Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, work loss, and expense for patients in the United States and affects 15–17 million people today. Its prevalence has increased 60% over the last two decades, and it is now the fourth leading cause of death in the U.S. with over 100,000 deaths per year.1–3 The burden of COPD on society is expected to increase substantially over the next three decades.4–6
When COPD reaches end stage, pharmaceutical treatments provide only limited improvement. There are two surgical options available-Lung Volume Reduction Surgery (LVRS) and lung transplantation. LVRS is still under investigation and shows improved function in select patients but no survival advantage to date.8 Lung transplantation is an option for only a few patients with severe COPD with CO2 retention. Because of the scarcity of suitable lung donors in year 2000 to 2001, the mean waiting time was 526 days.9 A narrow window of opportunity for lung transplant exists in any patient who is sick enough to benefit from the operation but healthy enough to survive the 12–24 month wait for a donor lung and subsequent surgery. The artificial lung is years away from clinical trials and should be reserved for the sickest patients as a bridge-to-transplant or possibly as a bridge-to-recovery after acute lung injury.10–13
In advanced COPD, carbon dioxide retention is a common and grave sign caused by a raised equilibrium level between increased work of breathing with more CO2 production and decreased ventilation with decreased CO2 removal because of small airway closure.14 Hypoxia can be readily treated by low flow oxygen supplementation, but hypercapnia remains a difficult management problem. Arteriovenous carbon dioxide removal (AVCO2R) is a simple arterial venous shunt with 10-15% cardiac output through a low resistance gas exchanger to achieve near total extrapulmonary CO2 removal. AVCO2R is characterized by uncoupling of CO2 removal and oxygenation. AVCO2R allows removal of almost total CO2 production in a sheep model of ARDS,15,16 while O2 is diffused across apneic native lungs; i.e., apneic oxygenation. AVCO2R allows a reduction in airway pressure and ventilator-dependent days with improvement in survival in a prospective randomized outcome study in adult sheep with severe respiratory failure (LD50).17
An ambulatory AVCO2R system is being developed for the treatment of severe COPD, which includes long term arterial and venous access and a compact low blood resistance gas exchanger.18 Initial data demonstrate that an 8 mm ring-reinforced polytetrafluoroethylene (PTFE) tunneled AV loop (carotid artery and jugular vein) on sheep can generate up to 2 L/min blood flow, which can be adjusted downward. In collaboration with MC3 Corp, we also developed a prototype gas exchanger for ambulatory AVCO2R from our patented technology of BioLung® (Ann Arbor, MI). The hemodynamic and gas exchange performance of the BioLung® in an AVCO2R configuration has been tested in tunneled PTFE AV loop and demonstrated an ultra-low blood resistance (2.8 mm Hg/L) and sufficient CO2 removal (105 ml/min at 1 liter blood flow and 2 L/min sweep gas).
The purpose of this study is to 1) downsize the gas exchanger to allow ambulation with AVCO2R, 2) use an ultra-tight hollow fiber for gas exchange to prevent possible liquid leakage for long-term (weeks) use, and 3) evaluate the short-term performance to achieve near-total CO2 exchange.
Materials and Methods
Ambulatory AVCO2R Gas Exchanger Prototype Design
The Ambulatory-AVCO2R prototype was designed and fabricated at MC3 Inc. (Ann Arbor, MI) to be compact with minimal blood resistance. Blood enters the device by way of a 1/4" inlet connector in the center of the fiber bundle, flows radially through evenly spaced, parallel-wound fibers, and then flows out two tangentially placed, symmetric outlets which taper from 3/8" to 1/4". The outlets are brought together by a Y-connector before attachment to the graft material. The dual outlet design is used to promote uniform perfusion of the fiber bundle. The housing and components are fabricated out of medical grade acrylonitrile-butadiene-styrene (ABS) using a rapid prototyping machine (FDM 2000, Stratasys Inc., Eden Prairie, MN). The fiber bundle consists of OxyPlus 90/200 polymethylpentene fiber mat with 1.3 m2 surface area (Membrana GmbH, Wuppertal, Germany). The volumetric size of the device is 340 ml with 6 inch length, and 3.7 inch outlet to outlet width, and 2.4 inch within (Figure 1).
