of this oxygenator.
A new disposable membrane oxygenator with a built-in heat exchanger has been developed and evaluated experimentally with the use of simulation circuits and in dogs. The results of experiments showed that this device had good performances of gas and heat exchanges. Clinical application of our new device was performed in 15 patients undergone open heart surgery, and studies of blood gas conditions and of blood injuries during extracorporeal circulation were made. Blood gas conditions were within physiological ranges except that arterial blood PO2 was occasionally so high as to be decreased by the use of a mixture of O2 and air. As for blood injuries, especially hemolysis was far less than that caused by Kolobow membrane oxygenator.
We have developed a new type of membrane oxygenator made of microporous polypropylene (PP) hollow fibers, and evaluated in vitro. The PP hollow fibers have 200 microns inner diameter and 50% in porosity. The performance of the membrane oxygenators with both 1.8 and 3.3 square meters of surface area is 52 ml/min. M2 of o2 transfer rate and 58 ml/min. M2 of CO2 transfer rate at 1000 ml/min. M2 of blood flow rate. The new type of membrane oxygenator has prominent characteristics; that is, compact size, simple and durable construction, easyhandling, high and stable gas transfer and low blood trauma. These favorable results show that this oxygenator is applicable to clinical use.
A membrane oxygenator of high gas transfer performance is used as extracorporeal membrane oxygenator for acute respiratory failure (ECMO), too. The membrane oxygenator used in ECMO is required to have a long life and to prevent hemolysis. We completed the multilayer and hollow fiber type membrane oxygenator for ECMO and developed control system of perfusion rate. The material of the membrane of both oxygenators is microporous polypropirene. The multilayer type oxygenator had low pressure drop, high O2 and CO2 transfer rate and prevented hemolysis during 24 hours perfusion with dogs. It was observed with SEM that coagulation and platelets adhesion on the membrane surface was very little. The hollow fiber type oxygenator had high O2 transfer rate, but its CO2 transfer rate was not enough. Its pressure drop was very high for ECMO in long term. The ECMO control system was very useful for long term perfusion.
The pulsatile flow in the helically coiled tube induces the composite secondary flow which is different from that appeared in the steady flow. This type of secondary flow is enable to cause the further augmentation of mass transfer. In this study the gas transfer performance with pulsatile flow is investi-gated experimentally for the helically coiled membrane oxygenator by using the scotch-yoke pulse generator. The effects of frequency and amplitude of pulsation to the oxygen transfer are clarified and the augmentation of oxygen transfer is obtained up to 70% compared with that in the steady flow under the experimental conditions taken.
The Oxygen exchanger and the heat exchanger performances were studied by perfluorochemical emulsion with oxygen carrier, by using some kind of bubble oxygenator (Tokyo Women's Type “T-W sheet”, Shiley “S-100A and 070”, Bentley “BOS-10”, JMS “200”, and Wada-Siposs with tube disperser “Adult and Infant type” in extracorporeal circulation. Wada-Siposs infant bubble oxygenator was expecially showed good oxygen exchanger performance. The coil type heat exchanger is made by Dr. Wada, which is new type, was studied.
The dual cooler heater for extracorporeal circulation was developed. The device is consisted of the compressor (400W) for cooling and heater (1 KW) for warming. If the pressure of the water circuit happens to exceed 1.5 kg/cm2, the pump of the device stops automatically. Clinical experiences of the device was satisfactory in cooling and rewarming of the patient.
Imperfect movement of the diaphragm of the artificial heart pump will bring rise to various problems. The authors made in vitro observations on the movement of the diaphragm used in various types of artificial heart pumps. Two types of diaphragms were studied, one a three layer diaphragm with a supporting mesh in the middle and the other a single layer diaphragm with the same thickness of 0.3mm. The supporting base plate was oval in shape with grooves of various configration on its inner surface. This was observed with a video unit while changing the driving conditions. In the three layer diaphragm, twist was observed in the movement between the diaphragms on two sides, but this was resolved by applying powder between the diaphragms. Excessive extension was observed in the single layer diaphragm. As for the base plate, a conclusion was reached that one with grooves on the inner surface radially from the gas flow inlet and that with circular grooves at the H-D junction was satisfactory. It was found that instead of using a base plate having a single gas flow inlet very favorable results could be obtained by using a base plate having a multiporous gas flow inlet.
