Two-dimensional orientational response of smooth muscle cells to cyclic stretching.

It was hypothesized that an orientated cellular tissue for incorporation into vital, functioning hybrid artificial organs can be prepared by periodically applying mechanical stresses on a hybrid tissue. Therefore, the effect of cyclic stretching on the two-dimensional (2-D) orientation response of arterial smooth muscle cells (SMCs) was studied. Smooth muscle cells derived from bovine aortas were seeded onto transparent elastomeric membranes made of polyurethane, and subjected to periodical stretching with various amplitudes from 5-20% at frequencies of 15 to 120 RPM for up to 24 hours. Phase-contrast microscopic views of SMCs were time-lapse video recorded. The orientation angle to the direction of stretching (OA) and cellular longitudinal length (CLL) of individual cells were analyzed by a computerized image processor. After several hours, SMCs subjected to the stress exhibited orientation responses perpendicular to the direction of stretching, evidenced by a significant increase in OA. The responses were more rapid under operating conditions with higher amplitudes and frequencies of stretching. Meanwhile, little significant change in CLL was observed. These findings indicate that an applied mechanical stress induces a significant orientation response, without morphologic alteration of SMCs. The mechanically induced orientation response provides a fundamental basis for more structured hybrid organs and tissue engineering.


Inflammatory reaction induced by agarose implants reduced by adding adrenal cells to the polymer.

Microencapsulation of adrenal cells is proposed for reducing the non-specific inflammatory reaction observed around polymer implants. This hypothesis was tested by comparing both host cellular reaction and the surrounding graft cell populations that appeared when either agarose embedded cells or empty agarose beads were implanted. The authors' results showed that the fibrotic material that surrounded the implanted empty agarose microbeads was not as severe when adrenal cells were present. Similarly, the T lymphocyte population surrounding the graft was considerably reduced, along with the percentage of CD4 and CD8 positive cell subpopulations. The activation macrophage marker IaD disappeared. The authors' results support the hypothesis that embedded adrenal cells may be a suitable solution for reducing early inflammatory events due to microcapsule implantation.


Toxicity of heat sterilized peritoneal dialysis fluids is derived from degradation of glucose.

Heat sterilization makes peritoneal dialysis (PD) solutions cytotoxic. Two compounds in the solutions, lactate and glucose, can be degraded by heat. This study's goal was to discover which of the compounds was responsible for the cytotoxicity. The influence of sterilization temperature on degradation of the compounds was also subjected to investigation. Solutions of glucose and lactate and a mixture of lactate and glucose were prepared. These were sterilized in glass ampules in an oil bath at different temperatures for varying times. Toxicity was determined as inhibition of cell growth with a fibroblast cell line (L929), and ultraviolet (UV) absorbance was measured at 284 nm. Lactate solutions did not show cytotoxicity after heat sterilization. Glucose solutions that were heat sterilized showed an increase in UV absorbance at 284 nm and were cytotoxic. The mixture of lactate and glucose exhibited the same cytotoxicity as glucose alone. Lower sterilization temperatures lead to increased cytotoxicity and an increase in UV absorbance at 284 nm. Results indicate that the toxic products formed during heat sterilization of PD fluids are derived from glucose.


Evaluation of the biocompatibility of a new method for heparin coating of a cardiopulmonary bypass circuit.

The biocompatibility of the Terumo (Terumo Corporation, Tokyo, Japan) covalent heparin coating method in a cardiopulmonary bypass (CPB) circuit was evaluated in ex vivo and in vivo experiments. In the ex vivo experiment, fresh human heparinized blood primed both a miniature heparin coated circuit (HCC) and the identical noncoated circuit (NCC), and was circulated simultaneously for 2 hr (n = 6). In the in vivo experiment, 10 rabbits underwent 2 hr of CPB under systemic heparinization (ACT > 400 sec) with HCC (n = 5) and with NCC (n = 5). In the ex vivo study, thrombin/anti-thrombin III complex, thromboglobulin, platelet factor IV, granulocyte elastase, and C3a were significantly lower in the HCC than in the NCC at 60 and 120 min of circulation (p < 0.05). In the in vivo study, platelet counts (percent of value at 10 min of CPB) were significantly higher in the HCC than NCC (HCC:NCC 87 +/- 10:71 +/- 12 at 60 min, 81 +/- 17:56 +/- 16 at 120 min). Scanning electron microscopic examination of the circuits showed less significant adhesion and pseudopod formation of platelets in the HCC than NCC in both ex vivo and in vivo situations. These results demonstrate that this heparin coated CPB circuit provides superior biocompatibility compared with a noncoated circuit by reducing the activation of the coagulation cascade, platelets, leukocytes, and complement.


Plasma leakage through microporous membranes. Role of phospholipids.

Plasma leakage through microporous membrane oxygenators is a well known complication of prolonged extracorporeal circulation. The authors hypothesized that adsorption of bipolar plasma molecules, such as phospholipids on the microporous membrane, results in formation of a hydrophilic layer over the hydrophobic surface of the membrane; this, in turn, leads to plasma leakage at normal surface tensions. A lipid phosphorus assay was used to measure phospholipid adsorption onto the fibers of microporous membrane oxygenators tested under a variety of experimental conditions. Adsorption of phospholipids on the microporous membrane was concentration dependent. Reproducible plasma leakage occurred both in vitro and in vivo, and the time to leakage was dependent on the concentration of phospholipids adsorbed upon the microporous membrane. Based upon these results, the authors conclude that adsorption of phospholipids contributes to the development of plasma leakage through microporous membrane oxygenators.


Laboratory experience with a novel, non-occlusive, pressure-regulated peristaltic blood pump.

Current blood pumps have potential safety problems, including the ability to generate extreme positive and negative pressures. These problems were addressed in the design and testing of a non-occlusive, peristaltic blood pump. The pump consists of a tubing of unique design (pump chamber) wrapped under tension around a rotor with rollers. The pump chamber design is such that the pump is passively filling; flow is dependent upon the pressure of the blood supply and the size of the pump chamber. Thus, negative pressures cannot be generated. With the outlet occluded, the pump produces the maximum attainable pressure, which can be set by adjusting the tension of the pump chamber around the rollers. The design characteristics make the pump suitable for prolonged use. The pump was tested in vitro for pressure safety, hemolysis, and durability. The pump prototype was used in 25 experiments involving extracorporeal circulation on sheep, with an average duration of approximately 6 hr and bypass flow rates between 0.5 and 2.0 L/min. No pump related complications occurred in any of these experiments. The pump described here is suitable for short- and long-term perfusion applications, and does not require additional pressure regulation, as do current blood pumps.


Tissue viability measurement by in situ fluorometry.

A prototype laser-fiber optic based sensor for in situ monitoring of nicotinamide adenine dinucleotide (NADH) has been developed. This system is based on a compact neodymium-yttrium-aluminum-garnet (Nd:YAG) laser with associated harmonic generators. Light distribution to and from tissue is handled by a fiber optic network, including a long optical fiber to be inserted into the target tissue. Immobilizing the enzyme lactate dehydrogenase on the fiber tip converts the monitoring channel into a lactate sensor. A new dual beam reflection approach for blood volume artifact compensation is tested. Detection sensitivity of free NADH in the micromolar region is achieved. The method and system configuration appear feasible for continuous in situ monitoring of two important indices of ischemia and hypoxia in a clinical setting.


Subcutaneous capillary filtrate collector for measurement of blood glucose.

The capillary filtrate collector (CFC) is a device that creates an ultrafiltrate at 50-100 microliters/h from subcutaneous capillaries, and carries this filtrate out of the body for chemical analysis. From inside out, components include three looped hollow fiber ultrafiltration membranes, a polytetrafluoroethylene (PTFE) cuff, polyurethane tubing, a "Y" connector leading to a sampling port, a hub, and a needle placed into a 5 ml vacutainer tube. Animal studies have demonstrated that the CFC filtrate glucose level is exactly that of blood at the time the filtrate is created. The authors have performed clinical trials to determine the correlation of blood glucose and CFC glucose levels, and the time delay between contemporary samples. Seven diabetic patients wore the CFC device, tubing, and vacutainer tube for 1 month. In home monitored diabetic patients, fingerstick glucose measurements were performed at the usual daily schedule. The vacutainer was then evacuated, and this average sample analyzed and compared with the average of prior blood glucose levels. An optical device then was applied to measure the linear velocity of CFC fluid through external tubing, and predict the time for fluid to pass from fibers to the sampling port (average, 25 min). Capillary filtrate collector samples drawn at this time had glucose concentrations that generally correlated with blood levels. In diabetic patients on hemodialysis, the vacutainer was evacuated at the start of each treatment, and CFC and blood samples were drawn every 20 min during the treatment. Comparison of glucose-versus-time curves indicated a reasonable correlation between blood and CFC samples, with a delay related to flow rate (which declined 50% during dialysis).(ABSTRACT TRUNCATED AT 250 WORDS)


Surface fixation of hydrogels. Heparin and glucose oxidase hydrogelated surfaces.

The authors report a new photochemical technique for the fixation of hydrogels onto the surface of fabricated devices and sensors. The preparative method is based on two different types of photochemistry: photocross-linking due to intermolecular photodimerization of cinnamoyl groups, and photoinduced covalent bonding due to the photoreactivity of azido groups. The immobilization of heparin, useful as a thromboresistant coating, onto poly(ethylene terephthalate), and the immobilization of glucose oxidase onto the surface of a carbon fiber electrode, were demonstrated. In the former, immobilized heparin was found to be continuously released from the hydrogel, and the release rate was effectively controlled by the thickness of the hydrogel. In the latter, upon the addition of glucose, a spontaneous electrical response was observed to function as a glucose sensor. No delamination was found for either system after vigorous washing with water. Thus, durable surface hydrogelation, simultaneous immobilization of bioactive substances, and functioning of the systems were demonstrated.


In search of sterile, endotoxin-free dialysate.

Sterile dialysate, free of endotoxin (ET) and other cytokine inducing factors, will probably become a future standard. High-flux dialysis with bicarbonate and reuse has the membrane, the pressures, and bacteriologic potential for ET fragments to pass from dialysate to the blood side of the membrane with activation of monocytes and production of cytokines. Ultrafiltration through polysulfone filters has been shown to remove bacteria, ET, and its fragments and other cytotoxic inducing factors. The authors found that in spite of sterile, ET-free, reverse osmosis (RO) water, ET was usually present at the dialyzer inlet and arose from the RO storage tank water with bacteria < 30 CFU/ml, in spite of repeated disinfection. The authors now remove bacteria, ET, and fragments from RO tank water with a 5 mu cellulose filter followed by ultrafiltration with a Fresenius F-80 polysulfone dialyzer inserted between the wall RO delivery port and each delivery system. At the dialyzer inlet, monthly bacterial counts were < 30 cfu/ml, and ET values (n = 38) were not detectable in 89% and < 0.5 EU/ml in 11%. The F-80 filters were used for 180+ dialyses along with the 5 mu filters, which replaced the frequently endotoxin contaminated 10 mu filters in the Monitral-S delivery systems. The costs did not increase.


