The present authors developed arteriovenous CO2 removal (AVCO2R) as a simplified form of extracorporeal membrane oxygenation. 1–4 AVCO2R uses a low resistance, hollow fiber, micropore gas exchanger in a simple arteriovenous shunt (10% of cardiac output) that is capable of achieving near total CO2 removal and complete lung rest during acute respiratory distress syndrome (ARDS). During AVCO2R, CO2 removal and O2 transfer are uncoupled. CO2 is transferred across the membrane gas exchanger, whereas O2 diffuses across the native lungs. In prospective, randomized, large animal studies and preliminary clinical trials, AVCO2R has been shown to reduce volu/barotrauma, decrease ventilator dependent days, and potentially improve survival for early onset ARDS. 1–7
A major problem with all extracorporeal gas exchange techniques that use a micropore gas exchanger is plasma leakage. 8 Furthermore, coatings applied to the surface of the gas exchanger to prevent plasma leakage may alter gas exchange efficiency or increase blood flow resistance. 9,10 A new perfluorocopolymer coating has been developed that can be applied to the commercially available micropore hollow fiber AVCO2R oxygenator (Affinity, Medtronic, Plymouth, MN) to prevent plasma leakage, reduce blood surface interactions, and improve gas exchange. The purpose of this study was to evaluate the short term (6 hour) performance of AVCO2R using the perfluorocopolymer coating in a prospective, randomized, controlled, unblinded, large animal study.
Materials and Methods
All animals received humane care according to the Guide for the Care and Use of Laboratory Animals prepared by the U.S. Department of Health and Human Services (1996) and published by the National Institutes of Health. The study was approved by the Institutional Animal Care and Use Committee (IACUC) of The University of Texas Medical Branch, Galveston, Texas, with strict adherence to the IACUC guidelines regarding humane use of animals. The management of the sheep parallels the present authors’ standards of patient care. An investigator was also present to outline and supervise management. The present team also consisted of a full time staff veterinary anesthesiologist who supervised all anesthesia, sedation, and animal management issues. IACUC personnel, with no conflict, made daily rounds to check compliance with the animal management protocol.
The experimental design was a prospective, randomized, controlled, unblinded, large animal performance study comparing the Affinity micropore hollow fiber gas exchanger with (n = 5) and without (n = 5) perfluorocopolymer coating interposed in an AVCO2R circuit in the sheep model of CO2 retention. Adult sheep (Suffolk ewes, 30–40 kg) underwent general anesthesia induced by ketamine (7–15 mg/kg, intramuscularly) and isofluorane by mask; then they were blindly orotracheally intubated and maintained by 4.0–5.0% isofluorane titrated to a mean arterial pressure 70–110 mm Hg. A tracheostomy was performed to allow respiratory rate to be regulated during the 6 hour performance evaluation. A groin cut down allowed femoral artery and vein cannulation for hemodynamic monitoring and blood gases. A pulmonary artery catheter (Edwards Critical Care, Irvine, CA) was placed into the right jugular vein for measurement of systemic and mean blood pressures and right heart pressures plus thermodilution cardiac output, respectively. Under general anesthesia, a left neck cut down exposed the carotid artery and jugular vein for cannulation (12 F arterial, 14 F venous), after which the gas exchanger was attached for 6 hours, as previously described. 5 Animals were systemically anticoagulated (300 IU/kg bovine lung heparin, Upjohn, Kalamazoo, MI) before cannulation, and activated clotting time (ACT) (Hemochron 400, International Technidyne, Edison, NJ) was maintained between 200 and 300 seconds with a continuous heparin infusion throughout the study. Sheep were sedated with continuous intravenous Guaifenesin (1.5–2 ml/kg/hr) to suppress spontaneous respirations. Controlled mechanical ventilation with a low respiratory rate and high FiO2 maintained PaCO2 between 40–45 mm Hg by adjusting tidal volume (300–400 ml) and respiratory rate (5–7 breaths/min). PaO2 greater than 80 mm Hg was maintained by adjusting FiO2. The sheep were treated with AVCO2R for 6 hours. Inflow and outflow systemic blood gases were analyzed by System BG3 and Co-Oxymeter 482 (Instrumentation Laboratory, Lexington, MA). CO2 removal was calculated as the product of sweep gas flow (Qg, 100% O2), and exhaust gas CO2 concentration was measured by a CO2SMO Respiratory Profile Monitor (Novametrix Medical System, Inc., CT). Qg was held constant at 2 L/min. Trans-gas exchanger resistance was calculated from the blood pressure drop measured across the gas exchanger, and blood flow was measured by a real time flow meter (HT109, Transonic Systems, Ithaca, NY). Systemic hemodynamics were continuously monitored. The gas exchanger was monitored for foaming or deterioration of gas exchange.