Prototype Performance in the Sheep Model
All animals received care according to the “Guide for the Care and Use of Laboratory Animals (1985)” prepared by the U.S. Department of Health and Human Services and published by the National Institutes of Health (NIH). The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Texas Medical Branch, Galveston, with strict adherence to the IACUC guidelines regarding humane use of animals. Our management of the sheep parallels our standards for patient care. Our team, including a faculty veterinary anesthesiologist (DJD), provides 24-hour bedside care, 7 days per week. Animal Resource Center personnel, with no conflict of interest, make daily rounds to check animal management protocol adherence.
Adult female Suffolk sheep (3–4 years old, 35–45 kg) are given ketamine (12.5 mg/kg im, ± 5 mg/kg iv titrated to effect) for initial sedation. The sheep are then intubated with a 10 mm in diameter endotracheal tube. Placement is confirmed by capnometry. Halothane 4% is administered via the anesthesia ventilator (Ohmeda 7000, BOC Health Care, Liberty Corner, NJ). Anesthesia is maintained during the surgical procedures with 1–2.5% halothane titrated to a heart rate of 75–120 beats per minute. The sheep's neck and groin are prepped and draped in the supine position. Using the Seldinger technique, a pulmonary artery/thermal dilution cardiac output catheter (Swan-Ganz, Baxter Health care Corp., Edwards Critica-Care Division, Irvine, CA) is introduced into the right external jugular vein. A sterile cut-down is performed on the right femoral artery and vein, then cannulated with 16 gauge, 60 cm catheters (Intracath, Becton-Dickinson, Sandy, UT) for hemodynamic monitoring and intravenous infusion. A tracheostomy is then performed. Anesthesia is then administered via the tracheostomy.
Five Devices Tested in Three Sheep for 6 Hours Performance
Prior to cannulation for the AVCO2R device, animals are given 150 mg/kg iv heparin bolus, and a heparin infusion is continued throughout the study to maintain activated clotting time (ACT, Hemochron 400, International Technidyne, Edison, NJ) between 180–300s. Sterile cutdown and cannulation of the left internal jugular vein (BIO-MEDICUS@ 14 Fr. Pediatric venous cannula, Medtronic Inc., Minneapolis, MN) and left carotid artery (BIO-MEDICUS@ 12 Fr. Pediatric Arterial cannula, Medtronic Inc., Minneapolis, MN) are then performed. The ambulatory AVCO2R devices (n = 5) are then primed with 270 ml of normal saline, de-aired, and connected to the vascular cannulae. Once the devices are secured to the sheep, halothane is discontinued. The animals are transported to the ICU for recovery and connected to a volume controlled ventilator (Servo 900C; Siemens-Elema, Sweden). With the AVCO2R devices in place, the sheep now have two systems to perform gas exchange-the native lung and the AVCO2R device. During the test, sheep spontaneous respirations were suppressed by a bolus intravenous pentobarbital (180–200 mg/kg) and controlled ventilation was adjusted to 4 breaths per minute (bpm) respiratory rate and tidal volume of 2–8 ml/kg to keep PaCO2 at constant level of 40–50 mm Hg. To maintain adequate PaO2 levels (>80 mm Hg), the fraction of inspired oxygen percentage (FiO2) was sequentially titrated between 0.4 and 1.0 as needed and PEEP was maintained between 5–10 mm Hg. Between the tests, the sheep are allowed to be recovered to spontaneous breath and free access to food and water from sedation. The sweep gas was turned down to 0.5 L/m to avoid excess CO2 removal.