LDL apheresis in atherosclerotic disease with hyperlipidemia.

Low density lipoprotein (LDL) apheresis was carried out in 28 atherosclerotic patients with clinical signs of poor peripheral circulation and abnormally high LDL levels. The LDL apheresis using extracorporeal adsorption with a dextran sulfate cellulose column (Liposorber, Kaneka, Japan) was done 10 times over 3 months. Hyperlipidemia was rapidly corrected after the initial two aphereses, whereas clinical signs of arteriosclerosis obliterans (ASO), such as coldness of the legs in 17 of 19 patients (89.5%), intermittent claudication in 14 of 17 patients (82.4%), foot pain at rest in 15 of 18 patients (83.3%), poor arterial pulsation in 12 of 16 patients (75.0%), and diminution of ulcer/necrosis in 3 of 5 patients (60.0%), improved in parallel. Improvement in plethysmographic and thermographic findings were observed in 10 of 10 patients (100.0%) and 13 of 14 patients (92.9%), respectively. Our tentative conclusion is that LDL apheresis using the Liposorber system was very effective in removing LDL from blood, and clinical symptoms rapidly improved in all patients concomitant with a reduction in plasma LDL levels. Hyperlipidemia may be a risk factor for symptomatic ASO in the lower extremities, and its active correction may be worth trying.


The efficiency of new leukocyte removal filters. CF-1 and CF-2.

Two new leukocyte removal filters, Nipro CF-1 and CF-2 (Nipo Medical Industries, Osaka, Japan), were evaluated. These non-woven polyester filters, which are gravity flow devices that require no priming and no rinsing after use, were developed for preparing 400 ml of whole blood or red cell concentrates from 400 ml of whole blood. A flow cytometric technique was developed to measure extremely low white blood cell (WBC) counts. To evaluate the efficiency of these filters, leukocyte counts were measured by three techniques: 1) electronic, 2) visual, and 3) flow cytometry. Flow cytometric counting was done using a Coulter EPICS-C cytometer (Coulter Corp., Hialeah, FL). Nipro CF-1 removed 99.97 +/- 0.01% (mean +/- SD, n = 14) of leukocytes measured by flow cytometry, and CF-1 recovered 90.7 +/- 4.47% (n = 21) of red blood cells. After filtration through CF-2, more than a 6 log10 (> 99.9999%) depletion of WBCs was detected in six samples, a 6 log10 (99.9999%) depletion of WBCs was detected in two samples, a 5 log10 (99.999%) depletion was detected in five samples, and a 4 log10 (99.99%) depletion was detected in one sample. CF-1, in which size and priming volume was smaller than other commercial leukocyte removal filters, accomplished a 3 log10 reduction in WBC count, compared with other commercial filters. CF-2 achieved a 4-6 log10 depletion of WBCs assayed by flow cytometry.


In vitro perfusion of hybrid artificial pancreas devices at low flow rates.

Type I diabetes is characterized by insulin insufficiency due to lack of functional beta cells. To replace injection therapy, schemes such as the Hybrid Artificial Pancreas (HAP) were developed. This consists of an acrylic housing enclosing a semipermeable hollow fiber membrane. Donor islets can be seeded in the annular space through a port in the housing, and thus are separated from the recipient's bloodstream or perfusate. Before scaling the HAP to human size, the dynamics of its insulin response to a perfusion glucose challenge must be better understood. In this study, the HAP's insulin response after a step increase in the lumenal glucose concentration was determined as a function of the radial thickness of the annular space (0.173-0.973 mm) and islet distribution at a flow rate of 1 ml/min. Devices containing a single, 65 mm long fiber were used. Rat islets were isolated using standard collagenase digestion techniques. In unseeded HAP perfusions, the washout time for glucose and insulin from the annular space was dependent on flow rate and radial thickness. Both solutes were removed in < 3 min from the smallest devices when perfused at 10 ml/min. Thus, solute transport within the HAP is very fast. In the seeded HAP perfusions, the devices were subjected to a step increase in the lumenal glucose concentration. Sequential samples of the HAP effluent were collected and assayed for glucose and insulin. The spatial distribution of the islets in the annular space was one of the most important factors in determining the HAP's insulin response.(ABSTRACT TRUNCATED AT 250 WORDS)


A blood pump with an interatrial shunt for use as an electrohydraulic total artificial heart.

A recently designed blood pump subsystem for the completely implantable electrohydraulic total artificial heart (EHTAH) has been developed and is under evaluation. The subsystem consists of joined left and right ventricles, atrial cuffs with an interatrial shunt (IAS), and two outflow grafts. The ventricles were developed to fit within the pericardial space based on the results of anatomic fit trials. An optimized configuration for animal use, which was adaptable for human use with minimal modification, was identified. The core dimensions of the ventricles with an energy converter are approximately 10 x 11 x 7 cm. Maximum output and stroke volume are 9.2 L/min and 81 ml, respectively. The IAS is used to balance the volumetrically coupled EHTAH, and is made by forming an orifice in the common septum of the left and right atrial cuffs. Performance and durability of the IAS were examined in animal experiments for up to 9 days. The diameter of the IAS was 3.4-5.5 mm, and the left-right atrial pressure difference ranged from 2 to 10 mmHg, with 0.57-1.48 L/min of theoretically calculated shunt flow. No evidence of thrombus formation was found in or around the IAS at autopsy. The entire EHTAH system with a new blood pump is being assembled for long-term animal studies.


The spring-driven implantable pump. A low-cost alternative.

In the current era of cost containment in medicine, manufacturing economics have become increasingly important. The authors devised an implantable pump powered by spring force from an elastomeric Belleville washer, which is also the outer flexible wall of the drug reservoir. Use of formed and injection molded parts provides for low-cost manufacturing, in contrast to the precision welded alternative designs. Additional advantages include insensitivity to changes in ambient temperature and pressure. Finite element modeling of the elastomer spring allows prediction of the effects of parameter changes on performance, so that expansions and reductions of scale can be made without compromising the uniform spring rate of the device. A concern that subcutaneous fibrous encapsulation might markedly alter reservoir pressure was not supported by experimental data. In a unit implanted subcutaneously in a dog, reservoir pressures measured over a 4 year period were stable. This new, simple, implantable infusion pump can serve as an economical vehicle for prolonged parenteral drug treatment of ambulatory subjects in circumstances where continuous single-rate infusion is appropriate.


Islet transplantation using an immunoprotective membrane in dogs that have undergone a pancreatectomy.

The use of a selectively permeable membrane to transplant nonsyngeneic tissue without accompanying immunosuppressive therapy has been investigated using two approaches. The first hybrid artificial pancreas is implanted as a vascular shunt in which blood circulates through the lumen of a tubular membrane. The islet tissue is distributed within a chamber surrounding the membrane enclosed by an acrylic housing. Studies with diabetic dogs that have had pancreatectomies have demonstrated that these devices could replace exogenous insulin therapy for at least 6 months in five animals. This report presents data on two of these dogs, demonstrating viability and function of the transplanted tissue after 1 year. As an alternative to the vascular device, islets sealed within cylindrical permselective membrane chambers have been implanted in the peritoneum. Preliminary data from three dogs indicate that the nonvascular implants can also regulate fasting glucose levels in the diabetic dog model.


Glucose-sensitive membrane and infrared absorption spectroscopy for potential use as an implantable glucose sensor.

The applicability of using infrared absorption spectroscopy for an implantable glucose sensor was tested by measuring absorbance at 9.66 microns for glucose in aqueous solution at known concentrations. A commercial Fourier transform infrared spectrometer was used with an attenuated total reflection technique (ATR). Absorbance measurements were reproducible and linearity was excellent (coefficient of correlation: 0.996), in spite of pH and temperature changes over values that span the human physiologic ranges (pH 6.8-7.8, temperature, 32-43 degrees C) and 18-34% decreases in incident infrared energy. The minimum detectable concentration of glucose, however, was 31 mmol/L (560 mg/d) and, to use infrared sources and detectors compatible with an implantable device, an absorbance peak between 1 and 3 microns must be used. To solve the detection sensitivity and wavelength problems, the ATR prism was coated with a hydrophobic liquid membrane. The absorbance of water varied at 2.95 microns in inverse linear proportion to glucose concentration between 2-31 mmol/L (35-560 mg/dL, r = -0.992). Estimated incident infrared energy at 2.95 microns (0.2 micron bandwidth) was low enough to theoretically allow the use of a lithium battery small enough for implantation. These findings support the concept of using infrared absorption spectroscopy for an implantable glucose sensor.


Immunoprotection of xenocytes in a hollow fiber bioartificial liver.

A new, hollow fiber bioartificial liver (BAL) was tested in an anhepatic rabbit model to assess the hollow fiber membrane as an immunologic barrier. The extracorporeal BAL contained rat hepatocytes (xenocytes) entrapped in collagen gel inside the lumen of hollow fibers with 100 kd nominal molecular weight cut-off. Blood from the anhepatic rabbit flowed in the extracapillary compartment. After 4 h of BAL hemoperfusion, the hepatocyte gels were tested for evidence of rabbit immunoglobulin and complement. Samples of the gels were stained with fluorescein isothiocyanate (FITC)-labeled antibodies directed against rabbit IgM, rabbit IgG (Fc and F[ab]2), and rabbit complement (C3) and studied by immunofluorescence microscopy. Enzyme-linked immunosorbent assay and Western blotting were used, respectively, to quantify and identify proteins inside the BAL and in the rabbit blood. These studies suggest that very little rabbit IgG (primarily fragments of IgG) and no IgM or C3 crossed the hollow fibers during hemoperfusion. Rat albumin steadily accumulated in the rabbit blood during hemoperfusion, which indicated membrane permeability to molecules of that size and stable hepatocyte function by the BAL. The authors conclude that hollow fibers with 100 kd nominal molecular weight cut-off provide immunoprotection for xenocytes in an extracorporeal BAL.


Effects of left ventricular pressure unloading during LVAD support on right ventricular contractility.

The effects of left ventricular pressure (LVP) unloading with a left ventricular assist device (LVAD) on right ventricular (RV) end-systolic pressure volume relationships were studied. A Thoratec (Berkeley, CA) LVAD was implanted in open chest anesthetized pigs via apical cannulation, and an electromagnetic flow probe and computer controlled pneumatic occluder were attached to the pulmonary artery. RV and left ventricular (LV) pressures were measured with Millar catheters, and changes in RV volume during ejection were determined by integrating the flow signal. As an index of contractility, RV maximal systolic elastance (Emax) was calculated as the slope of the end systolic, pressure volume relationship between an isovolumic beat and a series of transiently occluded beats at different times in the ejection phase. After an 83 +/- 15% decrease in LV pressure time integral during LVAD pumping, there were no significant changes in cardiac output, mean systemic arterial pressure, or in RV dP/dtmax. Most important, RV Emax during LVAD unloading (0.63 +/- 0.16 mmHg/ml) was unchanged from control (0.62 +/- 0.10 mmHg/ml). Therefore, in the normal intact porcine heart, the effective contractility of the right ventricle is not altered by significant LV pressure unloading produced with a LVAD.


