Circulating immune complexes in rheumatoid arthritis. Selective removal by cryogelation with membrane filtration.

We have developed a system of extracorporeal circulation that removes proteins of the molecular weight of the circulating immune complexes of rheumatoid arthritis by cryogelation with hollow-fiber membrane filtration. A 52-year-old woman with a 36-year history of severe, unremitting, high-titer, seropositive rheumatoid arthritis who had failed to respond to anti-inflammatory, antirheumatic, and cytotoxic drugs was chosen for a trial of this system. A rapid and sustained decrease in circulating immune complexes as measured by C1q binding occurred, accompanied by a much slower improvement in clinical factors of disease activity. Rheumatoid factor changed very little and loss of other serum proteins by the procedure was relatively modest. This new procedure was successful in removing circulating immune complexes in a patient with rheumatoid arthritis, and in inducing a remission in one who has not had such in 36 years, while sparing volume and other plasma proteins.

Biomodulation effects of extracorporeal circulation in apheresis.

The association of biochemical and cellular abnormalities in various disease states provides the rationale for apheresis technologies. Plasmapheresis by plasma exchange has severe technical and clinical limitations due to the nonselective removal of plasma factors. Plasmapheresis methods for the more selective removal of plasma components include membrane filtration, sorption, and physico-chemical methods such as precipitation. These methods can also eliminate the need for plasma product replacement and be more specific to the clinical needs. While plasmapheresis technologies are designed primarily for solute removal, the methodology itself will have a biomodulating influence and will impact on the course of the disease state. Extracorporeal biomodulation is defined as the act of effecting changes either procedurally induced or procedurally associated in the cellular or biochemical milieu of the body. Factors to be considered in an extracorporeal procedure such as plasmapheresis include the duration of an individual treatment, the degree of solute removal selectivity, the prescribed frequency for the treatment, the type of equipment employed, the choice of anticoagulant, and the materials for blood and plasma contact. Thus, the modulatory effects of the methodology occur not only in the humoral system but also among the cells. The effects of the modulation will extend beyond the procedure time. The general direction in material research for extracorporeal circulation is to minimize the biological response. However, the modulating effects of the procedure, independent of the removal effects, suggest that the proper choice of materials in the extracorporeal circuit can benefit the patient. With the various techniques of solute removal and material availability, the clinician may chose the biomodulating system for the treatment of a given disease state.

Therapeutic trial of cryofiltration in patients with rheumatoid arthritis.

Cryofiltration, a new technique for on-line plasma separation and its treatment by cold filtration, enables the selective removal of immune complexes and eliminates the need for replacement proteins. Fifteen patients with rheumatoid arthritis were treated for nine to 10 consecutive sessions over a three- to five-week period. Circulating immune complexes decreased by an average of 78 percent and rheumatoid factor by 32 percent. This was accompanied by significant clinical improvement in morning stiffness, articular index, 50-foot walking time, grip strength, and target joint circumference. Cryofiltration might thus be beneficial for a subgroup of rheumatoid arthritis patients in whom conventional therapy has failed.

Technical and economic feasibility of reusing disposable perfusion cannulas.

OBJECTIVE(S): The reuse of disposable devices is a potential source of significant cost savings to hospitals. Venous and arterial perfusion cannulas under new and reused conditions were selected to identify the clinical, safety, technical, logistic, and economic issues that must be addressed to realize these savings. METHODS: Single- and dual-stage venous and arterial cannulas from two manufacturers were tested when new, after initial clinical use, and after a single clinical use plus up to nine simulated reuses. Reuse was simulated by end-to-end bending, coupling and uncoupling of the connectors, and by two 1-hour soaks in plasma at 4 degrees and 40 degrees C, respectively. Cannulas were decontaminated and then processed by a peracetic acid-based liquid chemical sterilization system after each use/reuse. Sterilization was validated by eliminating Bacillus subtilis spores from the cannulas on each of five consecutive cycles. Cannulas were tested for physical changes, functional integrity, biocompatibility, and in vivo performance in sheep. A cost analysis was also performed. RESULTS: Sterilization was successfully achieved. Mechanical changes were less than 20% on all variables studied and were undetectable by experienced cardiac surgeons in selective evaluation. No clinically important differences were found between new and reused cannulas, even after nine simulated reuses. Reusing cannulas four times would reduce the cost per procedure from $53 to $19 (64%). CONCLUSIONS: Preliminary data suggest that the perfusion cannulas tested can be safely and efficaciously used five times. Limited reuse of these disposable cannulas is technically feasible and cost-effective. Cannula reuse would result in a small incremental savings; however, with more expensive devices and higher-volume sterilization procedures, the savings could be considerably greater. This program provides a model for evaluation of other single-use medical devices for reuse.

