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Ann Thorac Surg 2007;84:1136-1143
© 2007 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Thirty-Day In-Parallel Artificial Lung Testing in Sheep

Hitoshi Sato, MD, Candice M. Hall, BS, LVT, Nathan G. Lafayette, BS, Joshua R. Pohlmann, BS, Niru Padiyar, MD, John M. Toomasian, MS, Jonathan W. Haft, MD, Keith E. Cook, PhD*

Department of Surgery, University of Michigan, Ann Arbor, Michigan

Accepted for publication May 18, 2007.

* Address correspondence to Dr Cook, 7679 Kresge I, 200 Zina Pitcher Pl, Ann Arbor, MI 48109 (Email: keicook{at}umich.edu).

Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
Background: Thirty-day testing of the MC3 Biolung (MC3 Inc, Ann Arbor, MI) total artificial lung (TAL) was performed to prepare for future clinical testing.

Methods: TAL inlet and outlet grafts were sewn to the pulmonary artery and left atrium of 8 sheep (35.6 ± 1.6 kg), and the TAL was attached the next day. Hemodynamic and sheep blood gas data were measured every 1 to 4 hours. TAL blood gases were measured twice daily, and organ function was assessed three times per week. The TAL was replaced if its resistance increased 300% or if the oxygen content difference across the TAL decreased 25% versus baseline. After 30 days, the sheep were euthanized and necropsied.

Results: Five sheep survived 30 days. Three sheep were euthanized before 30 days due to bleeding, mechanical graft failure, or gastric distress. Survivors had normal, stable hemodynamics and blood gases. Average device use was 9.5 ± 2.1 days. TAL oxygen transfer was 108 ± 9.2 mL/min with 51% ± 6.3% of cardiac output flowing to the TAL. TAL resistance and flow were 1.3 ± 0.3 mm Hg · min/L and 2.4 ± 0.2 L/min at baseline versus 2.6 ± 0.9 mm Hg · min/L and 2.0 ± 0.2 L/min for the remaining 30 days. Platelet and white blood cell counts increased 88% and 84% from baseline, respectively, after 10 days and were stable thereafter. Ischemic lesions in the kidney were seen in most sheep at necropsy, but organ function was normal.

Conclusions: Thirty-day respiratory support was feasible with the Biolung, but improvements in biocompatibility and anticoagulation regimen are warranted to reduce the thrombogenicity of the device.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
The purpose of a total artificial lung (TAL) is to act as a bridge to lung transplantation or, with further development, as a treatment for acute respiratory insufficiency that is unresponsive to mechanical ventilation. By assuming most of the respiratory requirements, the TAL can support the patient until transplant or allow the natural lungs to heal. The device would be attached to the pulmonary circulation with blood flow provided by the right ventricle. Initial use of these devices will be paracorporeal. The TAL will not require a pump or large extracorporeal circuit as with extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass (CPB). Thus, the TAL should have better biocompatibility, allowing for longer use with a lower complication rate. The compact nature of the device should allow for ambulation by lung transplant candidates.

Previous studies using the MC3 Biolung (MC3 Inc, Ann Arbor, MI) in an in-parallel, pulmonary artery (PA)–to–left atrial (LA) configuration indicated that 1 week of respiratory support was feasible. Sheep hemodynamics, device gas exchange, and organ function were stable over the course of the experiment, but device thrombus formation, elevated white blood cell counts, and kidney infarcts were noted. The purpose of this study was to extend the previous study to 30 days to prepare for clinical trials, with particular emphasis on the issues of device thrombogenicity, infection, and organ function.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Total Artificial Lung
This study used the Biolung without an inlet compliance chamber as the TAL [1]. The PA-to-LA attachment mode creates a pulmonary system with a lower impedance than the normal pulmonary circulation, allowing for normal right ventricular (RV) function without an inlet compliance chamber [2]. The device has a 1.7 m2 surface area fiber bundle using 380-µm outer diameter polymethyl pentene (PMP) Oxyplus fibers (Membrana Gmbh, Wuppertal, Germany) and a solid polyurethane housing with a priming volume of 300 mL. The blood flow resistance of the TAL is approximately 1.8 mm Hg · min/L [3]. Custom blood inflow and outflow conduits consisted of approximately 6 inches of .625-inch internal diameter Tygon tubing (Saint-Gobain Performance Plastic, Wayne, NJ) that is bonded to 18-mm vascular grafts (Boston Scientific, Natick, MA).

Surgical Procedure
The sheep used in this study received humane care in compliance with the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health publication No. 85-23, National Academy Press, Washington DC, revised 1996), and all methods were approved by the University of Michigan Committee for the Use and Care of Animals.

