Evaluation of Three Different Methods to Prevent Dialyzer Clotting Without Causing Systemic Anticoagulation Effect

Thrombogenicity is one of the most important biocompatibility markers of artificial material. Anticoagulation is commonly used to reduce thrombogenicity of the extracorporeal circuit (ECC) during intermittent hemodialysis (IHD). In some situations, systemic anticoagulants are contraindicated. The aim of our study was to compare thrombogenicity parameters during IHD with three different methods without a systemic anticoagulation effect. In a prospective, randomized, and crossover study, we examined 10 stable patients during IHD with (i) regular saline flushes of ECC; (ii) regional citrate anticoagulation (RCA); and (iii) AN69 ST membrane after ECC priming according to the manufacturer's recommendations. Before IHD and after 10, 60, 120, and 240 min, we measured the platelet count and the plasma concentrations of platelet factor 4 (PF4) and thrombin/antithrombin complexes (TAT). All 10 procedures with RCA were successfully completed after 4 h, whereas 6/10 procedures with saline flushes and 5/10 procedures with AN69 ST were finished prematurely because of clotting (P < 0.05). The TAT production was significantly increased during saline flushes and AN69 ST compared with RCA (P < 0.05). Platelet activation demonstrated by rising PF4 was present during all three methods. Markers of coagulation cascade activation were progressively increasing during IHD with RCA, saline flushes, and AN69 ST. The activation was significantly lower during RCA, and according to thrombogenicity, RCA is the most effective among compared anticoagulation methods.     

Optimal anticoagulation strategy in haemodialysis with heparin-coated polyacrylonitrile membrane.

BACKGROUND: Binding of polycationic unfractionated heparin onto the modified AN69 polyacrylonitrile membrane, whose surface electronegativity has been neutralized by layering polyethyleneimine (AN69ST), produces stable coating. We investigated whether the heparin-coated membrane was suitable for regular haemodialysis with low heparin doses. METHODS: Sheep were instrumented for extracorporeal circulation perfusing a dialyser equipped with either the AN69ST or the original AN69 membrane. Dialysis sessions were performed after priming the dialyser with heparinized saline. The session was conducted without systemic administration of heparin. In chronic haemodialysis patients, the AN69ST membrane was tested for safety, clotting and thrombin generation according to protocols of 4-h haemodialysis sessions with tapered heparin doses. The goal was to define optimal heparin requirements with the heparin-coated membrane in the setting of continuous or intermittent administration of heparin. Both unfractionated and low molecular weight heparin (LMWH) (enoxaparin) were tested. RESULTS: In sheep, systemic heparin-free haemodialysis was conducted for 6 h without clotting using the heparin-coated dialyser. In the same conditions, massive clotting was observed within 90 min of dialysis with the native AN69 membrane. In man, through kinetic measurements of activated partial thromboplastin time (APTT), heparin anti-Xa concentration and thrombin-anti-thrombin complexes levels (TAT), significant dialyser clotting was avoided when APTT and anti-Xa concentration at 180 min of dialysis, were maintained at >40 s and >0.2 IU/ml, respectively. With the AN69ST heparin-coated membrane, thrombin generation was reduced then suppressed, as compared with the original AN69, primed in the same conditions. Safety of haemodialysis conducted with the AN69ST heparin-coated membrane and low doses of unfractionated heparin (50% reduction of the reference dose) was validated by a survey of 2590 sessions in 32 patients. Doses of LMWH were also safely reduced by 50%. In addition, haemodialysis without systemic administration of heparin was possible with minor risk of clotting. CONCLUSION: During the rinsing phase, the ionic interactions between the new AN69ST polyacrylonitrile membrane and unfractionated heparin induce stable heparin coating. This allows a significant reduction of systemic anticoagulant requirements without increasing the risk of clotting, both in the experimental setting and in the chronic haemodialysis patients. Further studies are required to assess this advantage in patients with acute renal failure and at risk of bleeding and to reduce the metabolic consequences of long-term treatment with heparin.     

Role of contact system activation in hemodialyzer-induced thrombogenicity.