Prion disease and medical devices.

Prions are novel proteinaceous-infectious agents that have been implicated in transmissible spongiform encephalopathies. It is now generally accepted that noninfectious prion proteins are normally produced by the host and may undergo a conformational change to an abnormal, pathologic form, which appears to be responsible for disease symptoms. Many methods of decontamination and sterilization are claimed to be ineffective against prion proteins. Incidences of iatrogenic transmission of prions due to medical devices have been reported, and the recommended clinical practices when handling suspected cases are reviewed. Recent results with a peracetic acid based sterilant indicate that it may be a safe and effective means of prion inactivation on medical devices.

Are selective macromolecule removal plasmapheresis systems useful for autoimmune diseases or hyperlipidemia?

Although technical limitations exist with existing selective removal systems, very few products are available and no major clinical trials have demonstrated the superiority or equivalence of selective removal systems over plasma exchange. It is generally recognized that selective removal systems are preferable, and that selective macromolecule removal plasmapheresis systems are useful for autoimmune diseases or hyperlipidemia. In the treatment of a disease with a selective removal device, the disease pathogen should be identified and the efficacy of removal demonstrated. In general, for plasmapheresis applications, there is a need to better understand the pathophysiology of the disease states and to identify the pathogenic molecules. With such information, development of the optimal selective removal method will be possible. There is the need for clinical studies to compare selective removal and plasma exchange for specific disease states. Incentives for the development of improved selective removal technologies where cost effectiveness could be demonstrated should be encouraged.

In vitro evaluation of a relationship between human serum- or plasma-material interaction and polymer bulk hydroxyl and surface oxygen content.

To evaluate serum- or plasma-material interactions and a relationship between such interactions and membrane properties such as bulk hydroxyl percentage and surface oxygen percent, medical polymeric membranes with extremely different hydroxyl percentage and surface oxygen percentage were evaluated with normal human serums or plasmas. Six types of mini-membrane modules (hydroxyl & surface oxygen %) were studied including cellulose triacetate (CA; 0 & 34.7%), Cuprophan (CP; 31.5 and 37.4%), ethylene vinyl alcohol (EVAL; 30.4 and 25.3%), polyacrylonitrile (PAN; 1.5 and 10.2%), polysulfone (PS-F; 0 and 14.2%), and a polymer alloy of polysulfone (PS-K; 0 and 16.2%). Post-perfusion values of biochemical solutes and complement components for PAN and both PS membranes were smaller than those for sham, CA, CP, and EVAL membrane module perfusions. C3a and C4a concentrations showed no significant differences among all membranes except PS-K. Mononuclear cell transformation functions to all mitogens for serums in contact with CA and CP membranes were suppressed versus sham and PAN and both PS membranes. Fibrinogen concentration changes for plasma in contact with EVAL, PAN, and PS-F membranes were significantly smaller than sham, and a significant prolongation of APTT was found for only EVAL versus sham, CA, and CP. Higher surface oxygen percentages (CA, CP > EVAL > PAN, both PS) but not hydroxyl content were associated with lower protein adsorption and higher suppressive transformation function results. These results suggest that surface oxygen percentage may be an important indicator of biocompatibility.

Reprocessing of reusable medical devices.