The Biolung was implanted in 8 sheep (average weight, 35.6 ± 1.6 kg). The sheep were given 75 µg/h transdermal fentanyl (Janssen Pharmaceutica Products, Titusville, NJ) 12 hours before the procedure, and surgical anesthesia was induced with 12 mg/kg intravenous (IV) sodium thiopental (Abbott Laboratories, North Chicago, IL).

Perioperative care, instrumentation, and graft attachment proceeded according to previously published methods from our 7-day studies [4]. Before thoracotomy, baseline blood samples were taken to assess white blood cell and platelet counts, plasma free hemoglobin, and a blood chemistry panel, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), blood urea nitrogen (BUN), and creatinine.

A left thoracotomy was performed, and a baseline lung biopsy was performed for comparison with tissue after TAL use. Penicillin (500 mg, IV), heparin (100 U/kg, IV), and ketorolac (60 mg, IV) were administered. The outlet and inlet graft conduits were attached to the LA and PA, respectively, by end-to-side anastomoses and then tunneled through the fifth intercostal space. A flow probe (Transonic 24AX, Ithaca, NY) was placed around the main trunk of the PA, distal to the conduit, and its cable was tunneled to the sheep’s back. Unlike the previous 7-day study [4], a 0.625-inch PVC tubing shunt was placed between the inlet and outlet conduits. Blood flow through the shunt was limited to approximately 20% of cardiac output by using a Hoffman clamp.

A heparin drip was supplied to the distal end of the inlet conduit once the activated clotting time (ACT) fell below 240 seconds, and the delivery was adjusted to maintain the ACT between 200 and 240 seconds. The sheep was then recovered according to previous methods [4] and moved to a custom-built cage that allowed all activity except turning around. The sheep were awake and ate and drank freely during the 30 days of TAL support.

The next morning, heparin (150 U/kg) and methylprednisolone (500 mg, Solu-Medrol, Pfizer, New York, NY) were given IV. The shunt was removed, and the TAL was attached between the inlet and outlet grafts using sterile technique without sedation (see Fig 1). The TAL sweep gas was set at 5 L/min of oxygen (O2) to ensure that condensed water vapor was blown out of the device. Due to the excessive carbon dioxide (CO2) transfer in these devices, 0% to 5% CO2 was also blended into the sweep gas to maintain normal arterial partial pressure of CO2 (PaCO 2). After 5 minutes, a baseline data set was obtained that included heart rate; mean arterial, central venous, device inlet, and device outlet pressure; cardiac output and device flow; and arterial, device inlet, and device outlet blood gases. Afterwards, heart rate, all pressures, cardiac output, and device flow were recorded hourly.


Figure 1
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  		Fig 1. The MC3 Biolung total artificial lung (TAL) attached to the flank of a sheep.

 
Ketorolac (30 mg) was given every 6 hours for 3 days after attachment. Penicillin (500 mg) and gentamicin (2.5 mg/kg IV, Abbott Laboratories) were given every 6 and 8 hours, respectively, for 3 days.

Arterial blood gases and ACT were taken every 1 to 4 hours. Heparin delivery was adjusted to maintain the ACT between 200 and 240 seconds during the course of the experiment. Device inlet and outlet blood gases were recorded in the morning and late afternoon every day. White blood cell count, platelet counts, and plasma free hemoglobin level were measured daily, and a blood chemistry panel was run every Monday, Wednesday, and Friday.

Every 7 to 9 days, the right neck was cleaned with 70% isopropyl alcohol and 2% iodine solution and blood was drawn from the right external jugular vein with venipuncture. Bacterial cultures were then run by the University Laboratory for Animal Medicine. If high fever (>104°F), elevated white blood cell count, or both was observed, an additional bacterial culture was submitted, and a cephalosporin (1 gram IV every 12 hours; Cefotaxime, American Pharmaceutical Partners, Inc. Schaumburg, IL) and gentamicin (80 mg, intramuscularly every 8 hours) were administrated.

Devices were replaced if device resistance increased 300% or if oxygen content difference across the device decreased 25% compared with baseline. Device replacement occurred in the same fashion as initial attachment. After 30 days, surviving sheep were euthanized using Fatal-Plus (Vortech Pharmaceuticals, Ltd, Dearborn, MI) and necropsied. The hearts were dissected to separate the RV free wall from the left ventricle and septum. Each component was weighed to determine the RV free wall–to–left ventricle and septum weight ratio, rw.