BACKGROUND: The contact system is generally believed to be the main trigger of the coagulation cascade during extracorporeal circulation. However, the extent of contact activation, its role for intradialytic thrombin generation as well as the influence of different dialyzer membranes have not been well established. METHODS: In a novel full-scale ex vivo recirculation dialysis model, we investigated the thrombogenicity of three widely used hemodialyzers (Cuprophan Renak RA15-U, Polysulfone F6HPS and AN69XT Nephral 200). The activation of the contact system was evaluated using a newly developed ELISA for factor XIIa-C1-inhibitor complexes. Additionally, we determined free FXIIa (ELISA), thrombin-antithrombin (TAT) complexes, platelet factor 4 (PF4), complement activation (C5a), granulocyte elastase and blood cell counts. The findings in blood from normal volunteers were compared with factor XII-deficient blood. RESULTS: With normal blood AN69 exhibited the highest thrombogenicity in comparison to Cuprophan and Polysulfone, as assessed by TAT generation and platelet consumption. AN69 caused a rapid increase of the FXIIa-C1-inhibitor complexes and of free FXIIa. Despite significant TAT generation with Cuprophan and Polysulfone free FXIIa remained unchanged and the FXIIa-C1-inhibitor complexes stayed below the detection limit. With factor XII-deficient blood Polysulfone exhibited the same TAT generation, whereas the thrombogenicity of AN69 was greatly reduced. CONCLUSIONS: Our data challenge the common assumption that activation of the contact system with generation of FXIIa is the main trigger for coagulation and thrombus formation in hemodialysis. Only the negatively charged AN69 membrane with enhanced thrombogenicity strongly induced contact activation.     

Tissue factor, its inhibitor, and the thrombogenicity of two new synthetic membranes

BACKGROUND: The aim of the study was to compare the effect of new high-flux hemodialysis membranes made from polyacrylonitrile (AN69ST) and polysulfone (Helixone) on the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) playing a key role in hemostasis. Established thrombogenicity markers were also determined. METHODS: In a clinical prospective randomized study, 10 patients were examined using either membrane at the start and at minutes 15, 60, and 240 of hemodialysis. RESULTS: Increases in the plasma TF levels reached significance at the end of hemodialysis with both membranes, with the Helixone also after 15 min. TFPI levels tended to rise significantly from minute 15 onward while not differing from baseline at the end of the procedure. Judging by the increase in thrombin-antithrombin III complexes, both membranes significantly activated coagulation at the end of hemodialysis. Platelet factor 4 levels, released during thrombocyte and endothelial stimulation, were elevated from the start of procedures. There were no significant differences between the AN69ST and the Helixone in any of the assessed markers. CONCLUSIONS: The AN69ST and Helixone membranes do not differ in their effects on TF and TFPI or even in established thrombogenicity markers.     

The clinical evaluation of low-dose heparin in haemodialysis: a prospective study using the heparin-coated AN69 ST membrane.

BACKGROUND: The AN69 ST haemodialysis membrane, a new membrane resulting from coating polyethyleneimine upon the polyacrylonitrile surface, binds heparin. In patients at risk of bleeding, a pilot study has demonstrated the efficient anticoagulant effect of this heparin-coated membrane. Study design. In chronic haemodialyzed patients, we evaluated whether this anticoagulant effect can be validated in a controlled, prospective, open study. Pragmatically, we tested the hypothesis of no difference of the massive clotting rate in two groups of patients haemodialyzed either with 50% reduced standard doses of nonfractionated heparin using the heparin-coated AN69 ST or with a full dose of heparin (100%) using another type of dialysis membrane that does not bind heparin. Secondary objectives included evaluation of partial clotting, changes in haemoglobin levels, erythropoietin consumption and dialyzer performances. RESULTS: One hundred and eighty-four patients were elected and 170 finally included in an 18-month follow-up study. They were allocated to one of the two arms of the study. In the heparin-reduced group (n = 85, mean age: 73 +/- 11 years), 12 472 sessions were performed after priming the AN69 ST dialyzer with 2 L of heparinized saline (5000 IU/L heparin) and using 50% reduced doses of previously administered heparin. In the control group with standard heparin (n = 85, mean age: 74 +/- 13 years), 14 154 sessions were analysed (NS), and mean heparin doses were 2718 +/- 1388 and 4800 +/- 1564 IU per session, respectively (P < 0.001). In the heparin-reduced group, massive clotting occurred in 1.4 per 1000 sessions, whereas it occurred in 1.6 per 1000 sessions in the standard heparin group (P < 0.05). Mild to moderate partial clotting in the venous drip chamber and in the dialyzer was evaluated in a subset of patients, on a visual scale. It was more frequent in the experimental group than in the control group (P < 0.001). Platelets, haemoglobin levels, erythropoietin needs and dialyzer performances remained unchanged in both groups. The global mean death rate was 16.8% per year and did not differ significantly between groups. CONCLUSION: The use of the heparin-coated AN69 ST membrane allows a 50% reduction of standard doses of nonfractionated heparin administration for routine haemo- dialysis without increasing the risk of massive clotting of the extracorporeal circuit. This result needs confirmation since massive clotting questions clinical practice and is team dependent.     