Does a porcine hepatocyte hybrid artificial liver prolong the survival time of anhepatic rabbits?

To examine cultured porcine hepatocytes as a bioreactor of a hybrid artificial liver (HAL) in rabbits, a small version of a multiplated HAL was manufactured. In vitro and ex vivo studies were performed to evaluate the small HAL. The HAL consisted of 50 glass plates (10 x 5 x 0.04 cm each) on which porcine hepatocytes were cultured in a monolayer at confluent cell density. After 2 days of standard cultivation, the glass plates with hepatocytes were placed in the module and were used for studies. The module contains about 5 grams of hepatocytes (1/10 of 2 kg.bw rabbit liver). After undergoing perfusion culture for 5 days, the HAL showed satisfactory hepatic function. Glucose and urea were synthesized at the rate of 4.06 +/- 0.7 mg/module/hr and 0.62 +/- 0.09 mg/module/hr, respectively, and loaded ammonia was metabolized at the rate of 1.29 +/- 0.26 mg/module/hr. Ex vivo extracorporeal plasma perfusion studies revealed that the module with cultured porcine hepatocytes, which were heterogeneous to rabbits, showed a tendency to prolong the survival time of anhepatic rabbits. These results indicate that the HAL system, using multiplated porcine hepatocyte monolayers, is a promising artificial liver support system for clinical cases.


Effects of uremia and dialysis on brain electrophysiology after recombinant erythropoietin treatment.

Quantitative electrophysiologic assessments are sensitive and useful indices of clinical state, and they are valuable in evaluating brain electrical activity before and after recombinant human erythropoietin (r-HuEPO) treatment. To study the hypothesis that, theoretically, anemia might be a cause of brain dysfunction in uremia, the authors assessed 18 patients (10 men and 8 women) on hemodialysis (RDT, age range, 35-58 years) before treatment (T1), and after 12 weeks (T2) and 24 weeks (T3) of r-HuEPO treatment, utilizing the following electrophysiologic tests: visual evoked potentials (VEP), brainstem auditory evoked responses (BAER), and somatosensory evoked potentials (SEP). The r-HuEPO was injected subcutaneously two times a week after RDT to produce hematocrit (Hct) levels of 30-35%. This drug induced a decrement of latency in P100 VEP (134.2 +/- 7.9 msec in T1 versus 116.5 +/- 6.9 msec in T2, p < 0.001, and versus 107.6 +/- 5.7 msec in T3, p < 0.005) and in the four main components of BAER. The most significant SEP changes were P27-N35 from peroneal nerve (p < 0.01), as an augmentation of SEP amplitude. Correction of anemia with r-HuEPO leads to a significant improvement in brain function in patients on RDT. The increased Hct level leads to enhanced brain oxygen delivery, directly improving brain metabolism. When the Hct rises, cerebral blood flow falls from high levels to normal, decreasing delivery of uremic "toxins" to the brain. The decrease in cerebral blood flow may decrease intracranial pressure and, in this way, may exert its beneficial effects by a rheologic pathway.


Dialysis leg cramps. Efficacy of quinine versus vitamin E.

A controlled randomized double-blind study was done to determine the frequency and severity of leg cramps in 40 patients on dialysis with a history of leg cramps. All patients entered a 2 month placebo washout and were randomized into a 2 month double-dummy phase of quinine 325 mg at bedtime versus vitamin E 400 IU at bedtime. Of the 29 patients completing the study, 16 received quinine and 13 vitamin E. During placebo washout, the vitamin E group had a mean of 10.4 leg cramps per month, and the quinine group had a mean of 10.9. The vitamin E and quinine groups had a 1 month reduction in leg cramps to 3.3 and 3.6, respectively (p < 0.0005 for both groups combined); this was sustained at 2 months. A severity of pain index showed a statistically significant decrease for both groups. The 95% confidence interval for the difference between the number of leg cramps after vitamin E versus quinine treatment (95% confidence interval, -3.8, +3.2) suggests similar efficacy. Quinine and vitamin E were effective treatments for leg cramps in these patients. Considering the potential toxicity of quinine, vitamin E is recommended as the initial treatment of choice for patients on dialysis with leg cramps.


Registry report. Use of total artificial hearts: summary of world experience, 1969-1991.

Eleven models of total artificial hearts (TAHs) have been used for transient or permanent circulatory support in patients with failing hearts. From April 4, 1969 to July 1, 1991, 230 TAHs were used in 226 patients (four patients received a second TAH) at 39 centers worldwide. Five patients received a Symbion TAH as a permanent circulatory support device; the remaining 221 received TAHs as bridges to cardiac transplantation. The principal investigators received written requests for demographic and clinical information after each implant and annually thereafter to assess survival. The mean patient age (+/- SD) was 43 +/- 12 years (range, 13-69 years); 88% of patients were men. The primary indications for implantation were deterioration while on a transplant waiting list (34%) and acute cardiogenic shock (33%). The duration of implantation ranged from < 1 to 603 days; 65% received heart transplants. The incidence of infection and embolic events occurring during implantation times were 36% and 9%, respectively (stroke, 5%; transient ischemic attacks 4%). Most deaths were caused by sepsis (33%) and multiorgan failure (32%) during the implantation period; sepsis (36%) and rejection of the donor heart (19%) were responsible for most deaths in patients who died after transplantation. The 1 year survival rate was 37% for all patients receiving a device and 50% for those who received a transplanted organ. In the overall Symbion TAH population (187 patients), 40% survived 1 year and 56% of the transplanted group survived 1 year; 39 non-Symbion TAH implants resulted in one long-term survivor (3%).(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of mechanical ventilation and spontaneous respiration on hemodynamics in calves with total artificial hearts.

The effects of respiration on hemodynamics were evaluated in four Holstein calves with total artificial hearts (TAH). The electrohydraulic actuated E4T-TAH has a continuously reciprocating actuator packaged between two alternately ejecting blood pumps that passively fill. The hemodynamic parameters (right atrial pressure [RAP], left atrial pressure [LAP], pulmonary artery pressure [PAP], aortic pressure [AoP]), and right and left pump filling (Rt% fill and Lt% fill) were measured when the animal was intubated and mechanically ventilated. These measurements were repeated with spontaneous respiration after the animal was extubated. With mechanical ventilation, LAP, PAP, and AoP were significantly higher during inspiration than during expiration. However, RAP during inspiration was slightly lower than that during expiration. The Rt% fill during inspiration was significantly lower than during expiration, but Lt% fill during inspiration was significantly higher than during expiration. During spontaneous respiration, these changes were opposite to those observed during mechanical ventilation. That mechanical ventilation generates positive intrathoracic pressure during inspiration, but spontaneous respiration generates negative pressure may explain these results. The change in venous return to the right atrium caused the change in RAP to be opposite in direction to that of the other pressures.


Initial in vivo tests of an electrohydraulic actuated total artificial heart.

The authors are involved in developing a total artificial heart (TAH) for permanent human use. This device was designed to fit human anatomy, and it has housings made of carbon fiber-epoxy composite and titanium. Tissue valves and protein coating of blood contacting surfaces minimize the need for anticoagulants. A continuously reciprocating electrohydraulic actuator is packaged between two alternately ejecting and passively filling ventricles. The control system varies the pump rate to maintain average left ventricular filling at 90%. This TAH in vivo successively progressed through 1, 5, 9, and 45 day implants in calves of 84, 94, 82, and 82 kg preoperative body weights. The operating modes include automatic and fixed rate. The chronic and acute effects of varying the right pump displaced stroke volume indicated the need for it to be limited to 85% of that of the left for stable hemodynamics at maximum flow. The pump exhibited afterload insensitive and preload sensitive performance. Pump output ranged from 4.0-9.5 L/min at left atrial pressures of 7-16 mmHg at pump rates of 80-160 beats/min in these four experiments. These data suggest that this device will meet clinical hemodynamic requirements; it has the potential for total implantable cardiac replacement.


Experimental studies of pulsatile flow and endothelial cell adaptation in ventricle shaped cell culture chambers.

The authors' long-term research goal is to minimize the risk of thromboembolic complications in cardiac prostheses by lining blood contacting surfaces with a functional monolayer of autologous endothelial cells. These cells recognize changes in hemodynamics and can adapt effectively to experimentally manipulated flow conditions. By implication, the morphology of endothelial cells, in conjunction with their function, might serve as an indicator of the flow patterns in a particular location. It was hypothesized that, by understanding flow patterns at a given site, the local morphology and function of the endothelial cells in such a region could be predicted. To test this hypothesis, a series of ventricle shaped flow chambers were designed and perfused with pulsatile flow. The flow field in the chambers was studied by computer aided dye visualization and nuclear scintigraphy. The results showed that the large scale motion of the fluid in the cavity was highly coherent and consisted of distinct flow patterns. The temporal and spatial characteristics of the flow patterns, and their implications with respect to endothelial cell endurance in this in vitro environment, were examined in detail.


A skeletal muscle actuator for an artificial heart.

The authors developed a system to use skeletal muscle as an artificial heart actuator. This system consists of a flexible rod, sheath, crank, and cam to transmit the muscle power to a pusher plate pump and actuate it. The latissimus dorsi muscle was dissected at the lower ribs, and its end was connected with the flexible rod. The contraction of skeletal muscle was linearly transmitted, with the rod introduced inside the sheath, to the pump. The whole system was implanted in dogs (14-18 kg) and pump performance was evaluated with a mock circulatory system (preload = 10 mmHg, afterload = 75 mmHg). In these experiments, the pump output was maintained at 0.8 to 2.0 L/min (60 bpm) for 200 min, with a non-preconditioned muscle that was stimulated continuously. The output obtained was 2.5 mW/gram. Efficiency of this system was about 50% of the muscle power available. When the muscle was stimulated intermittently every 30 min, pump flow was maintained at > 0.8 L/min for 20 hr. Advantages of this system are: 1) the muscle power was linearly transmitted effectively, 2) this system could be installed with minimal surgery and without interruption in blood flow to the muscle, 3) the muscle is free from high intraventricular pressure that caused ischemia and, 4) the muscle can be set to the proper length in diastole to potentiate strong contractions.


Improved patency of an elastomeric vascular graft by hybridization.