Device resistance, R, and total and TAL oxygen transfer (VO 2) were calculated according to previously published methods [5]. Data from all 30-day survivors were included in statistical analysis and graphic presentation. Data were averaged every 3 days, and statistical comparisons used data from baseline and all three day averages through days 28 to 30. Comparisons were performed with SPSS software (SPSS, Chicago, IL) by using a mixed model with the sheep number as the subject variable and the 3-day period as the fixed, repeated-measure variable. Post hoc analysis using a Bonferroni-corrected confidence interval was then used to compare all variables with the first data set to examine changes with time.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
The device was successfully attached in 8 sheep, and 5 sheep survived 30 days. Three sheep were euthanized before 30 days because of mechanical graft failure (day 10), persistent bleeding due to low platelet counts (day 4), and a diffuse acute gastric mucosal lesion (bloats, day 6).

Sheep Physiology
Both mean arterial pressure (MAP) and central venous pressure (CVP) remained within normal, healthy ranges, with neither varying statistically (p > 0.99, Table 1 and Fig 2). The MAP averaged 99 ± 2.8 mm Hg from day 1 to 30, and the CVP averaged 7.1 ± 2.3. Cardiac output was within a normal range during the entire experiment and remained statistically unchanged (p > 0.99), averaging 4.1 ± 0.5 (Table 1). Heart rate was also stable, averaging 131 ± 9.2 (p > 0.99). The hemoglobin (Hb), PaO 2, and venous O2Hb (SvO 2) remained statistically unchanged (p > 0.398, p > 0.99, and p > 0.99, respectively; Tables 2 and 3), Go averaging 8.5 ± 0.4 g/dL, 105 ± 6.0 mm Hg, and 46.2 ± 2.7 mm Hg, respectively. The PaCO 2 was significantly greater on days 1 to 3, 4 to 6, and 10 to 12 but not significantly different on all other days. Overall, PCO 2 changed very little, remained within normal ranges, and averaged 35.9 ± 0.8 mm Hg from days 1 to 30.


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  		Table 1 Hemodynamics
 

Figure 2
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  		Fig 2. Mean arterial pressure (mAP, squares) and cardiac output (CO, circles) at baseline (BL) and at days 1 through 30 after total artificial lung attachment. Data are averaged over 3-day periods and presented with the standard deviation.

 

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  		Table 2 Gas Exchange
 

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  		Table 3 Hematology and Organ Function
 
Device Function
Device blood flow resistance increased from baseline, but this increase did not reach significance (p > 0.679; Table 1 and Fig 3). Overall resistance averaged 2.7 ± 0.8 mm Hg · min/L from days 1 to 30, whereas average resistance at baseline was 1.3 ± 0.3 mm Hg · min/L. Flow through the TAL, QTAL, did not differ significantly from baseline over the course (p > 0.99). Blood flow was a little higher in the TAL than the natural lung, averaging 56% ± 13% of cardiac output at baseline and 51% ± 6.3% over the experimental course (p > 0.14 versus baseline at all times). Total VO2 was stable (Table 1), with no significant difference between times (p > 0.99). The TAL VO2 decreased slightly from 121 ± 19 mL/min at baseline to an average of 107 ± 8.6 mL/min for the rest of the experiment, but this was not statistically significant (p > 0.99).


Figure 3
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  		Fig 3. Artificial lung resistance (circles) and percentage of cardiac output (CO, squares) flowing to the total artificial lung (TAL) for baseline (BL) and at days 1 through 30 post-TAL attachment. Data are averaged over 3-day periods and presented with the standard deviation.

 
Each device was used an average of 9.5 ± 2.1 days, with 4 ± 2 devices needed per animal. Of the 15 replaced devices, 8 were replaced due to high resistance and 6 were replaced because of deterioration in oxygen transfer. One additional device was changed due to mechanical damage that occurred when the sheep jumped out of its elevated cage. Eight devices had most of the thrombi on the half of the fiber bundle closest to the inlet and outlet ports (see Fig 4), whereas 4 devices had diffuse clots. One device had thrombi mainly in the half of the fiber bundle furthest from the inlet and outlet connectors, and 5 devices had few thrombi.


Figure 4
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  		Fig 4. Typical MC3 Biolung after 30 days. Note thrombus formation at the end of the device closest to the inlet and outlet ports.