Advances in medical science and, in particular, minimally invasive surgical and diagnostic procedures have stimulated the development of new and improved medical devices. This has been made possible because of developments in engineering and material sciences. The design of devices for reusability is particularly important in an effort to provide cost effective healthcare. Concerns and issues include the ability to safely and effectively reprocess the devices, infection prevention and control, safety of the patient and healthcare worker, environmental concerns, and effective use of resources. From an infection prevention point of view, present requirements are based upon the intended use of the devices. Critical devices require sterilization. Semi-critical devices require, as a minimum, high level disinfection. Sterilization is, however, preferred whenever possible. Before sterilization or disinfection, devices should be cleaned adequately. Device designs should be readily amenable to cleaning and sterilization. In the past, design requirements focused primarily on the clinical user and device functionality, with reuse considerations left to the user. In the current market, the customer is redefined and, for reusable medical devices, includes all those associated with the device through the reprocessing procedure. In addition, regulations require that manufacturers give detailed instructions for reprocessing medical devices. The device users have the obligation to follow reprocessing instructions. Many choices exist today in device designs, including disposable or reusable devices. The user needs to balance cost versus convenience and reprocessing requirements for reusables. Current trends are to reuse more devices, including many of which were meant to be disposable. Cost effective designs can best be achieved when the user and manufacturer work together on the design.(ABSTRACT TRUNCATED AT 250 WORDS)

Removal of trypsin complexed alpha-2 macroglobulin by plasma fractionation.

The aim of this study is to assess in vitro the efficacy of a plasma fractionator to remove trypsin complexed alpha 2MG (alpha-2 macroglobulin) from human plasma in a manner analogous to the reticuloendothelial system (RES). Eval filter type "4A" (Kuraray Co., Osaka, Japan) was chosen as a plasma fractionator. Two and one half liters of bovine trypsin spiked human plasma was perfused in vitro through the fractionator in a single pass mode (n = 5). The concentrations of complexed alpha 2MG, total alpha 2MG, albumin, and IgM were measured before and after fractionation, and the concentration of free alpha 2MG and the sieving coefficients of each solute were calculated. The concentration of the trypsin complexed alpha 2MG measured by ELISA was significantly decreased by fractionation with Eval "4A" from 103.7 +/- 16.7 to 13.8 +/- 8.2 mg/L (reduction of 86.7%). Mean sieving coefficients of each solute were 0.133 +/- 0.079 in complexed alpha 2MG, 0.203 +/- 0.065 in free alpha 2MG, 0.203 +/- 0.065 in total alpha 2MG, 0.770 +/- 0.130 in albumin, and 0.070 +/- 0.010 in IgM. Although in vivo study will be required in patients with acute pancreatitis, in vitro study shows the feasibility of membrane plasma fractionation in eliminating trypsin complexed alpha 2MG.

A mechanistic model of plasma filtration.

A model describing the sieving and transmembrane pressure behavior of plasma filtration is developed and numerically simulated. The model assumes a mechanistic criteria for particle passage through a membrane with cylindrical pores. The initial pore diameter distribution and porosity are assumed to be known. Model inputs include the particle diameter distribution, concentration and total flow rate of the permeate plasma solution. Outputs of the model include transmembrane pressure, the time-averaged sieving coefficients, and size distributions of the deposited particles and accumulated filtrate particles. Optimal filtration is characterized by high, stable sieving coefficients for desired particles, high retention of larger particles and relatively small increases in transmembrane pressure. These characteristics are realized for membranes with mean pore diameters equal to or slightly larger than mean permeate particle diameters. Simulations demonstrate that the incorporation of membrane properties into models of plasma filtration is both significant and readily possible.

Myasthenia gravis therapy: immunoadsorbent may eliminate need for plasma products.

This in vitro study assessed the effectiveness of a new immunoadsorbent (Asahi IM-TR 350) in removing anti-acetylcholine receptor antibody from plasma with minimal loss of albumin. Plasma procured from a myasthenia gravis patient undergoing routine plasma exchange was perfused through the immunoadsorbent and recirculated in vitro to simulate a clinical treatment. To assess the temperature dependency of sorption, perfusion was performed at various temperatures. Plasma solute concentrations were taken before and after perfusion to calculate solute rejection coefficients. The immunoadsorbent has a high sorption capacity for anti-acetylcholine receptor antibody, while allowing a minimum loss of albumin. For patients with myasthenia gravis, this immunoadsorbent can provide an alternative to plasma exchange that does not require the use of plasma products.

Blood detoxification by membrane plasma filtration.

The recognition of macromolecule abnormalities in various metabolic or immunologic related disease states has led to the use of plasma exchange for therapeutics. Limitations of plasma exchange, however, exist. Membrane plasma filtration provides a practical alternative. Solute removal can be made selective by the choice of operating conditions as temperature and the selection of the membrane/module design. The optimal temperature range is a function of the plasma type, solute concentrations and membrane system. Operation at below physiologic temperature (cryofiltration) is particularly suited for the removal of cold aggregative solutes, while operation at near or above physiologic temperature is more suited for the separation of solutes having large size differences at normal physiologic temperature. Membrane filtration is simple and safe to perform, is more selective than plasma exchange, does not require plasma product infusion and is more versatile than selective sorption in its applications.

