In the United States, approximately 127,000 people die annually from chronic respiratory diseases.1 The only long-term cure is lung transplantation. However, donor lung shortages only allow approximately 1,800 transplantations annually.2 Extracorporeal membrane oxygenation (ECMO) can be used as a bridge to lung transplantation in a variety of patients and configurations ranging from cystic fibrosis patients with venovenous ECMO to pulmonary hypertension (PH) patients with venoarterial ECMO.3–6 However, ECMO offers limited patient ambulation4,5,7,8 and biocompatibility issues lead to patient deterioration over time.6,9,10 Blood damage and activation that necessitate blood product transfusions and greater anticoagulation greatly affect biocompatibility.6,9,10 Thus, a long-term treatment that would circumvent these shortcomings is needed as a bridge to transplantation and destination therapy.
Thoracic artificial lungs (TALs) may be suitable as a bridge to transplantation or destination therapy for patients with chronic lung disease. Thoracic artificial lungs consist of a low resistance gas exchanger attached in a pulmonary artery to left atrium (PA-LA) or pulmonary artery to pulmonary artery configuration. Flow through the TAL is driven by the right ventricle, avoiding the large ECMO circuit and pump that can damage and activate formed elements in blood.11–13 Although TAL systems have the potential to increase system biocompatibility and lower PA pressures of some patients, their attachment requires invasive surgical procedures. Thus, TAL’s are better suited towards long-term treatment of chronic respiratory disease rather than acute conditions, such as acute respiratory distress syndrome. A commercial gas exchanger designed originally for use in arteriovenous carbon dioxide removal, the Novalung iLA, has been used as a TAL in a small number of patients. However, as the Novalung iLA was not designed for this purpose, its relatively high resistance, low gas exchange capabilities, and relatively short device lifespan limited its use as a TAL. The MC3 Biolung, with its low 1.8 mmHg/(L/min) resistance,14 was designed specifically as a TAL and has been tested in sheep in 7 day and 30 day experiments.15,16 Without employing antithrombogenic coatings, the MC3 Biolung was able to support sheep for a period of 30 days.16 However, in 30 day studies, Biolung replacement was performed every 9.5 days on average because of thrombus formation.16 The Biolung has not been used clinically as a TAL.
The compliant thoracic artificial lung (cTAL) uses a flexible Biospan polyurethane (DSM, Berkeley, CA) housing with 45° inlet and outlet sections (Figure 1) and a 2.4 m2 surface area, polypropylene fiber bundle.17 This design maximizes spatial and temporal blood flow uniformity in an effort to reduce blood flow resistance, improves gas exchange efficiency, and limits device thrombosis.17 The cTAL’s rated flow exceeds 7 L/min, and its 0.5 mmHg/(L/min) resistance17,18 was able to unload the right ventricle in an animal model of PH using a PA-LA attachment.18 The present 14 day study examines whether the cTAL can maintain the gas exchange and resistance characteristics demonstrated during acute in vitro and in vivo studies while maintaining normal animal physiology.