 
All device replacements occurred without complication, requiring less than 5 minutes without TAL blood flow. Figure 5 presents the hemodynamic course of 1 sheep, showing typical cycles of increased device resistance and subsequent replacement. Device resistance increased steadily from 1.4 to 2.9 mm Hg · min/L between baseline and day 5, and TAL blood flow decreased from 2.2 to 1.5 L/min. After the device change on day 5, resistance decreased to 1.0 mm Hg · min/L and the flow increased to 1.9 L/min. During this same period, PO 2 decreased from 114 mm Hg to 96 mm Hg (not pictured) and then increased to 121 mm Hg after device replacement. A similar increase in TAL resistance and reduction in TAL flow was repeated before the second device replacement on day 14, but the reduction in flow was smaller.


Figure 5
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  		Fig 5. Total artificial lung (TAL) blood flow (diamonds) and resistance (circles) for a single, representative sheep at baseline (BL) and at days 1 through 30 post-TAL attachment days one through thirty. Data are averaged over 3-day periods.

 
Hematology and Organ Function
Platelet counts were similar at baseline and on days 1 to 3 but increased thereafter as a response to surgical trauma. Platelet counts peaked at days 4 to 6 (p = 0.015; Fig 6 and Table 3) and were higher than baseline thereafter. Heparin rate followed a similar trend, peaking at days 7 to 9, where it was significantly greater than at days 1 to 3 (p < 0.001). Thereafter, it remained at levels similar to days 1 to 3 (p > 0.15). White blood cell counts also peaked at days 7 to 9, but these changes did not reach statistical significance (p > 0.37). There were positive bacterial culture results in 3 sheep. One sheep had positive bacterial cultures only at day 30, 1 had positive cultures on days 8 and 21, and 1 had positive cultures on days 21, 24, 27, and 30.


Figure 6
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  		Fig 6. Counts for platelets (squares) and white blood cells (circles) at baseline (BL) and at days 1 through 30 after total artificial lung attachment. Data are averaged over 3-day periods and presented with the standard deviation.

 
Concentrations of AST, LDH, and CK were all significantly elevated versus baseline on days 1 to 3 but returned to baseline levels thereafter. A similar trend for ALT did not reach statistical significance (p > 0.99). Finally, BUN and creatinine were stable over the course, with no significant changes (p > 0.28 and p > 0.99, respectively).

Necropsy
The right–to–left ventricular heart weight ratio, rw, was 0.35 ± 0.05. Normal historical controls have an rw = 0.33 ± 0.02 (p > 0.99), indicating no RV hypertrophy. Multiple microabscess formations were found in 1 sheep in the cranial lobe. This sheep showed subcutaneous abscess formation along the flow meter cable and also showed extensive diffuse calcification and chronic inflammatory infiltrate throughout the right kidney. No lung infections were observed in the other sheep, but chronic inflammatory infiltrate was present in the right kidney of an additional sheep. Baseline lung specimens were all normal, but mild, focal interstitial fibrosis or thickening of alveolar septa was found in 4 animals at necropsy. Type II pneumocyte hyperplasia was seen in 1 animal. Gross findings also noted several white nodules on the kidneys of all sheep, but microscopic examination of these lesions indicated that ischemia was present in the kidneys of only 2 sheep. None of the animals had infection, thrombus, or ischemic lesions in the heart, liver, spleen, and gastrointestinal tract.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
Total artificial lungs are intended to be a bridge to and from lung transplantation; thus, several months of support are required from these TALs. These devices should be designed to provide total respiratory support with some degree of ambulation to allow for mild exercise in the period leading up to transplantation. During use, the TALs should cause minimal activation of the coagulation and immune systems and no blood trauma to prolong the useful life of each device and minimize patient complications. Use of a single device for the entire period of support should be a goal, but one should also be able to replace the device simply and without complication.

Design goals for device impedance depend on the attachment mode. Several attachment modes have been tested with these devices, including in parallel with the natural lung (PA to LA) as tested here, in series with the natural lung (proximal PA to distal PA), and a hybrid of the two. Different attachment modes and different TAL designs will likely be necessary for different conditions leading to lung transplantation.

During PA-LA attachment without PA banding, the impedance of the combined pulmonary and artificial lung system is less than that of the natural pulmonary vascular resistance and RV afterload is decreased. Thus, PA-LA attachment would be ideal for patients with significant pulmonary hypertension and RV dysfunction. For this setting, the device should be designed to have impedance similar to that of healthy natural lungs. This would allow 50% of the cardiac output to travel through the TAL at minimum while the right ventricle is unloaded. Higher blood flow to the TAL could also be achieved if the PA was banded or if pulmonary vascular resistance was above normal.

