End-stage lung disease (ESLD), caused by chronic obstructive pulmonary disease (COPD), is a major public health problem and is the third most common cause of death in the United States.1 The pathophysiology of COPD is a very large alveolar dead space caused by the primary disease leading to CO2 retention, hyperventilation, and ultimately exhaustion from severe dyspnea and tachypnea. Lung transplantation remains the definitive treatment; however, demand for transplantable organs far outweighs availability: in 2010, COPD accounted for more than 130,000 deaths in the United States, whereas less than 2,000 lung transplants were performed. Because of organ scarcity, median wait time for a transplant is 4 months, and 15.4% of patients die while awaiting transplant.2 Many other patients suffering from COPD may not be eligible for transplantation because of comorbidities or poor functional status.
Extracorporeal support (ECS) for CO2 removal was first proposed by Kolobow et al. 3 and is currently utilized as a bridge to transplantation and for relief of exacerbations of respiratory failure. Our laboratory is developing implantable artificial lungs meant for destination therapy in transplant ineligible patients with severe lung disease. The goal of destination therapy for COPD is palliation. Extracorporeal CO2 removal should decrease patients’ ventilatory drive alleviate tachypnea both at rest and with exercise. The challenges in developing a permanent implantable lung for COPD are device design and efficiency, anticoagulation, management with an air pump as opposed to oxygen, easy access (paracorporeal) for device evaluation and potential change out, infection, and vascular access.4,5 This study was designed to evaluate the subclavian vessels as a vascular access for a permanent artificial lung for CO2 removal in a large ovine model.
Normal O2 and CO2 exchange in awake, standing sheep is 4–5 ml/kg/min and 250–300 ml/min, respectively. Thus, the theoretical blood flow required to remove sufficient CO2 for palliative care is 1.0 L/min. These long-term use devices should allow ambulation, easy access to evaluate function and changes, minimal risk of systemic embolism, low resistance, and minimal anticoagulation therapy. Because artificial lungs for COPD must be developed in large animal models, we evaluated subclavian arteriovenous (AV) access in adult sheep.
All animals received proper care following the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals. This study was approved by the University Committee on Use and Care of Animals (UCUCA) at the University of Michigan, Ann Arbor, MI.
Sedation and Anesthesia
Four healthy sheep (61.3 ± 6.2 kg) were anesthetized following our laboratory protocols and maintained with 1–3% inhaled isoflurane throughout the procedure.6
Two 6-mm ringed expanded polyester gelatin polypropylene vascular grafts (Terumo/Vaskutek Gelsoft, Ann Arbor, MI) were anastomosed in end-to-side fashion to the subclavian vessels, then cannulated with 17Fr Novalung cannulae (GmbH, Hechingen, Germany), which were linked by ⅜ in. tubing (Tygon, Akron, OH) to create an AV shunt. Cannulae were secured and tunneled subcutaneously to exit the animal’s upper back. A Swan–Ganz catheter (Edwards Lifesciences, Munich, Germany) was also placed in the right internal jugular vein using Seldinger technique. After surgery, sheep were recovered, extubated, and transferred to our animal intensive care unit for extended monitoring. Once stabilized, the AV shunt tubing was clamped and cut to length, and a low-resistance membrane oxygenator (Novalung GmbH, Hechingen, Germany) was primed and attached to the AV shunt according to the manufacturer specifications.
Heparin infusion was titrated to maintain activated clotting time (ACT) between 250 and 300 seconds. The animals were followed for the next 2 days, evaluating cardiac function, membrane lung function, ambulation, ease of access, CO2 removal over a range of sweep flows, respiratory rate, and PaCO2 under ambient conditions. On the second day, the animals were anesthetized paralyzed and ventilated. Hypercarbia was induced by decreasing minute ventilation from 120 to 27 ml/kg/min, and gas exchange was measured. The membrane lung was ventilated with air over a wide range of sweep flows.
Blood gases were taken pre- and postdevice and analyzed using a blood gas analyzer (ABL 800 Flex, Radiometer, Westlake, OH). Flow through the AV shunt was measured using a ⅜in. tubing flow probe and a TS420 console (Transonic Systems Inc, Ithaca, NY).
Device CO2 removal was calculated as follows:
Device resistance was calculated as follows:
All four animals completed the study protocol, with no operative, technical or infectious complications in these short experiments. None of the animals exhibited any sign of upper extremity swelling or functional impairment, and the animals were able to ambulate (video available on request). The AV shunt did not negatively affect systemic hemodynamics during the experiment. Flow through the AV shunt and membrane lung averaged 21.9 ± 8.1 ml/kg/min (1.34 ± 0.14 L/min) throughout the experiments, which represents 14% of the cardiac output. Device resistance throughout the study was 3.6 ± 1.1 mm Hg/min/L.