Materials and Methods
The cTAL was attached to five sheep weighing 60–65 kg. All received humane care in compliance with the Guide for the Care and Use of Laboratory Animals and the Principles of Laboratory Animal Care. Sheep were administered transdermal fentanyl (100 µg/hour) 24 hours presurgery, and anesthesia was induced with propofol (400–600 mg IV). Left thoracotomy, instrumentation, graft attachment, and closure proceeded according to previous methods.18,19 Blood inflow and outflow graft-conduits with a combined prime volume of 116 ml were fabricated by bonding vascular grafts (Maquet Getinge, Wayne, NJ, or Terumo Cardiovascular, Ann Arbor, MI) to polyvinyl chloride tubing using previous methods.20 These were attached to the PA and LA for cTAL connection. Initially, graft patency was maintained by connecting the inlet and outlet grafts with 5/8” tubing and limiting blood flow to 1 L/min using a Hoffman clamp. To protect the cTAL during recovery, it was attached 6–40 hours postsurgery. Nafcillin (1,000 mg IV), gentamicin (120 mg IV), heparin (77–123 units/kg IV), buprenorphine (0.6 mg IM), and flunixin (60 mg IV) were administered. Continuous heparin was supplied to the distal end of the inlet conduit to maintain a targeted systemic activated clotting time (ACT) of 200–280 seconds as measured with glass particle activated P214 Hemochron reagent tubes (Accriva Diagnostics, San Diego, CA). Sheep were recovered according to previous methods.16
The cTAL was placed into a protective holder that eliminated shunt flows around the fiber bundle. The first holder version, used in sheep 1, clamped the fiber bundle sides with high pressure. The second version, used in all subsequent sheep, held the cTAL with minimal pressure. The cTAL was primed with 1.3 L lactated Ringers solution, 50 ml albumin (25% solution), 92 units/kg heparin, and 500 mg methylprednisolone. Heparin (77–123 units/kg) and methylprednisolone (500 mg) were also administered intravenously. The shunt was then replaced with the cTAL. A 5 L/min oxygen (O2) sweep gas was supplied to the cTAL gas inlet to allow for adequate oxygen exchange and clearing of condensation and plasma from the gas exchange fiber lumen. Attaching a vacuum to the gas outlet and maintaining a gas inlet pressure between negative 15 and 30 mmHg prevented air embolus. Lastly, blood flow was initiated through the device. Because of excessive carbon dioxide (CO2) transfer, CO2 (6.9 ± 0.3%) was blended into the sweep gas to maintain normal arterial partial pressure of carbon dioxide in the blood (pCO2) and respiratory rate.
The sheep were awake, and analgesia was accomplished through buprenorphine (0.6 mg IM) every 4–6 hours and flunixin (60 mg IV) every 12 hours or toradol (60 mg IM) every 6 hours, with adjustment as needed. Sheep were administered nafcillin (500 mg IV) every 6 hours and gentamicin (120 mg IV) every 8 hours for 3 days and then as needed. To reduce the effects of pulmonary edema and hemodilution, furosemide (40 mg IV) was administered every 12 hours until days 7 and 9 for sheep 4 and 5, respectively. Heparin administration continued as before attachment. Sheep 4 was transfused on day 6 to correct low hemoglobin, but transfusion lysis occurred over the following days because of an unmatched blood type.
If fever was observed, bacterial cultures were performed. After 14 days, animals were euthanized using sodium pentobarbital (16 ml IV) and necropsied. The PA, LA, and inlet and outlet grafts were inspected for thrombus formation. The heart, kidneys, and liver were inspected for signs of gross infarct. The lungs were inspected for atelectasis and edema.
Data Collection and Analysis
Blood gas analysis and ACTs were taken every 1–6 hours. Aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine, white blood cell counts (WBC), and platelet counts (Plt) were measured approximately every other day postsurgery. The WBC and Plt were corrected for hemodilution using standard methods.21 Mean arterial pressure (MAP) was recorded hourly from pressure transducers coupled with a patient monitor (Solar 8000, Marquette Electronics, Milwaukee, WI). Compliant thoracic artificial lung blood inlet and outlet pressures were measured with pressure transducers (ICU Medical, San Clemente, CA) coupled with a data acquisition system (Biopac Systems, Goleta, CA), and cTAL flow rate was measured via an ultrasonic flow meter and probe (TS410 with 14PXL, Transonic, Ithaca, NY). The cTAL blood flow resistance and oxygen transfer rate (VO2) were calculated once and twice daily using standard methods, respectively.22
Data represented as predevice were averaged over 6 hours predevice attachment, and data represented as baseline were averaged over 6 hours postattachment. All other data were averaged over 24 hour periods postattachment. The exception to this is the veterinary labs (AST, ALT, BUN, creatinine, WBC, and Plt). These baseline samples were measured at animal intake and averaged over 3 day periods postattachment. Sheep 2 had no intake labs. Statistical comparisons were performed with SPSS (IBM, Armonk, NY) using a mixed model with the sheep number as the subject variable and time as the fixed, repeated measure variable.16 Post hoc analysis using a Bonferroni-corrected confidence interval was employed to compare variables to baseline data to examine changes with time.16
Three of the five sheep survived the entire experiment, and no device exchanges were performed. Sheep 2 was euthanized on day 6 because of a bradycardic arrhythmia that was evident before device attachment but worsened thereafter. Sheep 5 was euthanized on day 11 after a blood conduit connection fractured.
