Novel Surfaces in Extracorporeal Membrane Oxygenation Circuits

The balance between systemic anticoagulation and clotting is challenging. In normal hemostasis, the endothelium regulates the balance between anticoagulant and prothrombotic systems. It becomes particularly more challenging to maintain this physiologic hemostasis when we are faced with extracorporeal life support therapies, where blood is continuously in contact with a foreign extracorporeal circuit surface predisposing a prothrombotic state. The blood-surface interaction during extracorporeal life support therapies requires the use of systemic anticoagulation to decrease the risk of clotting. Unfractionated heparin is the most common anticoagulant agent widely used in this setting. New trends include the use of direct thrombin inhibitor agents for systemic anticoagulation; and surface modifications that aim to overcome the blood-biomaterial surface interaction by modifying the hydrophilicity or hydrophobicity of the polymer surface; and coating the circuit with substances that will mimic the endothelium or anti-thrombotic agents. To improve hemocompatibility in an extracorporeal circuit, replication of the anti-thrombotic and anti-inflammatory properties of the endothelium is ideal. Surface modifications can be classified into three major groups: biomimetic surfaces (heparin, nitric oxide, and direct thrombin inhibitors); biopassive surfaces [phosphorylcholine, albumin, and poly- 2-methoxyethylacrylate]; and endothelialization of blood contacting surface. The focus of this paper will be to review both present and future novel surface modifications that can obviate the need for systemic anticoagulation during extracorporeal life support therapies

Thromboresistance Characterization of Extruded Nitric Oxide Releasing Silicone Catheters

Intravascular catheters used in clinical practice can activate platelets, leading to thrombus formation and stagnation of blood flow. Nitric oxide (NO)-releasing polymers have been shown previously to reduce clot formation on a number of blood contacting devices. In this work, trilaminar NO-releasing silicone catheters were fabricated and tested for their thrombogenicity. All catheters had specifications of L = 6 cm, inner diameter = 21 gauge (0.0723 cm), outer diameter = 12 gauge (0.2052 cm), and NO-releasing layer thickness = 200 ± 11 µm. Control and NO-releasing catheters were characterized in vitro for their NO flux and NO release duration by gas phase chemiluminescence measurements. The catheters were then implanted in the right and left internal jugular veins of (N = 6 and average weight = 3 kg) adult male rabbits for 4 hours thrombogenicity testing. Platelet counts and function, methemoglobin (metHb), hemoglobin (Hb), and white cell counts and functional time (defined as patency time of catheter) were monitored as measured outcomes. Nitric oxide-releasing catheters (N = 6) maintained an average flux above (2 ± 0.5) × 10−10 mol/min/cm2 for more than 24 hours, whereas controls showed no NO release. Methemoglobin, Hb, white cell, and platelet counts and platelet function at 4 hours were not significantly different from baseline (α = 0.05). However, clots on controls were visibly larger and prevented blood draws at a significantly (p \u3c 0.05) earlier time (2.3 ± 0.7 hours) into the experiment, whereas all NO-releasing catheters survived the entire 4 hours test period. Results indicate that catheter NO flux levels attenuated thrombus formation in a short-term animal model

The Hemocompatibility of a Nitric Oxide Generating Polymer that Catalyzes S-nitrosothiol Decomposition in an Extracorporeal Circulation Model

Nitric oxide (NO) generating (NOGen) materials have been shown previously to create localized increases in NO concentration by the catalytic decomposition of blood S-nitrosothiols (RSNO) via copper (Cu)-containing polymer coatings and may improve extracorporeal circulation (ECC) hemocompatibility. In this work, a NOGen polymeric coating composed of a Cuo-nanoparticle (80 nm)-containing hydrophilic polyurethane (SP-60D-60) combined with the intravenous infusion of an RSNO, S- nitroso-N-acetylpenicillamine (SNAP), is evaluated in a 4 h rabbit thrombogenicity model and the anti-thrombotic mechanism is investigated. Polymer films containing 10 wt.% Cuo-nanoparticles coated on the inner walls of ECC circuits are employed concomitantly with systemic SNAP administration (0.1182 μmol/kg/min) to yield significantly reduced ECC thrombus formation compared to polymer control + systemic SNAP or 10 wt.% Cu NOGen + systemic saline after 4 h blood exposure (0.4 ± 0.2 NOGen/SNAP vs 4.9 ± 0.5 control/SNAP or 3.2 ± 0.2 pixels/cm2 NOGen/saline). Platelet count (3.9 ± 0.7 NOGen/SNAP vs 1.8 ± 0.1 control/SNAP or 3.0 ± 0.2 × 108/ml NOGen/saline) and plasma fibrinogen levels were preserved after 4 h blood exposure with the NOGen/SNAP combination vs either the control/SNAP or the NOGen/saline groups. Platelet function as measured by aggregometry (51 ± 9 NOGen/SNAP vs 49 ± 3% NOGen/saline) significantly decreased in both the NOGen/SNAP and NOGen/saline groups while platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry was not decreased after 4 h on ECC to ex vivo collagen stimulation (26 ± 2 NOGen/SNAP vs 29 ± 1 MFI baseline). Western blotting showed that fibrinogen activation as assessed by Aγ dimer expression was reduced after 4 h on ECC with NOGen/SNAP (68 ± 7 vs 83 ± 3% control/SNAP). These results suggest that the NOGen polymer coating combined with SNAP infusion preserves platelets in blood exposure to ECCs by attenuating activated fibrinogen and preventing platelet aggregation. These NO-mediated platelet changes were shown to improve thromboresistance of the NOGen polymer-coated ECCs when adequate levels of RSNOs are present