Using a total artificial heart with accessory chamber, the authors newly developed an automatic drive control unit which would respond very sensitively to venous return and would provide a corresponding stroke volume. With this artificial pump the accessory chamber membrane responds to the change in venous return, that is the capacity of the accessory chamber is changed. In order to determine the diastolic time the movement of the accessory chamber membrane is detected. When the venous return becomes poor, the capacity of the accessory chamber increases and when it again becomes small, this triggers the automation. As for systolic time, when the diaphragm comes to the full systole position by the wave pattern of the positive drive pressure, the ceiling is reached. This is utilized as the trigger. As a result, 1. A stroke volume curve which responded very well to venous return volume was obtained. 2. Regardless of the inlet pressure the maximum stroke volume was always attained. 3. Within the inlet pressure range of 5-20cmH2O, the heart rate was 70-90 per minute and % systole was 30-35% and automatic drive control was possible.
The authors made a study on a new left atrium-aorta bypass method employing an assist heart pump having an accessory chamber with a capacity of 40ml. With this heart pump having an accessory chamber, the negative pressure to the atrial side was reduced and favorable sensitivity against the atrial pressure was demonstrated also in the mock circulation. Further, by making the length of the left atrium cannula as short as possible and by increasing the diameter of the cannula, suction was facilitated and thrombus formation was reduced. Thus it was possible to extend the survival period to 48 days in our long term chronic experiment. In the 40 cases of left atrium-aorta bypass performed from 1974 to 1976, the results were very pessimistic, but with the improvement made on the left atrium cannula and the revision made in the driving method, especially in the movement of the accessory chamber membrane, it was confirmed that this new method was effective from the standpoint of hemodynamics and prevention of thrombus formation.
Biventricular bypass experiments in six calves were carried out using nonpulsatile centrifugal pumps. One animal survived for 34 days with a normal range of hemodynamics and metabolism. This study suggests that it is possible to maintain total circulation in a physiological condition with nonpulsatile flow.
Even the TAH goats survive almost for a half year, the main interest is still what the factor to make them alive much longer is. 25 cases of long-term survivals were classified into 4 groups according to the difference of materials of blood pumps and administration of anticoagulants. The blood chemical data were analyzed and the factor scores of them were displayed two-dimensionally. Results showed that the groups of Avcothane coating pumps and those of no anticoagulants traced good course in two-dimensional displays of vitality.
In many long survivals among total artificial heart (TAH) animals, we experienced several cases of blood regurgitation through the aortic valve of the remained natural heart. In order to prevent blood flow regurgitation, a new method of TAR was investigated. The ascending aorta was ligated and occluded completely. Pulmonary and systemic circulations were maintained by artificial heart and coronary arteries were perfused by beating natural heart. In goat experiments, more than 100 days long survival was achieved. Remained natural heart kept beating until death and cardiac muscle atrophy was not observed on autopsy. This procedure seems to be applicable to clinical use of TAH and LEAD.
The air driven blood pump for total and partial cardiac support has a defect in durability. To solve this problem, we present a new type of blood pump, driven by a linear motor. This pump consists of a straight conduit sandwiched between two stators, and of a metalic rotor. The rotor is driven back and forth in the conduit by excitation of two stators. As the result of this movement, the fluid is sucked into and ejected from this conduit. The movement of this rotor is controlled so easily by changing source current and frequency that many output flow patterns can be generated. The pump characteristics were examined, using overflow tank system. Maximum output flow rate was over 3 [1/min] at mean load pressure 100 [mmHg]. Pump beat number was able to vary from 15 to 120 [bpm]. And it was shown that this pump can be operated in complete silence.
Comparison of TAH, LVAD, compliance chamber and control animal groups in terms of hemodynamic, hematological and metabolic data has disclosed that most of the changes in observed parameters after TAH implantation are transient phenomena which are observed during the animal's adaptation period to the cardiac prosthesis. On the other hand, permanent problems which appear to be inherent to chronic animal experiments are infection, calcification of the implants and associated valvular failures.
Double chambered alternate pumping paracor=poreal device has been tested in dogs of sever mitral regurgitation. They were separated in 2 groups. In the 1st group, the device used had tube-type chamber of high resiliency and l-ventri=cle had been maintained completely unloaded from commencement till death. In the 2nd group, the device used had sack-type chamber of low resiliency and allowed to generate some pressure in the l-ventricle after 2nd postope=rative day. At autopsy, gut necrosis was found in 4 of 12 dogs in the 1st group, but only 1 of 9 in the 2nd group. Since gut necrosis was found at times in l-ventricular aortic bypass in normal dogs when the bypass flow rate was higher than normal in our past experiments, the mainten=ance of the complete unloading of normal l-ventricle for long time may affect to produce gut necrosis under the condition of abnormal high bypass flow rate, though it is not cont=ractive on the other hand that these results might be some side effects of thrombus form=ation in the device.