Conjugated human hemoglobin as a physiological oxygen carrier--pyridoxalated hemoglobin polyoxyethylene conjugate (PHP).

Problems associated with specific physiological properties of Hb-based blood substitutes, such as low P50, short plasma half-life and nephrotoxicity are still major issues to be addressed. Extensive investigations aimed at overcoming these problems have resulted in the preparation of pyridoxalated-hemoglobin-polyoxyethylene conjugate (PHP). PHP was developed from human hemoglobin by two major chemical modifications; pyridoxylation for the purpose of lowering the oxygen affinity (P50 of 19.5 +/- 1.2 mmHg), and coupling with polyoxyethylene (POE) to increase its molecular weight (to approximately 90 kdaltons). The circulating half-life of PHP is about 40 hours in dogs. Toxicological and physiological studies including renal function assessments have demonstrated that PHP does not have untoward effects on major organ functions. Its efficacy in transporting oxygen has been shown in ET and intracoronary perfusion, and in in vitro studies with sickle cells. Studies to date suggest that PHP is a promising candidate as a physiological oxygen carrier. In this paper the properties of PHP, its safety and efficacy aspects, and its potential as a clinical oxygen carrier are reviewed based on studies conducted in the Author's laboratory.

Temperature effect on bilirubin adsorption with the anion exchange resin BR-601.

Plasma perfusion with the anion exchange resin BR-601 is an effective method to treat patients with hepatic failure and hyperbilirubinemia. To assess the temperature dependency of bilirubin sorption in vitro, isotherm studies with human pathologic plasmas and an albumin-bilirubin solution were carried out. Results showed that BR-601 was more effective at 37 degrees C and 42 degrees C than at 4 degrees C and 25 degrees C for sorbing bilirubin. Therefore, plasma sorption at near physiologic temperature would be expected to be more efficient for plasma treatment than sorption at ambient temperature.

Effect of anticoagulant on biocompatibility in membrane plasmapheresis.

The effect of heparin or citrate anticoagulation on blood cellular, complement pathway and coagulation pathway was investigated in a membrane plasma exchange procedure. Two membrane plasma separators constructed of cellulose di-acetate (CA) and polyvinyl chloride (PVC) were evaluated with heparin or citrate alone for anticoagulation in a 26 year old male with myasthenia gravis. Maximum white blood cell counts decrease was 21% at 30 min for the CA with heparin while no decrease was observed for the other schemes. Platelet counts changes were comparable between heparin and citrate, while the PVC groups showed less changes than the CA groups. The CA groups, regardless of the type of anticoagulant used, indicated that complement activation occurred via the classical pathway within the module in addition to the activation via alternative pathway for the CA with heparin. In the PVC groups, complement activation was noted to occur only when heparin was used for anticoagulation. PT and PTT showed slight increases with citrate, while they were remarkably prolonged with heparin. Citrate showed less changes in cellular and humoral factors compared to heparin. CA with heparin was the most activating combination of membrane material and anticoagulant, while the PVC with citrate was the least activating combination.

Removal and recovery of cholesterol in thermofiltration.

Thermofiltration, a system of membrane plasmapheresis for LDL apheresis, was applied to the treatment of hypercholesterolemic patients to assess its lipid lowering potential, clinical feasibility and post-treatment lipid recovery. Plasma separated by a membrane separator was warmed above physiologic temperature, filtered with a plasma filter and returned to the patient on-line without requiring supplemental plasma product infusion. One calculated plasma volume was treated. Treatment schedules were weekly, biweekly or monthly. Patients treated by thermofiltration in this study were diagnosed as type II hypercholesterolemia. Reductions and sievings of high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol were evaluated. In addition, post-treatment solute recovery was assessed. The reduction ratios of HDL cholesterol and LDL cholesterol were 0.31 +/- 0.08 and 0.58 +/- 0.08, respectively (mean +/- S.D. of 7 patients). Sieving coefficients of the plasma filter for HDL cholesterol and LDL cholesterol were 0.62 +/- 0.12 and 0.03 +/- 0.02, respectively (mean +/- S.D. of 32 treatments). Cholesterol reduction fitted well to a single pool model. HDL cholesterol recovered significantly faster than LDL cholesterol and LDL cholesterol recovery differed among individuals. For some patients total cholesterol and LDL cholesterol levels were lowered by the biweekly treatment while for others the weekly treatment was required. Significant removal of LDL cholesterol with sparing of HDL cholesterol was achieved without the requirement for plasma products.