In Vitro and in Vivo Study of Sustained Nitric Oxide Release Coating Using Diazeniumdiolate-doped Poly(vinyl chloride) Matrix with Poly(lactide-co-glycolide) Additive

Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion and activation that can be released from a NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) within a polymer coating. In this study, various Food and Drug Administration approved poly(lactic-co-glycolic acid) (PLGA) species were evaluated as additives to promote a prolonged NO release from DBHD/N2O2 within a plasticized poly(vinyl chloride) (PVC) matrix. When using an ester-capped PLGA additive with a slow hydrolysis time, the resulting coatings continuously release between 7 and 18 × 10−10 mol cm−2 min−1 NO for 14 days at 37 °C in PBS buffer. The corresponding pH changes within the polymer films were visualized using pH sensitive indicators and are shown to correlate with the extended NO release pattern. The optimal combined diazeniumdiolate/PLGA-doped NO release (NOrel) PVC coating was evaluated in vitro and its effect on the hemodynamics was also studied within a 4 h in vivo extracorporeal circulation (ECC) rabbit model of thrombogenicity. Four out of 7 control circuits clotted within 3 h, whereas all the NOrel coated circuits were patent after 4 h. Platelet counts on the NOrel ECC were preserved (79 ± 11% compared to 54 ± 6% controls). The NOrel coatings showed a significant decrease in the thrombus area as compared to the controls. Results suggest that by using ester-capped PLGAs as additives to a conventional plasticized PVC material containing lipophilic diazeniumdiolates, the NO release can be prolonged for up to 2 weeks by controlling the pH within the organic phase of the coating

Mechanical component failures in 28,171 neonatal and pediatric extracorporeal membrane oxygenation courses from 1987 to 2006

Objective: To provide a descriptive summary of mechanical component failure associated with extracorporeal membrane oxygenation (ECMO), and to examine patient and ECMO variables that may be associated with mechanical component failure and guide further study. We hypothesized that duration of ECMO, era of ECMO, indication for ECMO, age of patient, and center ECMO volume would be associated with mechanical component failure. Design: Retrospective cohort study. Patients and Methods: Extracorporeal Life Support Organization registry was queried for all neonatal and pediatric ECMO courses recorded. Each ECMO course was treated as an independent event, and was included if duration was ≥25 hrs with occurrence between 1987 and 2007. Courses with a duration \u3e458 hrs or with an indication for ECMO during cardiopulmonary resuscitation were excluded from analysis. Mechanical component failure data were extracted from the Extracorporeal Life Support Organization registry for the oxygenator, raceway, other tubing, pigtail connectors, heat exchanger, and air in the circuit. Results: A total of 28,171 independent ECMO courses were included for analysis, of which 14.9% were associated with a mechanical component failure. Duration of ECMO, age group of patient, era of ECMO, and indication for ECMO were all associated with mechanical component failure. From our predictive model, we observed a continuous nonlinear relation suggesting increasing probability of mechanical component failure with increasing duration of ECMO support. Conclusions: Mechanical component failure over the course of this study was infrequent during neonatal and pediatric ECMO, and declined across eras as experience with the therapy grew. Increasing duration of ECMO was associated with an increasing probability of mechanical component failure. Indication for ECMO and patient age were also statistically associated with mechanical component failure probability, but ECMO center volume was not. © 2009 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

The relationships between air exposure, negative pressure, and hemolysis.

The purpose of this study was to describe the hemolytic effects of both negative pressure and an air-blood interface independently and in combination in an in vitro static blood model. Samples of fresh ovine or human blood (5 ml) were subjected to a bubbling air interface (0-100 ml/min) or negative pressure (0-600 mm Hg) separately, or in combination, for controlled periods of time and analyzed for hemolysis. Neither negative pressure nor an air interface alone increased hemolysis. However, when air and negative pressure were combined, hemolysis increased as a function of negative pressure, the air interface, and time. Moreover, when blood samples were exposed to air before initiating the test, hemolysis was four to five times greater than samples not preexposed to air. When these experiments were repeated using freshly drawn human blood, the same phenomena were observed, but the hemolysis was significantly higher than that observed in sheep blood. In this model, hemolysis is caused by combined air and negative pressure and is unrelated to either factor alone.</p