A newly devised hybrid graft with high antithrombogenicity for small caliber vascular grafts was developed. The design concept was based on the incorporation of a compliant open cell structured graft, autogenous endothelial cells (ECs), and artificial basement membrane. The latter, a gel complex of type I collagen and dermatan sulfate that showed enhanced adhesion and growth of ECs but reduced platelet adhesion, was coated onto a microporous polyurethane graft (internal diameter, 3 mm; length, 4.5 cm), with near-natural compliance. Ten seeded grafts were implanted bilaterally into the carotid arteries of dogs; anticoagulant or antiplatelet therapy was not administered. This hybrid graft showed a marked improvement in patency at 1 month compared with that of simply preclotted grafts (control specimens). This result was explained by the almost complete endothelialization when the graft was implanted, a high degree of adherent strength resistance to shear stress, and a high proliferative potential. Thus, this approach of combining biomechanical and cellular engineering designs may lead to an important functional small caliber graft.


Venous access pressures and the detection of intra-access stenosis.

Venous pressure measured by the dialyzer is an unreliable measure of intra-access venous pressure. During dialysis and zero extracorporeal blood flow, intra-access venous limb pressure (VPd) was measured directly 401 times in 133 subjects using a high flow "in-line" three-way stopcock adjacent to the venous return needle. Subjects with systolic VPd/systolic blood pressure (BP) > or = 0.4, inadequate blood flow, or edema in the access extremity were referred for angiography. Percent diameter lumen reduction by a stenosis (%D) > 50% was considered hemodynamically significant. The authors did 138 angiograms. It was found that VPd/BP increased with %D in both ePTFE bridge grafts and native fistulae. Measurements of venous limb VP/BP taken at the time of dialysis and at the time of angiography did not differ (n = 55). On 80 occasions, accesses had significant stenoses. The overall sensitivity of VPd/BP in ePTFE bridge grafts was 91% and specificity 91%. False negative results occurred in seven of 24 native and eight of 114 ePTFE graft studies; 14 of 15 patients had arm swelling caused by central stenosis. Recirculation > 15% was more sensitive (71%) in detecting stenosis in native accesses than was intra-access pressure. It was concluded that VPd/BP > 0.4 is a useful, sensitive, and specific criteria for detecting synthetic bridge graft accesses at risk for thrombosis.


The effect of Doppler flow screening studies and elective revisions on dialysis access failure.

A retrospective study was undertaken to see if screening ultrasounds and elective surgical revision could decrease access failure. Two hundred fifty-three accesses [177 gortex grafts, 76 arteriovenous (AV) fistulas] were studied with duplex imaging. Patients were subdivided by access type, flow, percent stenosis, and whether they were surgically revised. Data was examined to determine access failure within 6 months. Ten of 76 fistulas clotted (13.1%), while 53 of 177 grafts clotted (29.9%) (p = 0.005). In Gortex grafts, stenosis (p < 0.05) and decreased flow (p = 0.005) correlated with clotting. In unrevised grafts with flow < or = 801 ml/min, 13 of 14 (92.8%) clotted, whereas of those with flow > or = 1603 ml/min only, 10 of 38 (26.3%) clotted (chi-square = 24.74; p < 0.0001). Only 1 of 18 (5.6%) revised grafts with flow < or = 1300 ml/min clotted, while 29 of 69 (42%) unrevised grafts clotted (p = 0.004). We were unable to demonstrate decreased clotting in fistulae with revisions. In conclusion, screening duplex scanning was able to select groups with a higher risk of access failure over the subsequent 6 months. Elective revision with correction of areas of stenosis in grafts with flows < or = 1300 ml/min significantly decreased the incidence of clotting.


Vascular access thrombosis during recombinant human erythropoietin therapy.

The increased incidence of vascular access thrombosis (VAT) associated with recombinant human erythropoietin (r-HuEPO) therapy is multifactorial and controversial. Sixty-three hemodialysis patients who received > or = 12 weeks of r-HuEPO therapy were prospectively followed for the incidence of VAT. Those who experienced VAT (Group 1) were compared with those who did not (Group 2). The patients initially received r-HuEPO 50 U/kg intravenously three times a week. The dose was adjusted for a target hematocrit (t-Hct) of 30-33%. Twenty-five of the 63 patients (40%) experienced VAT (Group 1). These patients were older (mean, 54.0 +/- 14.0 years versus 47.3 +/- 15.0 years, p = 0.08). There was no difference between Groups 1 and 2 with respect to the baseline Hct level (21.5 +/- 2.9% versus 21.4 +/- 4.3%), the number of patients who achieved t-Hct (20 versus 28), and the mean time to reach t-Hct (18.6 +/- 15.1 weeks versus 16.9 +/- 16.2 weeks). However, 20 of 25 Group 1 patients (80%) were diabetic compared with only 18 of 38 Group 2 patients (47%, p = 0.0169, by Fisher's exact test). In addition, the types of vascular access differed markedly between the two groups: arteriovenous (AV) grafts/AV fistulae/Permcaths, Group 1: 21/3/1 versus Group 2: 15/21/2, p = 0.0018. It was concluded that the occurrence of VAT in r-HuEPO treated patients was not related to the patient's hematologic response to the drug, but rather, it depended upon the integrity of the patient's vasculature and the type of vascular access used.


Growth and functional assessment of pulmonary valves in pigs after replacement of sinuses of Valsalva.

Neopulmonary artery stenosis may occur after the arterial switching procedure to correct transposition of the great arteries. One technique to reduce this complication is to use a single rectangular piece of autogenous pericardium to reconstruct two adjacent sinuses of Valsalva and maintain pulmonary artery size. The long-term effect of this technique on pulmonary artery and valve growth and function is unknown. To assess this technique, Yorkshire-cross pigs (n = 5) weighing 29 +/- 1.7 kg (mean +/- SEM) were anesthetized, and during cardiopulmonary bypass, the pulmonary artery was transected distal to the pulmonary valve. Pulmonary artery diameter and commissure distances were measured. Two adjacent pulmonary artery sinuses of Valsalva were completely excised from the anulus to 4 mm distal to the commissures, leaving 2 mm of pulmonary artery tissue attached to the skeletonized commissure and on each side of the one remaining intact sinus of Valsalva. A single rectangular patch of fresh autologous pericardium was sutured to the anulus and remnant of the pulmonary artery along the commissure and edges of the one intact sinus of Valsalva. Pericardium composed two thirds of the circumference of the proximal pulmonary artery; this was anastomosed to the distal pulmonary artery. Weight gain occurred at a rate of 0.6 kg/day (median). The animals underwent right heart catheterization and cineangiography. They were killed 157.2 +/- 12.9 days post-operatively. The reconstructed pulmonary artery grew from 17.6 +/- 0.8 mm to 30.8 +/- 1.5 mm (p < 0.01), and the commissure distances grew from 17.0 +/- 1 mm to 27.2 +/- 1.6 mm (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Heparin-free hemodialysis with an oral anti-platelet agent.

Heparin-resistant blood clotting in hemodialysis, caused mainly by platelets activated with artificial materials, was ameliorated by oral administration of a newly developed anti-platelet agent, 4-cyano-5,5-bis (4-methoxy phenyl)-4-pentenoic acid (E5510, Eisai Co. Ltd., Tokyo, Japan). Six hemodialysis patients, who were given 0.5. 1, 2, and 4 mg of E5510 orally 1 to 2 hr before starting hemodialysis, underwent hemodialysis using a hollow fiber dialyzer (PMMA or cellulose acetate). The platelet aggregation rate was depressed according to dose response, and fell to less than 30% of the initial value with 2 mg of E5510. Plasma thromboxane B2 concentration was depressed significantly. Bleeding time was mildly but not significantly prolonged. Based on these results, we tried heparin-free hemodialysis using E5510 as sole anticoagulant. Six of nine patients were successfully hemodialyzed with minimal blood clotting in the dialyzer and drip chambers. Three patients needed additional low dose heparin to prevent blood clotting in the circuit's air trap. Neither hemorrhagic complications nor other side effects were observed in these cases. E5510 is considered to be a promising oral anti-thrombogenic agent for patients with heparin-resistant blood clotting or heparin-free hemodialysis.


Performance of a hydrogel composite pericardial substitute after long-term implant studies.

A novel composite patch has been tested as a pericardial substitute to reduce adhesion formation after cardiac surgery. The patch consists of poly 2-hydroxyethyl methacrylate (pHEMA) hydrogel reinforced with a polyethylene terephthalate (PET) mesh. The hydrogel-PET composite pericardial patches were implanted in canines for 6, 9, and 12 months. Upon termination, adhesion formation and epicardial reaction to the implant were rated. No adhesions formed between the patch and the native pericardium or epicardium. A thin fibrous layer on the epicardium progressively developed where the patch contacted the heart. The coronary anatomy remained visible. Histologically, the response to the implant was fibrous in nature. No significant signs of cellular inflammation were found. The gross appearance of the retrieved patches was nearly identical to that of preimplant patches. Mechanical tests showed no significant changes (alpha = 0.05) in patch strength or stiffness. Hydrogel water content initially increased during implantation. The thickness of the patch did not change significantly (alpha = 0.05) throughout the study. Scanning electron microscopy (SEM) revealed unequal layers of hydrogel on either side of the PET mesh and cracks in the hydrogel surfaces of retrieved patches. Both SEM and light microscopic observation of the patches showed traces of calcification in patches in the 9 and 12 month studies.


Study of anatomic constraints using three dimensionally reconstructed images for total artificial heart implantation.

The authors established a method of clarifying the three dimensional interrelationship among the mitral and tricuspid annuli, ascending aorta, main pulmonary artery, diaphragmatic surface of the heart (DS), and anterior thoracic wall, using four chamber view magnetic resonance imaging. This method was applied to measuring the parameters that restrict the size and shape of a total artificial heart (TAH) from three dimensional reconstructed images of six normal subjects. Assuming that the TAH is implanted on the diaphragm, which corresponds to DS, the width of the TAH is restricted to 7.6 cm, the transverse dimension of the cardiac base (D-B), and the height to 7.8 cm, the dimension from the DS to the center of the pulmonic annulus (DS-P1). Depth is restricted by the longitudinal dimension of the left ventricle projected on the DS (D-L). While D-L in early systole is 9.7 mm, in late systole D-L is reduced to 7.6 cm. The angle (DS) (AW) is 65.7 degrees; this is the angle between the DS and anterior thoracic wall that restricts the shape of the TAH. While these data in normal subjects may be useful for TAH implantation, in the patient with acute cardiac failure, further study of patients with chronic cardiac failure is necessary.


Effect of shear rates on protein adsorption in the total artificial heart.