CO2 removal and hemodynamics were evaluated every 3 hours for 6 hours. Device inflow and outflow blood gases and exhaust sweep gas CO2 concentration were analyzed by Synthesis 15 blood gas analysis system (Instrumentation Laboratory, Lexington, MA). CO2 removal was calculated as the product of sweep gas flow (Qg, 100% O2) and exhaust sweep gas CO2 concentration. Qg (sweep Gas flow) was controlled by an inline flow regulator. Blood flow was measured by a real-time flow meter (HT109, Transonic Systems, Ithaca, NY), and adjusted by a C clamp on inlet blood tubing. CO2 removal depends on sweep gas flow, blood flow, and CO2 level in arterial blood. To study the relationship of CO2 removal (dependent variable) with three independent variables (sweep gas flow rate, blood flow, and PaCO2) individually, two of three independent variables were set at a fixed level and correspondent CO2 removal was calculated at different levels of third variable: the correspondent CO2 removal at 1, 2, 5, 10, and 15 L/min of sweep gas with fixed PaCO2(40–50 mmH) and blood flow (1000 mL/min); at 500, 750, 1000, and 1250 mL/min of blood flow with fixed sweep gas flow (5 L/min) and PaCO2 (40–50 mm Hg). For the relationship of CO2 removal and PaCO2, correspondent CO2 removal at different levels of PaCO2 from 25 to 90 mm Hg was studied by linear regression at 1000 mL/min of blood flow and 5L/min sweep gas.
Systemic hemodynamic parameters were continuously monitored by HP 78534B Monitor. All data were recorded every 3 hours. The gas exchanger was monitored for foaming or deterioration of gas exchange.
All data were expressed as mean ± standard deviation. One-way ANOVA (Analysis of variance) was applied for the statistical test of significant difference of CO2 removal at different time points, at different sweep gas flows, and with different blood gases. The difference was regarded as statistically significant when p value was < 0.05, and markedly significant when p was < 0.01 (Student-Newman-Keuls Test). The relationships of sweep gas flow and CO2 removal, blood flow and CO2 removal, arterial blood CO2 tension and CO2 removal were studied in detail; the regression relationship is regarded significant as p < 0.05).
Sheep hemodynamic parameters (mean arterial pressure, mean pulmonary artery pressure, and central venous pressure, and cardiac output) remained within normal limits and unchanged throughout the 6-hour study period.
The gas exchanger device blood resistance was 2.37 ± 0.53 mm Hg/L/min and did not change significantly during the 6-hour study (2.40 ± 0.57at 3rd hour and 2.25 ± 0.46, p = 0.694, Kruskal-Wallis One Way ANOVA on Ranks, Figure 2). With controlled PaCO2 40–50 mm Hg and sweep gas 10 L/min, CO2 removal was 106.40 ± 15.60 and remained unchanged through 3rd hour and 6th hour (95.60 ± 14.62 and 92.20 ± 11.41, p = 0.283, One Way ANOVA, Figure 3).
The Relationship of CO2 Removal and Sweep Gas Flow
At a fixed blood flow, CO2 removal varied directly but not linearly with the sweep gas flow (Figure 1). At the beginning of the experiment, with 1 liter/min blood flow and 40–50 mm Hg PaCO2, 1 L/min sweep gas gave CO2 removal of 47.44 ± 9.93 ml/min, 5 liter/min sweep gave 100.00 ± 20.19 ml/min, and 15 l/min sweep gave 116.70 ± 14.44 ml/min. These values remained constant throughout the 6-hour study (Figure 4).
The Relationship of CO2 Removal and Device Blood Flow
With a fixed sweep gas of 2 L/min and PaCO2 range of 40–50 mm Hg, increasing blood flow through the device from 0.5 L/min to 1.25 L/min increased CO2 removal from 62 ml/min to 88 ml/min (Figure 5).
The Relationship of PaCO2 and CO2 Removal
With fixed sweep gas flow (5 L/min) and blood flow (1 L/min), CO2 removal was directly proportional to PaCO2. Their regression relationship is linear with excellent correlation in Figure 6 expressed as:
There was no device thrombosis, bleeding, or other complication during the course of the study.
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