Comparative analysis of procoagulatory activity of haemodialysis, haemofiltration and haemodiafiltration with a polysulfone membrane (APS) and with different modes of enoxaparin anticoagulation.

BACKGROUND: Treatment modalities of renal replacement therapy differ in their diffusive and convective mass transfer characteristics. It was the goal of this study to clarify whether an increase in convective mass transfer as performed with haemofiltration (HF) and haemodiafiltration (HDF) in comparison with high-flux haemodialysis (HD) is associated with an alteration in procoagulatory activity or with complement activation. METHODS: Ten stable chronic HD patients were monitored during 120 treatments in a randomized cross over design. A high-flux polysulfone dialyser (APS 900) was used for high-flux HD, pre-dilution HF and pre-dilution HDF. Constant flow of on-line substitution fluid for HF and HDF was 200 ml/min. The low molecular weight heparin (LMWH) enoxaparin was used for anticoagulation (i) as single bolus (50 IU/kg body weight, median 3700 IU) and (ii) as bolus of 1200 IU followed by a median continuous dose of 400 IU/h. Blood samples were collected before the LMWH bolus, after 10 min, 60 min, 120 min and at the end of treatment in venous and arterial blood lines to determine antiXa activity, thrombin-antithrombin-III complex (TAT), D-dimer and C5a generation. RESULTS: Net ultrafiltration did not significantly differ between HD, HF and HDF but total ultrafiltration in HF and HDF far exceeded total ultrafiltration in HD. With conditions of single bolus, or bolus and continuous anticoagulation with enoxaparin, after comparable treatment times (median duration 4.25 h), TAT and D-dimer generation at identical anti-Xa levels revealed significantly higher coagulation activity during HF and HDF, compared with high-flux HD as assessed by comparative area under the curve (AUC) analysis. Plasma concentration of C5a in venous bloodlines did not significantly differ during HD, HF and HDF. CONCLUSION: A higher convective mass transfer during HF and HDF, in comparison with high-flux HD caused by a greater total ultrafiltration volume was associated with increased procoagulatory activity in the extracorporeal circuit. Molecular markers assessing the activation of coagulation are appropriate to adjust the anticoagulation regime to high UF volumes in order to minimize bleeding risk and optimize patency of the extracorporeal circuit.     

Anticoagulant-free Genius haemodialysis using low molecular weight heparin-coated circuits.

BACKGROUND: Regional citrate anticoagulation or saline flushes are often used in haemodialysis patients at high risk of bleeding. In an alternative approach we evaluated the effects of covalent circuit coating with low molecular weight heparin (LMWH) for intermittent haemodialysis. METHODS: In vitro, we compared the thrombogenicity of an uncoated polyvinylchloride (PVC) tubing set with LMWH-coated tubing (AOThel) and a reference tubing with end-point attached heparin coating (Carmeda Bioactive surface) under dynamic blood contact. In vivo, five chronic haemodialysis patients were studied using the Genius dialysis system and F60S filters. Each patient underwent three dialysis sessions separated by a standard haemodialysis each: (1) standard dialysis (uncoated circuit and regular dalteparin dosage), (2) dialysis with LMWH-coated circuit and regular dalteparin dosage and (3) dialysis with a completely LMWH-coated circuit without anticoagulant use. RESULTS: In vitro, both coated tubings showed significantly reduced thrombin-antithrombin (TAT) complex levels compared with PVC. The reference coating (Carmeda) released substantial antifactor Xa (antiXa) activity into the plasma. The LMWH coating (AOThel) released low antiXa activity only during the initial rinsing. In vivo, all dialysis sessions were well tolerated and completed without major clotting. Antithrombin levels and platelet counts were similar in all groups. P-selectin and D-dimer levels increased similarly in all groups. TAT levels were comparable in all groups during the first 3 h and significantly increased in the anticoagulant-free group after the fourth hour. CONCLUSIONS: LMWH surface coating reduces thrombogenicity in vitro without releasing significant amounts of heparin from the surface. In vivo, anticoagulant-free haemodialysis using a completely LMWH-coated circuit is feasible and safe in stable chronic dialysis patients with normal coagulation.     