Plasma protein adsorption is the first event in blood-material interaction and influences subsequent platelet adhesion and thrombus formation. Thromboembolic events are strongly influenced by surface characteristics of materials and fluid dynamics inside the blood pump. In vitro flow visualization, and an animal experiment with a moving actuator total artificial heart (TAH), were performed to investigate fluid dynamic effects on protein adsorption. The different levels of shear rate inside the ventricle were determined by considering the direction of opening of the four heart valves in the implanted TAH, and the visualized flow patterns as well. Each ventricle of the explanted TAH was cut into 12 segments according to the shear rate level. The adsorbed protein on each segment was quantified using an ELISA method after soaking in 2% (w/v) SDS/PBS for 2 days. Adsorbed protein layer thicknesses were measured by the immunogold method under transmission electron microscopy. Scanning electron microscopic observation showed that the right ventricle, immobilized with albumin, displayed different degrees of platelet adhesion on each segment, whereas the left ventricle, coated with polythyleneoxide-sulfonate, indicated nearly the same platelet adhesion behavior, regardless of shear rates. The surface concentrations of adsorbed proteins in the low shear rate region are higher than those in the high shear region, which was confirmed statistically.


Permeation of silicone oil through a diaphragm in an electrohydraulic ventricular assist system.

This study was designed to investigate the permeation of silicone oil through a pump diaphragm made of Pellethane in the authors' electrohydraulic ventricular assist system (EHVAS) and to evaluate influences on organ function. The permeability of the diaphragm to silicone oil was investigated by in vitro experiments. Influences on organ function were evaluated in five goats with an EHVAS by monitoring serum silicon levels (SSi), blood chemical parameters, and histologic findings. Elevation of silicone oil levels in Pellethane sheets immersed in silicone oil demonstrated that the Pellethane diaphragm was, in fact, permeable to silicone oil. The permeation rate of silicone oil was calculated to be 1.75 ml/year in the authors' EHVAS from the data of a diffusion apparatus test. Serum silicon levels did not increase during the EHVAS pumping, and renal and hepatic function were not affected. No abnormality or deposit suggestive of silicone oil was observed. However, the problem of permeation of silicone oil through the pump diaphragm must be solved to allow for a circulatory assist device for long-term use.


Heparin induced thrombocytopenia in patients undergoing intra-aortic balloon pumping after open heart surgery.

Heparin is usually administered to patients with intra-aortic balloon pumps (IABP) to prevent thromboembolism. In addition to thrombocytopenia caused by IABP mechanical damage to platelets, exposure to heparin can cause heparin induced thrombocytopenia (HIT). Heparin induced thrombocytopenia is caused by an immune mechanism in which heparin antibodies are produced, causing platelet aggregation, leading to bleeding or thromboembolic complications. Over a 9 year period, 35 of 764 (4.5%) patients with IABPs have been diagnosed as having HIT. Surgical procedures included coronary artery bypass (CABG) in 14 (40%), valve repair or replacement in 7 (20%), and CABG and other cardiac procedure in 14 (40%). Lowest platelet counts ranged from 17,000-114,000/mm3 (median, 44,000/mm3). Thirty-three of 35 (94.3%) had mediastinal hemorrhage requiring infusion of multiple blood products, and 6 of these 35 (17%) required return to the operating room. Seventeen of 35 (48.6%) experienced thromboembolic complications. Hospital mortality was 15 of 35 (42%). Etiology of thrombocytopenia in patients on IABPs is multifactorial. Patients on an IABP who develop thrombocytopenia should be tested for heparin dependent anti-platelet antibodies to rule out HIT. When a heparin antibody is present, heparin must be discontinued and alternate forms of anticoagulation/platelet inhibition initiated to reduce morbidity and mortality.


Changes with respect to time in the in vivo adsorption of plasma proteins onto artificial heart blood pumps.

The distribution of adsorbed plasma proteins (albumin, IgG, and fibrinogen) on 10 artificial heart blood pumps coated with 2 segmented polyurethanes was evaluated quantitatively after long-term in vivo experiments with goats to determine how the adsorption of plasma proteins on the pumps was affected by the kinds of biomaterials used, and by the pumping duration. The adsorbed plasma proteins on the materials were determined quantitatively using the iodine-125 conjugated antibody method. Microscopically, the adsorbed plasma proteins were marked by the gold colloid conjugated antibody method, and analyzed using a field emission scanning electron microscope. The macroscopic results showed that: 1) the adsorbed plasma proteins on KP-13 were more evenly and finely distributed than those on Cardiothane; 2) with KP-13, the adsorption of IgG and albumin at the center of the pumps was significantly less than in the peripheral areas, and the adsorbed IgG and albumin decreased significantly as the pumping duration increased; 3) in contrast, the adsorbed fibrinogen increased significantly with time; and 4) with Cardiothane, the tendencies for adsorbed IgG and albumin to decrease, and for adsorbed fibrinogen to increase, were less significant than with KP-13. Microscopically, the gold colloids marking plasma proteins were found to not cover the whole of the surface, but were found scattered randomly or in clusters, with no relationship observed between the distributions of the three plasma proteins.(ABSTRACT TRUNCATED AT 250 WORDS)


Influence of an impeller centrifugal pump on blood components in chronic animal experiments.

A chronic animal experiment was designed to examine the changes in blood components induced by the use of a centrifugal pump (CP). In the pump, an impeller spins in a blood chamber by magnetic coupling with a rotating magnet outside the blood chamber. A pulsatile ventricular assist device was implanted between the left atrium and the descending aorta in four goats weighing from 63 to 75 kg; the CP was installed to replace the assist device, without surgery and anesthesia, more than 2 weeks later when the influences of implantation surgery were diminished. Antithrombotic therapy was performed with oral administration of an antiplatelet agent, cilostazol, a cyclic adenosine monophosphate phosphodiesterase at a dose of 30 mg/kg/day. No significant differences were observed in any of the following parameters: 1) hematocrit, 2) plasma free hemoglobin, 3) lactic acid dehydrogenase, 4) adenosine diphosphate, 5) platelet count, 6) fibrinogen, and 7) antithrombin III, between the data before and after the use of the CP, nor were deformation or pseudopods of platelets seen. The CP developed in the authors' institute and evaluated in this study did not damage blood components, and it proved to be a promising device for long-term use.


Characteristics of artificial red cells. Hemoglobin encapsulated in poly-lipid vesicles.

Artificial red cells (ARC) were prepared by encapsulation of purified human Hb with polymerizable phospholipid, 1,2-bis (2,4-octadecadienoyl)-sn-glycero-3-phosphocholine (DODPC). The polymerized lipid bilayer of the ARC produced great physical stability that could not be achieved using a non-polymerizable lipid for encapsulation. ARC showed no change in particle size or distribution or leakage of Hb after repeated freeze thawing (stability test). ARC have also been studied with regard to biocompatibility. The authors' results showed low acute toxicity (> 8000 mg/kg) and adequate blood compatibility. The result of transfusion tests in dogs showed that ARC had sufficient oxygen transporting capabilities.


Peritoneal dialysis solution calcium concentration regulates peritoneal fibroblast proliferation in CAPD.

Peritoneal fibrosis remains one of the major causes of dropout in continuous ambulatory peritoneal dialysis (CAPD), by reducing ultrafiltration capacity. Since studies in vitro have shown that cytoplasmic Ca2+ regulates the proliferation of most cell lines and the release of cytokines from immune cells, eight uremics and four controls at the start of CAPD were evaluated for the in vitro effects of different peritoneal dialysis solution (PDS) Ca2+ concentrations (1, 1.25, 1.75, and 2 mmol/L) on: 1) peritoneal fibroblast (PF) proliferation; 2) peritoneal macrophage (PM) and peritoneal lymphocyte (PL) release of interleukin-1 (IL-1) and interferon-gamma (IFN-gamma)--cytokines that are known to induce PF proliferation; and 3) cytoplasmic Ca2+ concentrations in PF, PM, and PL. Results showed that in both the uremics and controls, increasing the dose of Ca2+ in the medium induced a dose-dependent rise in PF proliferation, and in the release of IL-1 and IFN-gamma from PM and PL. Meanwhile, the cytoplasmic Ca2+ concentration of PF, PM, and PL also increased. With a PDS containing 1 mmol/L of Ca2+ in the uremics, these parameters were below normal; they exceeded the norm with a Ca2+ concentration of 1.75 and 2 mmol/L, and were normal with a Ca2+ concentration of 1.25 mmol/L. These data suggest that in CAPD patients, the use of a low Ca2+ PDS (1 and 1.25 mmol/L) may be useful in reducing the proliferation of PF and the production of IL-1 and IFN-gamma from PM and PL, thereby preventing peritoneal sclerosis.


Factors influencing transperitoneal calcium balance during CAPD.

A dialysate containing a calcium concentration of 1.75 mmol/L has been the standard in CAPD for a long time. This concentration was chosen to achieve a positive calcium balance to suppress hyperparathyroidism. In the measurement of peritoneal calcium mass transfer, conflicting results have been published, with positive and negative calcium balances reported. These differences have been explained by differences in the filtration rate, and a negative correlation between the filtration rate and the peritoneal calcium mass transfer can be found. Whereas nearly all patients in this study had a negative calcium balance using a glucose solution of 3.86%, a wide variation was found for the 1.36% glucose solution. There were several patients who had a positive calcium balance despite a positive filtration rate. The explanation for this finding lay in differences in serum concentrations of calcium, and especially differences in the size of the total exchangeable calcium pool that contains the plasma calcium compartment. A negative correlation between peritoneal calcium balance and the size of the total exchangeable calcium pool could be demonstrated. This finding may explain the differences in the peritoneal calcium flux reported in the literature. As an enlargement of the exchangeable calcium pool correlates with the progression of vascular calcification, therapeutic efforts should be directed toward prevention of an enlargement of this pool.


Low calcium peritoneal dialysis solution. Effects on calcium metabolism and bone disease in CAPD patients.

Calcium carbonate (CaCO3) is an effective phosphate (PO4) binder in uremics, and its use reduces aluminum (AI) intake. By maintaining high serum Ca2+ levels, it decreases serum parathyroid hormone (PTH) levels. Hypercalcemia, however, often limits the dosage. To evaluate the effects of a low Ca2+ peritoneal dialysis solution (PDS; 1.25 mmol/L) on calcium metabolism, the following were studied in continuous ambulatory peritoneal dialysis (CAPD) patients with hypercalcemia (six with high PTH levels, and high turnover bone disease [Group 1], and six with low PTH levels, and low turnover bone disease [Group 2] documented by bone biopsies): 1) serum Ca2+ and PO4 levels; 2) serum PTH levels; 3) serum AI levels; and 4) bone morphology. The follow-up was 12 months. In both groups, within the third month, there was a decrease in serum Ca2+. In Group 2, serum PTH increased, reaching the norm, and in Group 1 it further increased, exceeding the norm. Because in both groups serum Ca2+ was normal, it was possible to give oral CaCO3 (10.5 +/- 2.5 g/day) to control PO4 levels while stopping AI gels. This did not induce any increase in serum Ca2+, whereas serum AI fell significantly. In Group 1, to avoid a further rise of serum PTH, the low Ca2+ PDS was supplemented with calcitriol (mean 3.5 +/- 0.5 microgram/day); this was followed by a reduction in serum PTH with no increase in serum Ca2+ or PO4.(ABSTRACT TRUNCATED AT 250 WORDS)


Experimental Staphylococcus epidermidis implant infection in the mouse. Kinetics of rifampin and vancomycin action.