We have devised recently a new bicarbonate dialysate supply system, which we call “Bicarbonate Infuser (B. I.)”. B. I. was composed of a simple proportioning bicarbonate infusion unit connected to the usual single-pass dialysate supplyer. This small machine (16×30×20cm.) was able to prepare dialysate with stable electrolyte composition. We had clinical experences with B. I. in 7 uremic patients for about 6 month, and were successful for prevention of the dialysis disequilibrium syndrome and the symptom derived from acetate intolerance.
The non-buffer dialysis is a method the authors have newly taken up this time using a dialysate containing neither acetate nor bicarbonate in the solution. That is, to supplement Na+ and HCO3- in short, 7w/v % of NaHCO3 is given with a microsyringe continuously into blood from the venous siee, thus availability has been tested in vitro and in vivo. The test in vitro revealed that to make Na value in arterial blood from 142 (pre) to 134 (post mEq/l, it arrived at an ideal stage with 2.4-4.2ml/min. Meanwhile, in vivo, using dogs at HD of 3 hours to raise Na value of 141 (pre) to 135 (post) mEq/l and HCO3 value of 15 (pre) to 22 (post) mEq/l, satisfactory values were obtained with 1.8-2.7ml/min, in use of synchronized pH monitor. From these test results it can be considered that when NaHCO3 is injected appropriately, there should not be any danger of causing problems.
Gabexate mesilate as an agent for precise regional anticoagulation during hemodialysis was assesed. Gabexate mesilate (GM), a synthetic proteinase inhibitor, was evaluated as an agent for precise regional anticoagulation during hemodialysis in combination with minimum dose of heparin. Kaolin activated whole blood clotting time (KCT) was prolonged at 30μg/ml of GM which was the lowest level tested. As more than 500 of GM (250μg/ml plasma) was inactivated within 2min and nearly 50% was dialysed in simulated dialysis system, only a trace amount of GM might be effective in the blood leaving from dialyser. Clinically, 1, 200mg/hr of GM and 400u/hr of heparin was recommended for precise regional anticoagulation where no KCT prolongation of systemic blood was observed. Thus, methodology of administration with minimum dose of heparin was established.
Heparin has been usually used for extracorporeal circulation. But we reported extra-corporeal circulation without heparin by using prostaglandin I2 at 2nd ISAO meeting, 1979. While Gabexate Mesilate (GM) is known as a proteolytic enzyme inhibitor. Molecular weight is 4I7. Action of GM is antitrypsin, antiplasmin, antithrombin, and anti-CIesterase. Extracorporeal ciculation with GM was was done for 60-I20min in seven dogs. Whole blood clotting time was kept 3-I6 min. In two clinical cases with hemorrhagic foci, hemodialysis with GM was done 8times for 4-5 hours. Whole blood clotting time was kept 8-I3min. After hemodialysis hemorrhagic state did not exacervate.
As mentioned on the first report, hyper-water absorbent polymer (TTY-300) could remove approx. 4 times the amount of water done by the conventional dialysis (cellulose acetate membrane) at the same temp., and suggested the possibility of non-dialysate dialysis technique with TTY-300 combined with other resin. This time, we shall make a report of removals for creatinine, uric acid and BUN obtained after repeated experiments. For creatinine and uric acid, we encapsulated activated charcoal with urethane-silicone block-copolymer coating, and the experiments were carried out by a direct hemoperfusion technique. For BUN, we have developed new NH+4, adsorbent resin (TTY-500), and as a result, the combination of the TTY-500 and urease also sufficiently cleared.
If excessive water can be removed from the gastrointestinal tract of uremic patients, water intake will be more freely permitted and frequency of complications relating to overhydration such as hypertension and lung edema supposed to be minimzed. Oral administration of water-absorptive polymer is expected to absorb water in the intestine and to be purged as a part of feces. In vitro evaluation evidenced that polymer material such as polyvinyl alcohol base, starch-polyacrylamide-potassiumacrylate carboxymetyl cellulose base, absorbs about 300 times of water in weight, and about 40-50 times in the presence of electrolytes and solutes such as urea and creatinine.