Use of Dacron as an alternative carrier for evaluating oxidizing sterilants in the AOAC sporicidal test.

The AOAC sporicidal method (966.04) recommends the use of porcelain penicylinders and black waxed silk sutures as carriers for demonstrating the sporicidal activity of sterilants. However, the silk carriers are not suitable for evaluating the sporicidal efficacy of oxidizing agents, and an inert polyester material (Dacron) is recommended as an alternative. Dacron provides an equivalent microbial and physical challenge to silk. Microbiologically, both materials demonstrated similar HCI resistance, which is required by the AOAC test, as well as equivalent spore loading and spore wash-off. Electron microscopy showed that both materials present the same braided microstructure, providing an equivalent physical challenge to the test sterilant. Dacron was more consistent than silk, and did not require extraction prior to spore loading. The extraction method for black waxed silk was variable and incomplete, which may compromise the activity of oxidizing sterilants and add to method variability. Silk was also structurally altered in the presence of oxidizing sterilants and increased sterilant degradation. Dacron did not affect the sterilant and was inert in the presence of oxidizing agents. Dacron sutures are proposed as inert alternatives to silk for evaluating the sporicidal efficacy of oxidizing agents.

Analysis of low density lipoprotein apheresis: post-treatment rebound using mathematical models.

Double membrane low density lipoprotein (LDL) apheresis (thermofiltration) was applied to treat six hyperlipidaemic patients and five controls 14 and 5 times, respectively, and post-treatment plasma LDL cholesterol (LDLc) concentration rebound was measured. To simulate the rebound, a nonlinear model (NLM) was developed. It consists of two compartments representing plasma and liver. LDLc uptake by the liver is described by receptor-independent and by receptor-mediated transport as controlled by the liver cholesterol concentration. NLM analysis of patient data resulted in pre-treatment fractional catabolic rate (FCR) for LDLc of 0.19 day-1 and the maximum FCR for LDLc of 0.26 day-1 on the 4th day. NLM showed that in patients and controls the post-treatment LDL synthesis rate rose by 6% to 15%. The steady-state (kinetic) version of this model was used to develop a formula describing the relationship between the FCR for LDLc and blood plasma LDLc concentration which agrees well with published data.

Technical and economic feasibility of reusing disposable perfusion cannulae.

The reuse of disposable devices is a potential source of significant cost savings to hospitals. Venous and arterial perfusion cannulae under new and reused conditions were selected to identify the clinical, safety, technical, logistic, and economic issues that must be addressed to realize these savings. Single- and dual-stage venous and arterial cannulae from two manufacturers were tested when new, after initial clinical use, and after a single clinical use plus up to nine simulated reuses. Reuse was simulated by end-to-end bending, coupling and uncoupling the connectors, and by two 1-hour soaks in plasma at 4 degrees C and 40 degrees C, respectively. Cannulae were decontaminated and then sterilized by a peracetic acid based liquid chemical sterilization system following each use/reuse. Sterilization was validated by eliminating Bacillus subtilis spores from the cannulae on each of five consecutive cycles. Cannulae were tested for physical changes, functional integrity, biocompatibility, and in vivo performance in sheep. A cost minimization analysis was also performed. No clinically important differences were found between new and reused cannulae, even after nine simulated reuses. Mechanical changes were less than 20% on all variables studied and were undetectable by experienced cardiac surgeons in selective evaluation. Sterilization was successfully achieved. Reusing cannulae for times would reduce the cost per procedure from $53 to $19 (64%). Perfusion cannulae tested can be safely and efficaciously used five times. This study suggests that reuse would result in a small incremental savings; however, with more expensive devices and higher-volume sterilization procedures, the savings could be exponentially greater. Although this study demonstrates that it may be technically feasible and cost-effective to reuse disposable cannulae, the U.S. Food and Drug Administration does not sanction the reuse of disposable cannulae.