Staphylococcus epidermidis implant infections remain a therapeutic challenge; they frequently result in failure of conservative management and require removal of the implant. This resistance to antibiotic therapy has been ascribed to the presence of a protective bacterial biofilm at the surface of the implant. An animal model of implant associated infection has been developed in which preformed bacterial biofilm catheter segments are implanted intraperitoneally, resulting in a chronic standardized localized infection. The authors have determined the superior rapid action of rifampin (Cieba-Geigy) compared to vancomycin hydrochloride (Eli Lilly) and determined that the combination is superior to either used alone. No rifampin resistant surviving infection was noted, which indicates the significant contribution of mammalian host defenses. This animal model is an excellent vehicle for the study of Staphylococcus epidermidis implant associated infection and the evaluation of the relative efficacy of antibiotic regimens, singly and in combination.


A non-conventional reniform heart valve bioprosthesis with improved performance.

Conventional bioprosthetic heart valves have been designed with circular mounting rings. This article describes a mitral bioprosthetic valve consisting of three bovine pericardial leaflets with a "reniform" base. Its shape resembles that of the mitral anulus, and therefore, it provides a better anatomic fit. Hydrodynamic comparisons were made between conventional valves (CV) and equivalent sized reniform valves (ERV) that would adapt to the same anulus. Under steady flow of 30 L/min, pressure drops were compared in CVs and ERVs. For CV sizes 27, 29, and 31mm, the ratios of pressure drops compared with ERVs were 2, 1.49, and 1.30, respectively. With the same flow rate, the ratios of effective orifice areas (EOA) for CVs and ERVs in sizes 27, 29, and 31mm were 1.41, 1.21, and 1.14, respectively. Under pulsatile flow (mean flow, 5 L/min, 100 beats/min [bpm]), the pressure drop across CVs was averaged for sizes 27, 29, and 31mm, and found to be 1.51-fold the averaged pressure drops for ERVs. In addition, ERV sizes 27, 29, and 31mm had EOAs averaging 1.24-fold those of CVs. Similarly, for an 80 bpm frequency, the pressure drops across CVs for the three sizes averaged 1.48-fold that of ERVs. The EOAs of ERVs were 1.22-fold those of CVs averaged for the three sizes.


Assessment of the in vitro transport parameters for ethanehydroxy diphosphonate through a polyurethane membrane. A potential refillable reservoir drug delivery device.

Calcification (CALC) is the most frequent cause of failure in bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated porcine aortic valve or bovine pericardium. Site specific controlled administration of ethanehydroxy diphosphonate (EHDP), using numerous carriers, has been successful in inhibiting CALC of BHV tissue in an accelerated rat subdermal model, without adverse effects on serum calcium, bone development, or overall somatic growth. The current study was designed to evaluate refillable reservoir devices fabricated from polyurethane (Biomer Woburn, MA) with regard to their transport properties relative to EHDP. The refillable reservoirs were evaluated for EHDP release in vitro at 22 degrees C (under perfect sink conditions) into both a physiologic receptor phase (N-2 hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer, pH = 7.4) with (1.5 mM) or without Ca2+ present. Transport parameters for EHDP diffusion through the polyurethane membranes used to fabricate the reservoirs were significantly different for the two receptor phases evaluated. The mean diffusion coefficients (D) for EHDP through the polyurethane membrane into each receptor phase were not significantly different. However, an approximately 3.5-fold reduction was observed in the mean value of the partition coefficient (K) for EHDP when EHDP was evaluated for release into a receptor phase that contained 1.5 mM Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)


Initial clinical trial of a closed loop, fully automatic intra-aortic balloon pump.

A new generation, closed loop, fully automatic intraaortic balloon pump (CL-IABP) system continuously optimizes diastolic augmentation by adjusting balloon pump parameters beat by beat without operator intervention. In dogs in sinus rhythm and with experimentally induced arrhythmias, the new CL-IABP system provided safe, effective augmentation. To investigate the system's suitability for clinical use, 10 patients meeting standard indications for IABP were studied. The patients were pumped by the fully automatic IABP system for an average of 20 hr (range, 1-48 hr). At start-up, the system optimized pumping parameters within 7-20 sec. Evaluation of 186 recordings made at hourly intervals showed that inflation began within 20 msec of the dicrotic notch 99% of the time. In 100% of the recordings, deflation straddled the first half of ventricular ejection. Peak pressure across the balloon membrane averaged 55 mmHg and, in no case, exceeded 100 mmHg. Examination of the data showed that as soon as the system was actuated it provided consistently beneficial diastolic augmentation without any further operator intervention. Eight patients improved and two died (one of irreversible cardiogenic shock and one of ischemic cardiomyopathy). No complications were attributable to the investigational aspects of the system. A fully automated IABP is feasible in the clinical setting, and it may have advantages relative to current generation IABP systems.


Pivot design in bileaflet valves.

The design criteria leading to the development of a new bileaflet valve (Sorin Bicarbon) were derived from the analysis of functional requirements, the performance of existing prostheses, and the availability of an advanced carbon coating technology (Carbofilm). The hinge is the critical element affecting fluid dynamics, durability, and thrombus formation in bileaflet valves. A comparative study of three existing models led to a new hinge design that was based on coupling two spheric surfaces with different radii of curvature (leaflet pivot and hinge recess) and obtained by electroerosion into a Carbofilm-coated metallic housing. In this valve, the point of contact moves continuously by rolling, not sliding. This minimizes friction and wear and allows uninterrupted washing of the blood exposed surfaces even during diastole (a finding established in patients using transesophageal echocardiography). Tricuspid implantation without anticoagulation in 33 sheep did not lead to thrombotic events (follow-up, 40-400 days). In the first 36 clinical implants observed for 15 months (mitral position, size 29; two unrelated deaths), the mean diastolic gradient by echo Doppler was 4 +/- 1.25 mmHg; the functional area was 3.2 +/- 0.6 cm2. No leaflet fracture and no thrombotic or embolic complications were observed clinically using a standard anticoagulant regimen.


Clinical responses to ventricular assistance versus transplantation in a series of bridge to transplant patients.

Hemodynamic and peripheral organ responses to ventricular assistance were compared with transplantation in a cohort of patients bridged with the HeartMate 1000 IP left ventricular assist device (LVAD) (Thermo Cardiosystems Inc., Woburn, MA). The study population included 27 patients that were supported an average of 102 days (range, 15-324 days). Two hepatic (total bilirubin and serum glutamic oxaloacetic transaminase [SGOT]) and two renal (creatinine and blood urea nitrogen [BUN]) parameters were measured: 1) before LVAD insertion, 2) 30 and 60 days during ventricular assistance, 3) before transplantation while still on the VAD, and 4) 30 and 60 days after transplantation. Total bilirubin values were significantly greater just before LVAD implant (2.3 mg/dl) than before transplantation (0.7 mg/dl). Although there was no difference after 30 days of either treatment, the total bilirubin values were greater at 60 days after transplantation (1.1 mg/dl) than at an equivalent time on the LVAD (0.6 mg/dl). The SGOT values were also significantly reduced before transplantation. No differences at 30 and 60 days after either procedure were noticed. Creatinine and BUN values were greater before LVAD implant (1.7 and 37 mg/dl) than before transplantation (1.2 and 19 mg/dl). The creatinine values were also greater after transplantation at 30 and 60 days (2.0 and 1.6 mg/dl) than at comparable intervals after LVAD implantation (1.0 and 1.2 mg/dl), presumably as a result of the use of immunosuppressive drugs. End organ function was markedly improved while on the device, enhancing the physiologic status of the patients before transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)


Non-pulsatile circulatory support in 90 cases.

Survival after cardiac arrest is reportably less than 10%; after cardiogenic shock it is less than 50%; and in failure to wean post-cardiotomy (even with centrifugal pumps in several large series) it is only 11-21%. The authors' experience with non-pulsatile circulatory support in 90 consecutive cases from 1986-91 has shown improved survival. The emergent cardiopulmonary bypass system (CPS) was used in 67 of the 90 patients, with 65 patients resuscitated, 34 (51%) weaned, and 19 (28%) transferred to other cardiovascular support therapies. Of the patients weaned or transferred, 34 (51%) survived > 24 hr, and 21 (31%) survived > 30 days. In the current series, 108 major cardiovascular procedures were done during or after CPS implementation. An in-house trained nursing team working with surgeons and perfusionists contributed to early implementation of the CPS and the subsequent improved survival. The BioMedicus centrifugal pump (VAD) was used predominantly for post-cardiotomy failure to wean in 16 patients and as a bridge to transplant in 7 patients. Fourteen patients (61%) were weaned or transplanted. Of these 14 patients, 11 (48%) survived > 30 days. Non-pulsatile circulatory support devices are relatively inexpensive and available to most hospitals. With careful patient selection and early implementation, one can expect survival of 37% of patients who would otherwise not survive.


An abdominally placed, implantable left ventricular assist system for long-term use.

An implantable left ventricular assist system was developed for long-term use. The system includes an implantable blood pump, a portable control drive unit (CDU), and a monitoring system. The blood pump was designed to be positioned in the left abdominal wall and was made of segmented polyether polyurethane. A percutaneous drive line connected it to the external CDU. The CDU included a continuous pump performance monitoring system that measured electrical impedance between the two metal connectors of a blood pump. In animal experiments using six adult goats, the pump was installed between the left ventricular apex and the descending aorta, and it was placed in the abdominal wall. No antithrombogenic agents were administered during the course of the experiment. This LVAS was easy to use and provided stable hemodynamic conditions for > 8 weeks. Pump output (Op), estimated by impedance, was linearly related to Op measured with an electromagnetic flowmeter. Pump performance was effectively estimated, and the fill-empty drive was well controlled by impedance. There were no significant abnormal hematologic or blood chemistry values, no signs of infection around the pump pocket (except in one animal), and no obvious thromboembolic symptoms. Maximum flow was 6.7 L/min with use of a prototype portable CDU (dimensions, 500 x 168 x 435 mm; weight, 16 kg). In conclusion, this LVAS is promising for long-term clinical use.


Thrombin activity resides on LVAD Dacron inflow and outflow grafts.