Effect of Regional Citrate Anticoagulation on Thrombogenicity and Biocompatibility During CVVHDF

This study was designed to assess the principal markers of thrombogenicity and biocompatibility during continuous venovenous hemodiafiltration (CVVHDF) using regional citrate anticoagulation (RCA). In a prospective study, 11 procedures with a polysulfone membrane were performed in nine critically ill patients with acute renal failure and impaired hemostasis. Blood samples were taken before and during CVVHDF at diafilter outlet—before calcium-induced reversal of the effect of citrate—at 15, 60, 360, and 1440 minutes. In four patients, 10 CVVHDF sessions were performed with systemic heparin anticoagulation (HA) using a polyacrylonitrile membrane. During RCA, blood thrombocyte count, plasma thrombin-antithrombin III complexes, beta-thromboglobulin, and von Willebrand factor levels did not differ significantly from baseline. Plasma D dimer levels rose significantly at 360 minutes; however, the difference between diafilter inlet and outlet levels was nonsignificant. There was a significant increase in plasma C5a concentrations and a decline in blood leukocyte count in the early phase of CVVHDF. Just as in RCA, no increase in plasma thrombogenicity indices was observed during HA. However, clotting times in blood entering patients' circulation were significantly prolonged. Plasma C5a concentrations increased significantly at the beginning of CVVHDF. RCA can effectively inhibit the thrombogenic effect of the extracorporeal circuit in CVVHDF. The effect of HA may be similar, however, at the expense of systemic anticoagulation and risk of bleeding. RCA, performed in a way that overcomes thrombogenicity, does not completely eliminate complement activation and/or transient leukopenia during CVVHDF.     

Different effects of enoxaparin and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study.

BACKGROUND: Heparin inhibits prothrombotic tissue factor (TF) and releases its inhibitor, tissue factor pathway inhibitor (TFPI), from the endothelium, but repeated administration of heparin depletes vascular stores of TFPI. We studied the anticoagulant effects of unfractionated heparin (UFH) vs low-molecular-weight enoxaparin-used for thrice-weekly maintenance haemodialysis (HD)-on plasma levels of total TF and TFPI and on those of an activated coagulation marker prothrombin fragment 1+2 (PF 1+2). METHODS: Twenty-five patients dialysed using a single injection of enoxaparin (at a mean dose of 0.68 mg/kg) were randomly assigned to either receive UFH administered as a mean bolus of 42.1 IU/kg and continuous infusion of 57.8 IU/kg (n=12) or to be maintained on enoxaparin (n=13), and were followed prospectively for 12 weeks. Plasma immunoreactive TF, TFPI and PF 1+2 were measured at the start and after 10 and 180 min of HD, and compared with values in 15 healthy controls. RESULTS: Pre-dialysis TF, TFPI and PF 1+2 were higher than normal (all P<0.0001). TF and PF 1+2 did not change, while TFPI levels, compared with baseline, increased at each interval in enoxaparin-anticoagulated HD patients (all P<0.0001). TFPI increments correlated inversely with pre-dialysis TFPI (both P<0.0007). In patients switched to UFH, TF levels remained unchanged compared with pre-randomization values, TFPI increased at each interval of HD sessions (all P<0.035) and PF 1+2 increased pre-dialysis (P=0.015). The over-dialysis effects of UFH resembled those of enoxaparin. In contrast, baseline TFPI and its 10-min rise correlated inversely with the UFH loading dose (both P<0.040). Pre-dialysis PF 1+2 was inversely associated with TFPI increments (both P<0.034), and directly with pre-dialysis TFPI (P=0.018) and the UFH loading dose (P=0.045). CONCLUSIONS: Depletion of heparin-releasable stores of TFPI is an untoward effect of repeated anticoagulation during maintenance HD therapy. The traditional UFH regimen is more prothrombotic than single enoxaparin injections, with high loading doses of UFH being involved in TFPI exhaustion and subsequent hypercoagulability.     

Citrate anticoagulation control by ionized calcium levels does not prevent hemostasis and complement activation during hemodialysis

The purpose of this study was to determine whether or not regional citrate anticoagulation (RCA) controlled by ionized calcium (iCa(2+)) would overcome thrombogenicity, prevent hemostasis, and complement activation during hemodialysis (HD). RCA was performed in 10 patients during 10 HD sessions using a polysulfone membrane in an effort to keep iCa(2+) at dialyzer outlet at < or =0.4 mmol/L. Compared to baseline, plasma levels of thrombin-antithrombin III complexes rose significantly at 240 min, and tissue factor and complement C5a component levels at 30 and 240 min of the procedure. Thrombocyte count declined significantly at 30 and 240 min, while activated clotting time (ACT) did not increase significantly, and platelet factor 4 as well as von Willebrand factor levels did not alter significantly. While ACT correlated significantly with some thrombogenicity markers, iCa(2+) did not correlate with ACT, changes in hemostasis, or C5a. We conclude the usually recommended iCa(2+) levels in the HD extracorporeal circuit did not guarantee the complete overcoming of thrombogenicity, prevention of hemostasis, and complement activation.     