Physiology was largely normal and unchanged throughout the experiment. The daily average partial pressure of oxygen in the blood (PO2), PCO2, and MAP can be seen in Figure 2. The MAP was 84 ± 12.8 mmHg predevice and averaged 103 ± 0.8 mmHg thereafter, with no statistically significant comparisons to baseline (p = 0.24). Arterial PCO2 was 33 ± 1.0 mmHg predevice averaged 40 ± 0.4 mmHg thereafter and was only statistically greater than baseline on day 6 (p < 0.05). Predevice PO2 was significantly lower than baseline (65 ± 4 mmHg versus 138 ± 13 mmHg; p < 10–8), but PO2 did not vary significantly thereafter (average = 130 ± 1.1 mmHg; p = 0.99).
Normalized WBC and normalized Plt are summarized in Table 1. Neither normalized WBC nor normalized Plt (p = 0.27 and p = 0.75, respectively) varied significantly from baseline. Hemoglobin was 10.3 ± 0.4 g/dl predevice, dropped to 8.9 ± 0.6 g/dl at baseline after device attachment, and was stable thereafter (average = 9.0 ± 0.1 g/dl). The hemoglobin drop from predevice attachment to baseline was the only statistically significant comparison (p < 0.01). The ACT was 211 ± 7.3 seconds predevice, 310 ± 71 seconds at baseline, averaged 238 ± 2.1 seconds thereafter, and did not vary significantly with time (p = 0.99). Bacterial cultures were analyzed from sheep 3, 4, and 5, and all were negative.
The cTAL flowrate, resistance, cTAL inlet oxyhemoglobin saturation (SO2), cTAL outlet SO2, and VO2 did not vary significantly from baseline (p = 0.68, p = 0.99, p = 0.51, p = 0.07, and p = 0.27, respectively). Blood flow through the cTAL was 3.46 ± 0.15 L/min at baseline and averaged 3.18 ± 0.05 L/min thereafter (Figure 3). CTAL resistance was 0.99 ± 0.07 mmHg/L/min at baseline and averaged 1.04 ± 0.05 mmHg/L/min thereafter (Figure 3). In sheep 3, resistance increased over days 12–14, despite minimal visual thrombus formation in this device (Figure 4) and no drop in device blood flowrate. Blood flow averaged 3.48 L/min for days 1–11 and 3.40 L/min for days 12–14. This suggests a faulty pressure drop reading because of the thrombus formation in the transducer stopcock or a failure of the transducer itself. Compliant thoracic artificial lung VO2 was 206 ± 27 ml/min at baseline and averaged 180 ± 8 ml/min thereafter (Figure 5). Compliant thoracic artificial lung inlet SO2 and outlet SO2 were 57.8 ± 6.1% and 98.6 ± 0.9% at baseline and averaged 52.7 ± 1.0% and 96.0 ± 0.7% thereafter, respectively (Figure 5). At approximately day 7, plasma leakage was observed in the gas outlet of most cTALs. After the onset of plasma leakage, cTAL inlet and outlet SO2 trended downwards. Periodic gas flow rate increases were used to clear bulk plasma from the fiber lumen.