Patients on left ventricular assist devices (LVADs) are at increased risk for thromboembolism, and they experience elevations in platelet release and thrombin activity indices during device implantation. The Dacron grafts that lead from the ventricle to the LVAD and back to the aorta may harbor thrombin activity and protect this thrombin from anticoagulant action. To investigate this possibility, specimens isolated from LVAD grafts at the time of device explantation or implantation were incubated with citrated platelet poor plasma (cPPP), cPPP and 2 U/ml of heparin, cPPP and 2 U/ml of recombinant hirudin (r-hirudin), or cPPP and 50 U/ml of heparin. Thrombin activity was measured by the increase in incubated cPPP fibrinopeptide A (FPA) concentrations over cPPP FPA levels, without material contact. A chromogenic substrate for thrombin verified the effects seen. Thrombin activity was found at comparable levels on both the inflow and outflow LVAD grafts at explantation. This activity was not inhibited by low concentrations of heparin, but 50 U/ml of heparin and 2 U/ml of r-hirudin reduced the activity. At graft implantation (after preclotting), thrombin activity was higher than at explantation, but susceptibility to inhibition by heparin was also significantly greater. These results confirm that the LVAD Dacron grafts harbor surface thrombin activity resistant to anticoagulation that may be a primary source for LVAD thrombogenicity.


Heparin immobilization by surface amplification.

A method to increase the amount and improve the bioactivity of heparin (HEP) immobilized on a polymer surface was developed. The surface of polyurethane-urea (PU) coated glass beads was first modified with diisocyanates, followed by surface grafting of polyfunctional polymers (PFP), including: poly(vinyl alcohol), poly(ethyleneimine), and poly(allylamine). The functional groups of the surface grafted PFP (-OH, -NH, or -NH2) were modified with diisocyanates (TDI) to amplify the surface concentration of isocyanate groups, alpha, omega-diamino-terminated polyethylene oxide (PEO; molecular weight, 4,000 daltons) was then coupled to the surface grafted PFP, and the free amino groups were derivatized with TDI. Finally, HEP was coupled to the amplified surface through free -NCO groups of PU-PFP-PEO. The surfaces were quantified during each step of the procedures for -NCO groups and HEP. All grafted surfaces showed a four to eightfold increase in -NCO content and a twofold increase in immobilized HEP content compared with HEP immobilized directly onto the PU surface. The HEP bioactivity tests (including activated partial thromboplastin time, thrombin times, and factor Xa) demonstrated an increased bioactivity of HEP when immobilized through PFP-PEO compared with PFP and PU alone.


Albumin immobilized polyurethane and its blood compatibility.

Surface pretreatment with albumin on a blood contacting material inhibits platelet adhesion, activation, and subsequent thrombus formation. Although adsorbed albumin improves blood compatibility, rapid desorption occurs when this surface is exposed to circulating blood. In this study, human serum albumin was immobilized on a polyurethane (PU) surface to investigate its blood compatibility and extended effects on a blood-material interface. The PU surface was treated with hexamethylene diisocyanate (HMDI), and the PU-HMDI was further grafted with albumin to produce an albumin immobilized PU surface (PU-albumin). The PU-albumin surface was characterized by attenuated total reflection infrared electron spectroscopy for chemical analysis, scanning electron microscopy, and dynamic contact angle. Blood compatibility was evaluated by in vitro protein adsorption, platelet adhesion, and occlusion time in an ex vivo rabbit arterio-arterial shunt. Immobilization of albumin was confirmed by the disappearance of the -NCO peak observed at 2,250 cm-1 on the PU-HMDI surface by infrared spectroscopy and the existence of sulfur atomic percent by electron spectroscopy for chemical analysis. The concentration of PU-albumin was approximately 5.8 micrograms/cm2. The PU-albumin also showed a slight increase in hydrophilicity on the Wilhelmy plate method, and there was less fibrinogen adsorption than a PU control. In addition, PU-albumin had less platelet adhesion, platelet activation, and thrombogenicity. The ex vivo occlusion time of untreated PU was 50 min, that of PU-albumin was extended to 150 min, indicating that a PU-albumin surface has better blood compatibility than PU alone.


Binding kinetics of thrombin and antithrombin III with immobilized heparin using a spacer.

The immobilization of heparin onto polymeric surfaces using a hydrophilic spacer was effective in curtailing surface induced thrombus formation. In this study, the binding kinetics of immobilized heparin with antithrombin III (ATIII) and thrombin were investigated. Low molecular weight heparin (molecular weight, 6,000 daltons) was fractionated on an ATIII affinity column, and it was immobilized onto a styrene/p-amino styrene random co-polymer surface via hydrophilic spacer groups. This polymer substrate was coated onto glass beads (diameter range, 0.088-0.105 mm). PEO (molecular weight 3,400), modified by tolylene diisocyanate, was covalently coupled as a spacer group, followed by heparin. The bioactivity of immobilized heparin was approximately 16.2%, relative to free heparin, and nearly 1:1 binding between heparin and PEO was calculated. The binding constants of immobilized heparin and ATIII, and immobilized heparin and thrombin, were 0.958 x 10(7) M-1 and 1.76 x 10(8) M-1, respectively. The immobilized heparin bound with both ATIII and thrombin, and the binding mechanism was similar to that of free heparin.


Acute renal failure in critical illness. Conventional dialysis versus acute continuous hemodiafiltration.

The dialytic therapy of choice in critically ill patients with acute renal failure (ARF) is a matter of controversy. The clinical outcome of such patients managed with either conventional dialytic therapy (CDT) or acute continuous hemodiafiltration (ACHD) was compared through retrospective review of medical records from the intensive care unit of a tertiary institution. Records from 167 critically ill patients with ARF consecutively treated in the same intensive care unit were reviewed. Eighty-four patients with ARF treated by CDT were compared to 83 treated with ACHD. The etiology of ARF and the degree of illness severity were similar in both groups (failing organs: CDT 3.9 vs. ACHD 4.1; mean APACHE II score: CDT 25.8 vs. ACHD 28.1). Overall survival was 29.8% for the CDT patients and 41% for the ACHD group (NS). In those with two to four failing organs, survival was greater in the ACHD group (53.8% vs. 31.1%; p < 0.025). This was also true for patients with an intermediate APACHE II score (24-29) who demonstrated better survival when treated by ACHD (46.4% vs. 12.5%; p < 0.025). Acute continuous hemodiafiltration was associated with better control of azotemia and hyperphosphatemia and increased nutritional intake. This retrospective study suggests that ACHD may offer clinically significant advantages over CDT, particularly in patients with an intermediate degree of critical illness severity.


Urea kinetics during continuous hemofiltration.

Urea kinetic analysis allows for the calculation of the urea distribution volume and urea generation rate. This method was employed in patients with acute renal failure managed by continuous venovenous hemofiltration (CVVH). Based on serial serum urea nitrogen concentration measurements, each patient's treatment course consisted of both steady state and non-steady state periods. Thirteen data sets were obtained from 11 critically ill patients treated with CVVH. The duration of therapy was 9.5 +/- 7.5 days (mean +/- SD). Serum urea nitrogen concentration fell from 114 +/- 32 mg/dl to a steady state value of 79 +/- 17 mg/dl (p < 0.0005). The urea distribution volume was 0.55 +/- 0.11 L/kg (range 0.29-0.73), and the urea generation rate 11.7 +/- 3.1 mg urea N/min (range 7.1-17.3). The steady state serum urea nitrogen concentration had a linear relationship to the rate of urea generation (r = 0.92). Urea kinetic analysis permitted the simultaneous determination of the urea generation rate and distribution volume, on an individualized basis, in patients with acute renal failure treated with CVVH.


Peritoneal membrane plasmapheresis.

A novel process has been devised that uses the peritoneal membrane to remove plasma proteins from the body at a rate comparable to conventional extracorporeal plasma-pheresis. A vasodilator (4 mg histamine phosphate) is added to 1 liter of hypertonic solution (485 mOsmol/L), and infused intraperitoneally with a residence time of 4 hr. Plasma containing proteins is convected across the peritoneum through open pores into the cavity and removed. The next alternating infusion is with a hypotonic solution (214 mOsml/L) containing a vasoconstrictor (1.0 mg norepinephrine). This infusion restores the fluid removed from the subject in the previous exchange, and prevents the rapid fall-off in protein removal rates obtained with repeated infusions with vasodilators only. Peritoneal membrane plasmapheresis was successfully tested on canines, with protein removal rates of between 30% and 50% of total serum protein per day for 13 days over a 22 day period. Peritoneal membrane plasmapheresis represents a potentially inexpensive, continuous/nightly home treatment for protein mediated diseases treatable by extracorporeal plasmapheresis.


Intermittent venovenous hemofiltration as a chronic treatment for refractory and intractable heart failure.

Chronic heart failure (HF) is considered to be refractory when persisting despite an intensive drug regimen, or intractable when requiring "artificial" supports. Among them, hemofiltration (HE) has been used frequently, but only on an "acute" basis, to induce fast and safe water removal. Since 1985 the authors have treated refractory and intractable HF first by means of acute CAVH (continuous arteriovenous HE: 11 patients) and then (1988-1992) with IVVH (intermittent venovenous HE), initially done on an "acute" basis (13 patients) and then an a chronic basis (CIVVH): 8 subjects (6M, 2F; mean age, 60.8 years), 3 with RCHF and 5 with ICHF. This report deals with our experience in CIVVH. All patients were in severe failure. During a follow-up period of 63 months (range, 1-17/patient), 82 IVVH treatments (10.2/patient) were carried out, using this schedule: permanent Tesio catheter in superior vena cava, 0.6 m2 filter, double blood pump (blood flow = 80-250 ml/min); transmembrane pressure = 50-150 mmHg; mean ultrafiltration = 19 ml/min; replacement fluid = 8.6 ml/min; and session time = 340 +/- 88 min, according to individual dry weight (bioimpedance system). Six patients died (1-13 months after IVVH began); four of six had ICHF and two of six had RCHF; five of eight patients showed a significant amelioration of functional state, changing from fourth to third, to second and first degree failure, but this was after heart transplantation. In all cases a marked reduction in the drug regimen and in hospitalization was the rule.


Differential regional function of the right ventricle during the use of a left ventricular assist device.

The use of a left ventricular assist device (LVAD) as a bridge to transplant is associated with a 52% incidence of RV failure requiring additional inotropic or mechanical support (RVAD). This study evaluated the differential performance of the RV free wall and septum to identify the need for additional RV support. Cross-sectional views of the RV were obtained immediately before, and 1 hr after, Novacor LVAS implantation in 12 consecutive patients using transesophageal echocardiography. Each image was divided into a free wall portion (FW) and a septal portion (SP) by grids drawn from the center of gravity of the end-diastolic endocardial outline to the junction between the FW and the SP. Percentage change between preimplant and postimplant for RV ejection fraction (RVEF), fractional area change for the FW (FAC-FW) and the SP (FAC-SP), and fractional shortening of the FW to SP distance (F-S) is reported for patients based upon the need for RV support: minimal (Group 1), maximal (Group 2). After LVAS implantation, patients showed a reduction in SP fractional area change. However, this reduction was most pronounced in Group 2. The degree of SP impairment may explain the mechanism of RV failure in patients on an LVAD.


A miniature intraventricular axial flow blood pump that is introduced through the left ventricular apex.