Heparin-Coated Extracorporeal Circulation with Full and Low Dose Heparinization: Comparison of Thrombin Related Coagulatory Effects

Thrombin related coagulatory effects of a heparin-coated cardiopulmonary bypass system combined with full and low dose systemic heparinization were investigated in a prospective, randomized study in coronary bypass surgery patients. One hundred nineteen patients were divided into 3 groups. Group A (n = 39) had a standard uncoated extracorporeal circulation (ECC) set, and systemic heparin was administered in an initial dose of 400 IU/kg body weight. During ECC activated clotting time (ACT) was maintained at > or =480 s. Group B (n = 42) had the same ECC set completely coated with low molecular weight heparin. Intravenous heparin was given in the same dose as in Group A, and ACT was kept at the same level. Group C (n = 38) had the same coated ECC set as Group B, but intravenous heparin was reduced to 150 IU/kg, and during ECC, ACT was set to be > or =240 s. The same ECC components were used in all 3 groups including roller pumps, coronary suction, and an open cardiotomy reservoir. Thrombin generation as indicated by F1/F2 was significantly elevated at an ECC duration >60 min if heparin-coated ECC combined with low dose systemic heparinization was employed. Complexed thrombin (TAT) was significantly elevated after administration of protamine. Release of D-dimers indicating fibrinolysis was not significantly different between groups. Signs of clinical thromboembolism, i.e., postoperative neurological deficit, occurred in 2 patients in Group A and 1 patient in Group C. We conclude that heparin-coated extracorporeal circulation combined with reduced systemic heparinization intraoperatively leads to significantly increased thrombin generation, but not to increased fibrinolysis.     

Effect of regional citrate anticoagulation on thrombogenicity and biocompatibility during CVVHDF

This study was designed to assess the principal markers of thrombogenicity and biocompatibility during continuous veno-venous hemodiafiltration (CVVHDF) using regional citrate anticoagulation (RCA). In a prospective study, 11 procedures with a polysulfone membrane were performed in nine critically ill patients with acute renal failure and impaired hemostasis. Blood samples were taken before and during CVVHDF at diafilter outlet--before calcium-induced reversal of the effect of citrate--at 15, 60, 360, and 1440 minutes. In four patients, 10 CVVHDF sessions were performed with systemic heparin anticoagulation (HA) using a polyacrylonitrile membrane. During RCA, blood thrombocyte count, plasma thrombin-antithrombin III complexes, beta-thromboglobulin, and von Willebrand factor levels did not differ significantly from baseline. Plasma D dimer levels rose significantly at 360 minutes; however, the difference between diafilter inlet and outlet levels was nonsignificant. There was a significant increase in plasma C5a concentrations and a decline in blood leukocyte count in the early phase of CVVHDF. Just as in RCA, no increase in plasma thrombogenicity indices was observed during HA. However, clotting times in blood entering patients' circulation were significantly prolonged. Plasma C5a concentrations increased significantly at the beginning of CVVHDF. RCA can effectively inhibit the thrombogenic effect of the extracorporeal circuit in CVVHDF. The effect of HA may be similar, however, at the expense of systemic anticoagulation and risk of bleeding. RCA, performed in a way that overcomes thrombogenicity, does not completely eliminate complement activation and/or transient leukopenia during CVVHDF.     