Explanted devices from 14 day survivors had varying amounts of thrombus formation depending on which device holder was employed (Figure 4). Sheep 1’s cTAL employed the first-generation holder and had thrombus formation where the fiber bundle was clamped. The remaining devices employed the second-generation holder and had minimal thrombus formation. The bundles were largely clear of thrombus formation from the inlet to the outlet, with a small section of thrombus at device corners and thrombus formation on the side of the bundle stemming from a section of tape used during cTAL fabrication (Figure 4, bottom).
Neither BUN, creatinine, ALT, nor AST varied significantly from baseline (Table 1). Liver enzymes increased immediately postsurgery but fell thereafter and stayed within normal ranges. At day 13–14, there was a nonsignificant increase in the AST.
Necropsy organ inspections were unremarkable with the exception of the lungs. The lungs typically exhibited edema throughout and atelectasis in the upper lobes and the areas around the chest tubes and blood conduits. There were visual signs of infection around the blood conduits of sheep 4 because of inadequate tissue in-growth and chest wall sealing.
These studies were performed to determine whether the uncoated cTAL could maintain the gas exchange and resistance characteristics demonstrated during short-term in vitro and in vivo studies while maintaining normal animal physiology for 14 days.18,19 Overall, the cTAL demonstrated its capability to be used for at least 2 weeks without anticoagulant coatings and likely longer with more sophisticated biomaterials approaches. The device maintained a low, constant resistance. Plasma leakage through the gas exchange fiber resulted in some decrease in cTAL outlet SO2. Animal physiology was, in general, normal with initial changes because of surgical effects and a trend back towards normal values thereafter, with the exception of elevated AST levels in one sheep, increasing WBC, and pulmonary edema and atelectasis at necropsy.
Despite the lack of anticoagulant coatings, there was no significant resistance increase over 14 days. There was a consistent resistance spike after 1 day, but the resistance returned to baseline thereafter. This likely reflects some initial, transient protein or cellular binding that then resolves. Gross visual thrombus formation was minimal in all cTALs except the single device that was clamped excessively by its holder. Clamping led to stasis regions and clot formation on the sides of this fiber bundle. There was some thrombus formation stemming from a piece of tape that will be eliminated when manufacturing future cTALs. Overall, the cTAL proved more biocompatible than similar devices. The uncoated MC3 Biolung had a tripling of resistance over an average of 9.5 days during 30 day studies.16 A more comparable Biolung study, where devices were not replaced, demonstrated a more than sixfold resistance increase by day 7.15 The anticoagulant coated iLA membrane ventilator in a PA-LA configuration lasts 14–21 days before replacement is required.23–26 The uncoated cTAL would have functioned beyond 14 days, and the application of anticoagulant coatings could potentially extend its lifespan beyond a month.
Previous in vitro and acute in vivo experiments demonstrated a 0.5 mmHg/(L/min) cTAL resistance.17–19 However, the baseline resistance in this study was 1 mmHg/(L/min). In previous studies, the device was positioned ideally, sitting flat on the animal. In these long-term studies, the device was placed on its side at the animal’s flank. This can cause lower pressure and housing collapse in the superior regions of the device and may limit blood flow through these regions, raising resistance. Despite this, the cTAL’s resistance was lower than healthy lungs and the next least resistive devices (iLA membrane ventilator, 6 mmHg/[L/min]; MC3 Biolung, 1.8 mmHg/[L/min]).14,27,28
Compliant thoracic artificial lung VO2 was maintained throughout the experiment, but cTAL outlet SO2 decreased after the onset of plasma leakage through the gas exchange fiber. When gas exchange performance degraded, bulk plasma was cleared from the fiber lumen by temporarily doubling the sweep gas flowrate. Plasma leakage susceptible polypropylene fibers were used in the cTAL because nonporous polymethylpentene fibers are not commercially available with an outer diameter under 380 microns, and it was believed that plasma leakage did not occur in sheep. For clinical prototypes, small outer diameter polydimethylsiloxane-coated (1–2 µm coating thickness) polypropylene fibers will be necessary to prevent plasma and air leakage while maintaining sufficient gas exchange surface area.29–31