A new intraventricular axial flow blood pump has been designed and developed as an implantable left ventricular assist device (LVAD). The pump consists of a tube housing (10 cm in length and 14 mm in diameter), a three-vane impeller combined with a guide vane, and a DC motor. This pump is introduced into the LV cavity through the LV apex, and the outlet cannula is passed antegrade across the aortic valve. Blood is withdrawn from the LV through the inlet ports at the pump base, and discharged into the ascending aorta. A pump flow of > 8 L/min was obtained against 90 mmHg differential pressure in the mock circulatory system. In an acute dog model, this pump could produce a sufficient output of 200 ml/kg/min. In addition, the pump flow profile demonstrated a pulsatile pattern, although the rotation speed was fixed. This is mainly due to the changes in flow rate during a cardiac cycle--that is, during systole, the flow rate increases to the maximum, while the differential pressure between the LV and the aorta decreases to the minimum. Thus, this simple and compact axial flow blood pump can be a potential LVAD, with prompt accessibility and need for less invasive surgical procedures.


Prolongation of cardiac xenograft survival by double filtration plasmapheresis and ex vivo immunoadsorption.

A double filtration plasmapheresis (DFPP) technique and ex vivo immunoadsorption were applied to remove natural antibodies and avoid hyperacute rejection in discordant xenotransplantation. A swine heart was heterotopically transplanted into a dog's neck after DFPP and ex vivo immunoadsorption using a swine spleen or liver. Mean graft survival time was prolonged to 240 +/- 141 min in the group treated by combined DFPP and splenic adsorption, and 225 +/- 62 min in the group treated by combined DFPP and hepatic adsorption, whereas it was 9 +/- 5 min in the group without any treatment (p < 0.01). Mean removal rates of IgG and IgM were 85.5% and 93.3%, respectively. Anti-swine lymphocytotoxic antibodies and hemagglutination antibodies were also effectively removed. Deposits of canine IgM and C3 on the vascular endothelium of the graft were observed on immunofluorescence, which suggested that natural antibodies in the IgM fraction played an important role in xenohyperacute rejection.


Autopsy findings in patients on postcardiotomy centrifugal ventricular assist.

Reported experience with ventricular assist devices (VAD) routinely includes the rate of thromboembolic events, which is commonly calculated from clinically evident findings. Fifty-four patients have had postcardiotomy circulatory support with the Sarns centrifugal device at our institution. We have reviewed 43 patients who failed to survive VAD support to compare the thromboembolism rate diagnosed clinically to that determined at autopsy. In the 35 patients who had no autopsy, there was one clinically apparent thromboembolic event (2.3%). In eight similar patients who had autopsy, there was no clinically apparent thromboembolism. Five of these eight patients (63%) had acute thromboembolic infarcts determined at autopsy. Three had evidence of pulmonary thromboembolism, two cerebrovascular infarction, two liver infarcts, two splenic infarcts, two kidney infarcts, and one each gastric, pancreatic, prostate, adrenal, cervical, and ileal infarcts. All had left and/or right ventricular infarctions. It is concluded that patients dying following VAD have commonly suffered perioperative myocardial infarction. When evaluating complications associated with VAD, one should consider that the true incidence of thromboembolic events is underestimated by clinical findings.


Thermal, operational, and storage stability of immobilized carbonic anhydrase in membrane lungs.

The significant improvement in CO2 removal rates from blood through membrane lungs with EMCO and ECCO2R is achievable by means of the immobilization of carbonic anhydrase (CA) onto the membrane surface. The practical application of this technology requires that the enzyme be maintained for long periods without loss of activity. Thus, studies were performed to evaluate the thermal, operational, and storage stability of CA in a cellulose nitrate-encapsulated, silicone rubber membrane-immobilized form. Cellulose nitrate microcapsules containing 1000 micrograms/ml CA were prepared using a modified version of the method of Chang, and immobilized onto a 0.06 m2 section of commercial silicone rubber membrane material. The extent of enzyme activity in free solution and in the encapsulated form was determined after long-term storage at 4 degrees C, 37 degrees C, and 50 degrees C. Likewise, in an in vitro test circuit, CO2 removal efficiency in both CA treated and untreated membrane lungs was measured for extended time periods of 10 hr over a 10 day period. The thermal stability tests showed a significantly greater degree of retained enzyme activity in the encapsulated form, over the free enzyme in solution, at all temperatures. This was especially evident at higher temperatures and when the enzyme was stored for extended periods. In the operational stability tests, the CO2 removal efficiency of the treated membrane was not degraded, and stayed significantly higher than the untreated membrane for extended time periods. This further illustrates the potential for the use of the immobilized enzyme, carbonic anhydrase, for improved CO2 removal efficiency.


Dialysate and blood flow dependence of diffusive solute clearance during CVVHD.

To define the flow dependence of diffusive solute clearance (Kd) during continuous venovenous hemodiafiltration (CVVHD), urea, creatinine, and phosphate clearance were measured during CVVHD, while ultrafiltration was minimized. Studies were performed using AN69, polyacrylonitrile (PAN), and polyamide (PA) hollow fiber hemofilters. To assess the dialysate flow dependence of Kd, clearances were measured at constant blood flow (QB), while dialysate inflow (QDi) was increased incrementally from 8.3 to 33.3 ml/min. Kd increased linearly for all three solutes using all membranes. To assess its blood flow dependence, Kd was measured at blood flows of 50, 75, 100, and 150 ml/min, while QDi was held constant at 33.3 ml/min. The PA membrane showed no flow dependence; for the other membranes, Kd was flow independent for QB > 100 ml/min. At all values of QB and QDi, clearances for the AN69 and PAN membranes were two to three times that of the PA membrane (p < 0.01). Lactate uptake increased with increasing QDi for all three membranes, but did not result in blood lactate accumulation. It is concluded that: 1) small molecule clearance is dialysate flow limited during CVVHD; 2) increasing QB beyond 100 ml/min is unnecessary for maintaining solute clearance; and 3) the PA membrane is unsuitable for CVVHD because of its low diffusive solute clearance.


Solute clearance in continuous venovenous hemodialysis. A comparison of cuprophane, polyacrylonitrile, and polysulfone membranes.

Critically ill patients with ARF and MOSF were treated with continuous venovenous hemodialysis (CVVHD). The BSM 22 delivery system (CGH Medical, Denver, CO) and four different dialyzer membranes were used. Vascular access was achieved with a dual lumen catheter placed percutaneously into a large vein. Heparin was used for anticoagulation, and commercially available peritoneal dialysis fluid was used as dialysate. At a fixed blood flow rate of 100 ml/min, the dialysate inflow and outflow rates were regulated to control azotemia and fluid balance. Blood side and dialysate side clearances for urea nitrogen, creatinine, bicarbonate, and lactate were measured. All dialyzer membranes studied provided high urea nitrogen clearance approximating dialysate outflow rate and resulting in excellent control of azotemia. Some of the dialyzer membranes also had high creatinine and bicarbonate clearances. Bicarbonate loss was balanced by lactate uptake with all dialyzers. It is concluded that CVVHD is an efficient and safe therapy for acute renal failure, capable of maintaining nitrogen balance in patients with protein catabolic rates up to 2 g/kg/day. Urea nitrogen clearance is dependent upon dialysate outflow rate rather than the dialyzer membrane type or dialyzer flow geometry, and may prove to be the modality of choice for therapy of acute renal failure in unstable patients with MOSF.


Studies on the electrical stimulation-induced contractile responses of hamster and mouse gallbladders.

Isolated gallbladders of both hamsters and mice showed a contractile response consisting of initial and secondary contractile responses to electrical stimulation with rectangular pulses (50 volt, 40 Hz) of 6 msec duration for a period of 10 seconds. The duration time of the contractile response was very long. This was because the duration time of the process of the initial contractile response was as short as 5 to 40 seconds, but that of the secondary contractile response was as long as 8 to 15 minutes. Both initial and secondary contractile responses of the gallbladder in both hamsters and mice were little affected by atropine (1 x 10(-6)M, guanethidine (1 x 10(-6) M) and tetrodotoxin (1 x 10(-7) M). In both animals, further, the initial contractile response of the gallbladder was little affected by indomethacin (1 x 10(-5) M) and 5, 8, 11, 14-eicosatetraynoic acid (ETYA) (5 x 10(-6) g/ml), while the amplitude of the secondary contractile response of the gallbladder was significantly reduced by such drugs. From these results, we obtain the following conclusions: 1) In both animals, the intramural nerves of the gallbladder may have no influence on the both initial and secondary contractile responses of the gallbladder. 2) The initial contractile response is probably mediated by a direct effect of the electrical stimulation to the muscle in the wall of the gallbladder, while the secondary contractile response is probably attributable to prostaglandins released from the wall of the gallbladder by a direct effect of the electrical stimulation to the wall.


Non-thrombogenic hemofiltration system for acute renal failure treatment.

Continuous arteriovenous hemofiltration (CAVH) has become an accepted therapy for patients with acute renal failure. A major technical concern with CAVH is clotting of the hemofilter, resulting from blood-material interactions. This study compares the thromboresistance and performance characteristics of a Duraflo II heparin treated CAVH circuit with those of an untreated control circuit. The circuit consisted of a polysulfone hemofilter, tubing sets, and catheters. The heparin treatment did not change the mass transfer properties of the hemofilter. The thromboresistance of the heparin treated circuit was compared directly with that of an untreated circuit in a heparinless sheep model using bilateral circuits. The heparin treatment significantly enhanced the blood compatibility of the circuit, as indicated by the reduction in thrombus formation, prolonged work life, and superior performance in heparinless sheep. There was minimal heparin leaching from the hemo-filter. A heparin treated circuit may improve the safety and effectiveness of the CAVH procedure, and offers potential for a systemic heparin protocol to be modified for patients with bleeding disorders.


An electrically powered total artificial heart. Over 1 year survival in the calf.

An electric motor driven orthotopic artificial heart was implanted in a 110 kg female Holstein calf as part of a series of 12 such implants intended to demonstrate the in vivo durability and compatibility of the device. The device uses pusher plates set into motion by a reversing brushless DC motor and roller screw to alternately eject two cylindrical sac type blood pumps. The pumps use Bjork-Shiley Delrindisc convexo-concave or monostrut valves. The left pump provides an 88-90 ml dynamic stroke volume. Woven Dacron grafts and polyurethane coated Dacron/Lycra cuffs are used to attach the device to the major arteries and atria, respectively. A polyurethane conduit and anchoring skin button bring motor wires percutaneously to an extracorporeal controller. The controller provides balanced cardiac output sensitive to atrial or aortic pressures, without operator intervention. The system is hermetically sealed and uses a simple compliance sac to maintain thoracic pressure between the pumps. The calf recovered uneventfully from surgery and thrived thereafter. She was killed on the 388th post-operative day because of worsening cardiac insufficiency. The previous three operative survivors in this series lived 131, 134, and 204 days. These results indicate the device's good potential for durability and body compatibility.