Anticoagulant activity of enoxaparin and unfractionated heparin for venous thromboembolism prophylaxis in obese patients undergoing sleeve gastrectomy

BackgroundOne risk of bariatric surgery is venous thromboembolism and the optimal strategy to reduce risk requires further clarification.ObjectivesThe objectives of this study were to identify antiXa goal attainment with the institutional standard chemoprophylaxis, analyze discordance between antiXa and thrombin generation assay (TGA) in terms of adequacy of anticoagulation, and to identify correlations between patient characteristics or covariates and markers of coagulation status.SettingLarge academic medical center in Northeastern United States.MethodsA total of 60 sleeve gastrectomy patients were enrolled in this institutional review board–approved, prospective cohort study. Patients received the institutional standard prophylactic therapy (subcutaneous enoxaparin 40 mg twice daily or unfractionated heparin [UFH]). The UFH dose was weight based, 5000 units (<120 kg) or 7500 units (≥120 kg) every 8 hours. Various measures of coagulation status were measured at or near steady state.ResultsPatients receiving enoxaparin achieved goal antiXa more frequently compared with the UFH group, and statistical significance was demonstrated (93.8 % versus 4.5%, respectively; P < .0001). Target endogenous thrombin potential reduction from baseline was more frequently obtained in the enoxaparin group versus UFH (50% versus 27.7%, respectively; P = .12). AntiXa was below the limit of detection for the majority of UFH patients; while TGA suggested patients did experience anticoagulation at some level of effectiveness. Endogenous thrombin potential change in the enoxaparin group was correlated to several measures of body composition.ConclusionsPatients receiving enoxaparin achieved goal antiXa more often versus UFH. There was discordance between antiXa and TGA-based assessment of coagulation status. TGA may provide a more robust assessment of the adequacy of chemoprophylaxis.     

Activation of coagulation during hemodialysis: effect of blood lines alone and whole extracorporeal circuit

Activation of coagulation during hemodialysis (HD) is a relevant clinical problem, especially when patients at risk of bleeding are treated. However, little is known about the relative contribution of the various components of the circuit to the thrombotic process. Thus, an experimental model was developed that is aimed at evaluating biochemical markers of coagulation activation at different times and sites throughout the HD circuit. A HD blood-tubing set with integrated arterial and venous chambers (cartridge-line set) was used, which was added with the following sampling points: at the beginning of the arterial line (P1), before the blood pump (P2), after the blood pump (P3), and at the end of the venous line (P4). A bypass system allowed us to circulate the blood only into the blood lines for the first 20 min of the extracorporeal circulation. The extracorporeal circuit was rinsed with 1.7 L of heparinized saline (2,500 IU/L) that was completely discarded before patient connection. A continuous administration of unfractionated heparin (500-800 IU/h) without a starting bolus was adopted as a low heparin extracorporeal treatment. Samples were collected before the start of the extracorporeal circulation from the fistula needle (T0P0), after 5 (T1), 10 (T2), and 20 min (T3) from P1, P2, P3, and P4. After 20 min, the blood was returned to the patient using only saline and HD was then started, circulating the blood through the dialyzer. Further samples were obtained from P1 and P4 after 5 (T4) and 210 min (T5). Plasma levels of coagulation activation markers-thrombin-antithrombin complex (TAT) and prothrombin fragment 1 + 2 (F1 + 2)-were evaluated in all the samples in 12 stable HD patients. In each patient, the activated partial thromboplastin time (APTT) was measured at T0P0 and T1-T5 from P1. No significant changes were found at any time as far as F1 + 2 is concerned. However, TAT levels increased over time only after the start of HD, suggesting that the latter test could be more useful in order to detect coagulation activation during HD. The same experiments performed with nonheparin-primed extracorporeal circuit showed similar results. The blood lines used did not significantly activate coagulation during the first 20 min, whereas only 5 min of blood circulation throughout the whole circuit increased TAT values, which still remained lower than previous reports, even after 210 min of treatment.     

Low dose systemic heparinization combined with heparin-coated extracorporeal circulation. Effects related to platelets

BACKGROUND: A heparin coated cardiopulmonary bypass system combined with full and low dose systemic heparinization in coronary bypass surgery was investigated in a prospective, randomised study. Roller pumps, coronary suction and an open cardiotomy reservoir were used. METHODS: One hundred and nineteen patients were divided into 3 groups: group A (n=39) had a standard uncoated extracorporeal circulation (ECC)-set and systemic heparin was given in an initial dose of 400 IE/kg body weight. During ECC activated clotting time (ACT) was kept at = or >480 sec. Group B (n=42) had the same ECC-set completely coated with low molecular weight heparin, i.v. heparin was administered in the same dose as in group A, ACT was again kept at = or >480 sec. Group C (n=38) had the same coated ECC set as group B, but i.v. heparin was reduced to 150 IE/kg and during ECC ACT was maintained of = or >240 sec. RESULTS: Platelet decrease was significantly less in both groups utilizing coated circuitry as compared to control group A. Activation of thrombocytes as marked by b-thromboglobulin (not PF4) was significantly decreased in patients treated with coated circuits combined with low dose systemic heparinization and postoperative bleeding was significantly reduced. CONCLUSIONS: We conclude that in heparin coated extracorporeal circulation combined with either full dose or reduced systemic heparinization compared to uncoated circuits platelet count reduction is significantly less. Platelet activation as marked by b-thromboglobulin and postoperative blood loss are decreased with coated equipment and low i.v. heparinization.     