Physiology was largely normal during the experiment. The MAP and arterial blood gasses normalized after device attachment. The kidneys functioned normally. Liver enzyme levels showed some dysfunction postsurgery, but they trended back towards normal levels throughout the experiment. One exception was a nonsignificant increase in the AST on the last 2 day period. This was largely the effect of early euthanasia of sheep with lower AST and a single animal AST increase. Necropsy organ inspections revealed no derangements besides atelectasis and edema throughout the lungs. Common after lung surgery, pulmonary edema resulted from single-lung ventilation of the right lung and direct manipulation and inflammation of the packed away left lung. Atelectasis resulted from a low respiratory drive. Another factor that likely contributed to these findings was some level of patient discomfort after surgery. Local anesthetics and opioid analgesia are used, but sheep likely experience some thoracic discomfort postoperatively when taking deep breaths. Thus, their breathing is fairly shallow, and we cannot encourage them to breathe deeply as we would with a patient using an incentive spirometer. Adding CO2 into the sweep gas can aid in promoting deeper breathing. However, because respiratory rate can also increase to aid in removing the excess CO2, this method is imperfect and does not fully solve the issue.
There were hemodilatory effects of device attachment because of the large system prime volume of 1,416 ml, (1,300 ml cTAL, 116 ml grafts), but hematologic parameters remained consistent or rebounded the longer the cTAL was attached. Hemodilution was offset by the cTAL’s minimal blood product consumption, evidenced from the stable hemoglobin and rising Plt throughout the experiment. In clinical use, patients treated with the cTAL may need an initial transfusion after device attachment but should not need further transfusions. This contrasts to ECMO, where reported blood product median daily transfusions can range from 0.16 to 2 units/day for red blood cells and from 0 to 3 units/day for platelets.3,10,27,32 These transfusion requirements can be particularly high for patients with PH or other conditions that necessitate venoarterial ECMO.6 However, for a true comparison of hemolysis and blood product needs, the cTAL would have to be tested versus a commercial ECMO circuit in an identical animal model. It is expected that in the ECMO case, the high resistance ECMO circuit would result in high shear stresses in the ECMO pump and, in turn, blood damage and activation would occur.11–13 The cTAL prime volume and resulting hemodilution can be reduced by shrinking the size of the device or compressing its housing during priming. When the cTAL is primed, its flexible housing expands well beyond its postattachment volume. Once the device is attached, housing relaxes down to conform to the blood pressure in the device, resulting in excess prime and a fluid bolus to the patient. In future testing and clinical use, the housing could be compressed to its postattachment volume during priming to prevent excessive prime volume from being delivered to the patient.
The ultimate goal for the cTAL will be its use as a long-term bridge to lung transplantation and destination therapy. To progress towards this goal, the cTAL will be reduced in prime volume, use a solid walled fiber to reduce plasma leakage and air embolism risk, and anticoagulant coatings will be applied to all device surfaces. The cTAL’s superior fluid dynamic design coupled with these coatings may allow the cTAL to be used for months without replacement and longer with replacement. The lack of blood damage and need for continuing blood transfusions further indicates the cTAL’s potential long-term use.
The long-term efficacy experiments of the uncoated cTAL demonstrated the device’s ability to support a patient for 2 weeks without major thrombus formation and subsequent device failure. The cTAL’s gas exchange performance was reduced after the onset of plasma leakage. During cTAL support, there were no major physiological derangements, and the device had minimal blood product consumption. Even without anticoagulant coatings, the cTAL could have functioned beyond the current 14 day experimental time. The 60 day studies of the improved cTAL with anticoagulant coatings and plasma resistant gas exchange fiber will be performed to demonstrate its use as a long-term therapy.
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