Average CO2 removal for the coated gas exchanger was 107.6 ± 15.6 ml/min, whereas the uncoated gas exchanger removed CO2 at a rate of 93.0 ± 13.9 ml/min (p < 0.01) (Table 1). PaCO2 and CO2 removal for both coated and uncoated did not deteriorate significantly over the 6 hours of the study (Figure 1). Average AVCO2R blood flow was 1,130 ± 25 ml/min (coated) vs. 1,101 ± 79 ml/min (uncoated) (p = NS) (Table 1). Likewise, cardiac output and AVCO2R blood flow did not change over the duration of the study (Figure 2). No significant differences in pressure gradient or resistance across the devices (coated, 6.89 ± 1.14 mm Hg/L/min; uncoated, 6.42 ± 0.23 mm Hg/L/min) were noted (Figure 3). No foaming was observed in either the coated or uncoated gas exchange devices. Hemodynamics (mean arterial pressure, mean pulmonary artery pressure, and central venous pressure) remained within normal limits throughout the duration of the study.
Microporous membrane oxygenators are frequently used during extracorporeal life support because of increased gas exchange relative to solid silicone oxygenators. However, plasma leakage through the microporous membrane and adsorption of plasma proteins on the membrane surface leads to decreased gas exchange during long term use. 10 Plasma leakage (defined as movement of liquid through the micropores from the blood to the gas side of the membrane) causes deterioration of gas exchange and gross plasma leakage, which often requires replacement of the microporous membrane oxygenator. 8 A proposed mechanism for plasma leakage through the microporous membrane is by adsorption of bipolar plasma molecules (phospholipids) to the hydrophobic membrane surface, creating a hydrophilic layer on the membrane. This hydrophilic layer allows plasma to wet the membrane surface and advance into the pores causing plasma leakage. 8 Although plasma leakage is typically not a problem during large animal testing of microporous membrane oxygenators (which may be caused by a lower level of phospholipids), leakage remains a significant problem during long term use in humans.
Various coatings have been applied to microporous oxygenators to decrease plasma leakage potentially at the expense of gas exchange. In the current study, the blood side of the Affinity micropore oxygenator was coated with a new thin nonporous perfluorocoploymer coating with uniquely high gas permeability. A process for placing a thin layer of perfluorocoploymer continuously over polypropylene substrate was developed. 11 One side of the microporous substrate is exposed to a dilute coating solution comprised of the proprietary copolymer and solvent. Solvent of the coating solution is made to flow through the substrate while the polymer is effectively filtered out according to pore size. As a result, thin layers of polymer build up on one side of the membrane. Solvent and excess solution is removed by vacuum or evaporation once the desired thickness is attained. Using this general process, membrane formation was performed on the luminal surface of microporous hollow fibers to produce a nonporous membrane with enhanced wet-out resistance. The characteristics of the perfluorocopolymer are proprietary information and are not described in detail. This tough, inert, and hydrophobic coating lacks open micropores and is therefore able to withstand long term contact with blood without membrane wetting and transmembrane plasma leakage. The perfluorocopolymer coating is designed to be gas permeable so that gas exchange is not significantly reduced relative to identical uncoated membrane oxygenators. The present study confirmed that the perfluorocopolymer coating could be applied to a commercially available micropore hollow fiber gas exchanger with no deterioration in CO2 exchange.
The perfluorocopolymer coating’s comparable or superior gas transfer efficiency relative to uncoated microporous oxygenators has been attributed to the position of the gas-liquid interface. In uncoated microporous membranes, the gas-liquid interface is at the pore mouth, creating an area of stagnant liquid. Molecules moving from the gas to the liquid phase must diffuse through this stagnant liquid at the pore mouth. In the perfluorocopolymer coated membrane, the stagnant liquid is replaced by the thin layer of coating, which has less diffusional resistance to gas. In vivo testing of coated versus uncoated micropore membrane oxygenators in a calf for 24 hours showed dramatic loss in CO2 transfer in the uncoated oxygenator between 2 and 4 hours (D. Wang and J. B. Zwischenberger, unpublished data, 2001). The coated oxygenator showed no change in CO2 transfer even at 20 hours. The present prospective, randomized, controlled, unblinded, comparison study in a large animal model of CO2 retention showed that the coated micropore oxygenator had significantly improved CO2 removal with no significant difference in hemodynamics or blood flow resistance across the membrane (despite the additional thin coating) relative to the uncoated micropore oxygenator.
Further studies will evaluate long term (10 day) performance and blood compatibility in the present authors’ clinically relevant large animal model of ARDS. 12
Supported in part by NIH SBIR Grant and Compact Membrane Systems, Inc.
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