The Effects of a Polyacrylonitrile Membrane and a Membrane Made of Regenerated Cellulose on the Plasma Concentrations of Erythropoietin During Hemodialysis

In vitro studies have shown that some dialysis membranes significantly adsorb erythropoietin (EPO), a fact that might have an effect on anemia in long-term hemodialysis (HD) patients and on anemia treatment with recombinant human EPO. The purpose of the study was to determine whether the ability of adsorption demonstrated in vitro also has an effect on EPO concentrations in vivo. In a crossover study, the plasma concentrations of EPO were examined in 11 patients on chronic HD during HD using a polyacrylonitrile (AN69) membrane (high in vitro adsorption) plus EPO administered subcutaneously after the HD session, HD using a Cuprophan membrane (low in vitro adsorption) plus EPO administered subcutaneously after the HD session, HD using an AN69 membrane plus EPO administered subcutaneously after the HD session plus EPO administered intravenously immediately before HD, or HD using a Cuprophan membrane plus EPO administered subcutaneously after the HD session plus EPO intravenously immediately before HD. The intradialysis plasma concentrations of EPO (not detectable in the dialysate) determined at the dialyzer inlet and outlet at Minutes 5 and 240 of the procedure did not differ significantly after its subcutaneous administration from its predialysis concentrations with either the Cuprophan or AN69 membrane. A comparison of EPO concentrations between AN69 and Cuprophan did not reveal marked differences either. The course of concentrations after additional EPO intravenous administration was similar with no statistically demonstrable difference between the 2 membranes. In conclusion, under clinical conditions, AN69 and Cuprophan membranes do not differ in their effects on plasma EPO concentrations. The differences in EPO adsorption between AN69 and Cuprophan, demonstrated in vitro, do not seem to be of clinical importance.     

Influence of Blood Flow on Adsorption of β2-Microglobulin onto AN69 Membrane

Abstract: Adsorption onto the dialyzer membrane is a contributing factor to the elimination of β₂-microglobulin (β₂M) from the sera of uremic patients. The purpose of this prospective study was to ascertain the influence of the blood flow rate on adsorption of β₂M onto the polyacrylonitrile (AN69) hollow-fiber dialyzer membrane in 8 pa tients during regular hemodialysis (HD). Blood first passed through a low-flux polysulfone dialyzer and then through an AN69 dialyzer, which was not in contact with the dialysis fluid. During the investigation period (first hour of the HD session), the blood flow rate was 100 ml/min (first part of the study), 200 mumin (second part of the study), and 300 ml/min (third part of the study). Ultrafiltration was not performed during the investigation period. At the start of the HD sessions, the serum concentration of β₂M in the afferent blood line did not differ significantly among the 3 parts of the study. Serum β₂M was measured in samples taken from the afferent and efferent blood lines of the AN69 dialyzer at 5,10, 15, 30, 45, and 60 min. The serum β₂M concentration decreased significantly in blood that had passed through the AN69 dialyzer. This decrease, indicating membrane adsorption, was maximal during the first part and minimal during the third part of study. The decrease in the contact time between the blood and the AN69 could be the underlying cause. The calculated quantities of β₂M adsorbed onto the AN69 membrane (44.2 ± 10.2, 43.2 ± 12.1, and 42.6 ± 17.3 mg) did not differ significantly among the 3 parts of the study. These results suggest that an increase in blood flow rate from 100 to 300 ml/min did not significantly affect the quantity of β₂M adsorbed onto the AN69 membrane.     