The CO2 clearance with a range of sweep flow to blood flow ratios is shown in Figure 1. In the awake, standing sheep, high levels of sweep flow resulted in 180 ml/min CO2 clearance and a change in spontaneous respiratory rate from 60 ± 25 to 30 ± 11 breaths per minute. At the end of the 2 day experiment the sheep were anesthetized and hypoventilated to create hypercarbia in the range of PaCO2 73.9 ± 15.1 mm Hg after minute ventilation was gradually decreased as previously described. As sweep gas flow was increased, CO2 removal increased to a maximum of 3.4 ± 0.4 ml/kg/min at 15 L/min of sweep gas flow. At this rate of flow, PaCO2 decreased to 49.1 ± 6.7 mm Hg (Figure 2).
Upon necropsy, both grafts in all animals were secure, and all anastomoses were revealed to be patent and intact.
Extracorporeal gas exchange, particularly, CO2 removal is effective in the management of CO2 retention in end-stage COPD.7 Both animal and clinical trials have focused on short-term normalization of blood gases using venovenous access with a pump or using pulmonary artery (PA) to left atrium (LA) direct vascular access.6,8–14 Pulmonary artery/left atrium access allows perfusion of the device by the right ventricle and can provide full oxygenation as well as CO2 removal. However, it requires thoracotomy for placement and runs the risk of systemic embolism because of blood return to the LA. Arteriovenous access for CO2 removal has been evaluated with many laboratory and clinical trials and is a very effective way of achieving CO2 removal at relatively low blood flow.
Initial clinical trials were conducted with femoral artery and vein access, but the risk of femoral artery injury or exsanguination and the limitation of ambulation have resulted in the use of pumped venovenous access for selective CO2 removal in modern practice.15 Limited potential for ambulation prevents patients from participiating in rehabilitive therapies, which in recent years have been shown to be highly beneficial for extracorporeal life support.14
Peripheral vessels represent a more attractive access option for ambulatory and long-term therapy. Axillary and subclavian vessel cannulation for extracorporeal oxygenation has been demonstrated, via both direct cannulation and end-to-side “chimney graft.”13,16–20
A permanent implantable artificial lung designed for COPD palliation requires moderate blood flow and a device capable of achieving a CO2 content inlet/outlet difference of 10–15 ml/dl. (We define an implantable device as a device dependent on permanent vascular access, as opposed to an intravascular removable cannula.) These studies show that subclavian AV access is feasible and results in blood flow, which would allow high levels of CO2 removal, and that efficient CO2 removal can be accomplished in an awake animal using a commercial membrane lung.
We identified the following limittions in our study: (1) the use of a relatively low sample size. It became clear that results were reproducible, and feasibility had been demonstrated with these four animals. However, a larger sample size might uncover potential technical complications after graft or device attachment; (2) Anticoagualtion regimen, high ACT goals were targeted in this study given the increased thrombogenicity of sheep relative to humans. Although we did not observe any hematoma formation, a low incidence is to be expected. In human subjects, we would target lower ACTs, and postoperatively transition to oral antiplatelets and anticoagulants would be similar to the one given to patients with ventricular assist devices; (3) the need for mechanical ventilation show a reduction in PaCO2. Healthy animals drastically lowered respiratory rate in response to CO2 removal, thus preventing profound hypocapnea. Our goal with ambulatory CO2 removal is to provide a long-term solution to chronic lung disease, and therefore, it would be more applicable to evaluate CO2 removal in a chronic disease model.
Further studies will evaluate the development of an animal model of end-stage COPD, development of an anticoagulation protocol, development of a membrane lung specifically designed for this purpose, and chronic subclavian access.
Subclavian AV access results in flow of 10–20% of the cardiac output, which has no deleterious effects on the heart in normal animals but allows perfusion of a membrane lung sufficient to remove large amounts of CO2. In both normal and hypercarbic conditions, CO2 removal via subclavian AV access is sufficient to remove enough CO2 to decrease the resting respiratory rate by 50% under ambient conditions in adult healthy sheep. Finally, subclavian AV access is a reasonable starting point for further studies on development of a permanent implantable artificial lung for end-stage COPD.
Authors thank Terumo Cardiovascular Group forcontribution of graft material to our animal experiment, The University of Michigan Undergraduate Research Opportunity Program (UROP), the Cardiovascular Center Summer Undergraduate Research Fellowship, and the Esperance Family Foundation for supporting our visiting undergraduate summer student Alejandra Macias who helped with postoperative care of some animals. Finally, the authors acknowledge the efforts of Cindy Cooke for review and preparation of the manuscript.
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Keywords:Copyright © 2016 by the American Society for Artificial Internal Organs
ovine model; extracorporeal support; CO2 removal; pumpless; subclavian access