两种体外循环回路对瑞芬太尼的吸附作用

目的 比较希健-I型和AFFINITY(R) NT成人膜式氧合器体外循环回路对预冲液中瑞芬太尼的吸附作用.方法 实验分为3组(n=6):希健-I型成人膜式氧合器体外循环回路组(A组)、AFFINITY(R) NT成人膜式氧合器体外循环回路组(B组)和玻璃容器组(C组).将预冲液(6%羟乙基淀粉1000 ml和乳酸钠林格氏液500 ml)预冲入成人膜式氧合器体外循环装置或玻璃容器中,然后从静脉贮血器的静脉端或玻璃容器口注入瑞芬太尼,终浓度为100 ng/ml.于注入瑞芬太尼后2、5、10、15 min时,从静脉贮血器的动脉端或玻璃容器中抽取预冲液2 ml,采用气相色谱法检测瑞芬太尼的浓度.结果 三组不同时点间瑞芬太尼浓度比较差异无统计学意义(P>0.05).与C组比较,A组和B组各时点瑞芬太尼浓度下降(P<0.01);与B组比较,A组各时点瑞芬太尼浓度下降(P<0.01).结论 希健-I型和AFFINITY(R) NT成人膜式氧合器体外循环回路对瑞芬太尼均有吸附作用,前者的吸附作用大于后者.     

The effects of heparin bound surface modification (Carmeda Bioactive Surface) on human platelet alterations during simulated extracorporeal circulation

To determine if treatment with covalently bound heparin (Carmeda Bioactive Surface (CBAS)) to the synthetic surface of the extracorporeal circuit (ECC) would alter the stereotypic pattern of adverse platelet alterations, 450 ml of heparinized blood (lU/ml) was recirculated at a flow rate of twice the circulating volume (L/min) for 2 hrs at 37 degrees C through either untreated (CONT,n=7) or treated (CBAS,n=7) circuits constructed of identical components including a pediatric (0.8m 2) reversed hollow fiber membrane oxygenator. In CONT circuits, platelet count maintained 88+1% (x+/-SEM) of its initial level in the circuit prime sample, dropped to 36+/-6% after 5 min, and returned to 56+/-2% following 2 hrs of ECC. In CBAS circuits, platelet count in the circuit prime sample demonstrated 90+/-4%, decreased to 68+/-10% after 5 min (p less than 0.05) and declined further to 45+/-5% after 2 hrs (NS). Although platelets from both groups retained reactivity to ADP after priming the circuit, only at 5 min of recirculation did CBAS circuits significantly preserve this responsiveness. In CONT circuits, baseline plasma levels of platelet factor 4 rose from 24+/-3 to 581+/-82 ng/ml in the primed circuit and continued to rise to 2933+/-276 ng/ml by 2 hrs of ECC. In contrast, CBAS circuits markedly reduced this release after 2 hrs (577+/-165 ng/ml). Furthermore by 2 hrs of ECC, plasma levels of thromboxane B 2 in the CBAS circuits were significantly reduced when compared to CONT circuits (3035+/-1529 vs 29916+/-16293 pg/ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Kinin kinetics during different dialysis protocols with AN69 dialyser in ACEI-treated patients

The effect of different dialysis modes on kinin kinetics wasstudied in seven stable haemodialysis patients treated withAN69 dialysers and ACE inhibitors (ACEI). AN69 haemodiafiltrationwith calcium-enriched substitution (HDF), AN69 haemodialysiswith 1.75 (HD 1.75) and 1.50 (HD 1.50)mmol/l dialysate calcium,AN69 haemodialysis with 1.25mmol/l dialysate calcium and substitutionof 2.25 mmol/h calcium (HD +Ca), and cellulose acetate haemodiafiltration(CA HDF) were compared. Dialysis was uneventful in all patients.During dialysis, serum calcium, sodium, pH, albumin, and bradykininwere measured at the start and after 5 min at arterial, venous,and postinfusion side of the extracorporeal circuit. Serum predialysisbradykinin was 107±18fmol/ml (mean±SEM) in patientson HDF, 61±9 fmol/ml in patients on HD 1.50, 49±13fmol/ml in patients on HD 1.75, 35±3 fmol/1 in patientson HD±Ca, and 75±27 fmol/ml in CA HDF. No significantchange of mean bradykinin levels occurred after 5 min at thearterial and venous side of the dialyser or postinfusion. Individualhigh bradykinin levels, up to 2672 fmol/ml, were observed butwithout clinical consequences, suggesting that the thresholdvalue is difficult to determine. No significant correlationswere evidenced between bradykinin levels and any of the biochemicalmeasurements. The present data show an intraindividual variabilityof the bradykinin levels with variation coefficients rangingfrom 0.386 to 2.783. The present study illustrates that haemodialysisand haemodiafiltration with AN69 in ACEI-treated patients, underthe present conditions, does not result in anaphy-lactoid reactionsor in a clinically significant release of bradykinin. The occurrenceof anaphylactoid reactions with high bradykinin levels is probablythe result of several concurrent bioincompatible factors insensitized patients.