During in-series PA-PA attachment, all blood must flow through both the artificial and natural lung. This increases the pulmonary system impedance, and devices must thus be designed with minimal impedance. Conversely, in-series attachment fully uses the normal metabolic and filtration functions of the natural lung and is thus worth pursuing. With lower impedance devices, in-series attachment could be used in patients with minimal changes in pulmonary vascular resistance (PVR) and normal RV function. These patients should be able to tolerate a small increase in RV workload. Thus, more research is required in this area to further reduce TAL impedance for this application and determine techniques for attachment on the short human PA.

Joint development between our laboratory and MC3, Inc has led to the development of the current Biolung design. These studies have demonstrated that device design is appropriate for use in a PA-to-LA configuration for up to 7 days. The current 30-day study was thus designed to evaluate the potential for a clinical trial, including the effects on attachment on animal physiology, device durability, ease of device replacement, thrombosis, embolization, infection, and organ function.

In this context, the MC3 Biolung proved itself capable of 50% to 60% of respiratory support for 30 days. The course of the experiment was uneventful in most cases. Hemodynamics, blood gases, and organ function were normal over the course of the experiment and showed no trend toward deterioration. No RV dysfunction was present. Diversion of significant blood flow away from the pulmonary circulation has been shown in prior studies [6] to cause a decrease in processing of various vasoactive molecules, but neither this study nor the previous 7-day study [4] saw deleterious effects of flow diversion on systemic hemodynamics.

In previous 7-day studies, the most challenging aspect of PA-LA, in-parallel attachment proved to be postoperative sheep recovery [4]. This problem was caused primarily by slow removal of anesthesia due to the use of PMP fibers in the TAL and in-parallel attachment. Varying our procedure to allow the sheep to recover from surgery before device attachment was highly successful in this study because all of the animals recovered to standing by 3 to 4 hours after surgery.

Several hurdles remain for this device before clinical application. The most significant is that device biocompatibility should be improved. Device use in this study averaged 9.5 days. In most cases device resistance increased steadily over this period until reaching 3 to 4 mm Hg · min/L, after which the resistance increased exponentially. In addition, the first device used in each sheep typically lasted longer than the following devices. This is related to the platelet count, which was reduced for the first 2 to 3 days after surgery.

No significant hemolysis or platelet consumption was noted as a result of TAL use or replacement; thus, infusion of blood products was not necessary. One sheep, however, had a bleeding complication and was euthanized on day 4. Thoracic bleeding was noted at necropsy. It is suspected that bleeding occurred from the LA graft anastomosis due to graft tension that increases when the sheep stands if the graft length is left too short.

Despite no significant platelet consumption in the survivors, replaced devices typically had a significant amount of clot on the fiber bundle. The explanation lies in the markedly lower velocity and shear stress levels present in these devices compared with ECMO and CPB oxygenators [7, 8]. The gentle flow within the bundle eliminates shear-induced platelet activation and consumption. However, low blood flow velocity near the fiber surface leads to slow transport of artificial surface-activated coagulation cascade factors away from the membrane. The result is a typical stagnation-induced thrombus formation. Frequent device replacement thus remains necessary due to coagulation, but bleeding complications are typically not an issue because of maintenance of circulating platelet numbers and function.

Further use of the device should examine the ideal ACT range and other anticoagulants, including platelet inhibitors. However, the ability of systemic anticoagulation to eliminate surface thrombus is limited because of low blood flow velocities at the fiber surface. These devices will thus likely require surface coatings to reduce contact activation, fibrinogen adsorption, and resultant activation of the coagulation cascade and platelets. Surface coatings should help reduce the potential for thromboemboli, as well. Clot shedding from the device most likely caused the ischemic regions noted in the kidneys of 2 sheep in this study; however, all organ function remained normal. Surface coatings should also be pursued to decrease the inflammatory response to the device. In all sheep, neither initial device attachment nor device replacement led to significant systemic inflammatory events; however, mild focal lung fibrosis developed over the course of the experiment.

Infection is likely to be a smaller issue than thrombus formation. Positive cultures were found in 2 sheep, but the experimental setting is less than ideal for infection control. First, the sheep live in proximity to their waste, students are responsible for taking blood samples, and results for bacterial sensitivity to antibiotics are received from the Laboratory for Animal Medicine 1 week after the blood sample. Maintenance of sterility and infection control should be improved in a clinical setting.

This device must be used in models of chronic lung disease before clinical testing. Although the Biolung was capable of full-support, this study was performed with healthy sheep, and important differences in use will occur when there is a significant respiratory deficit. First, high pulmonary vascular resistance will divert a greater percentage of blood flow to the TAL and away from poorly functioning natural lungs. If additional diversion is necessary to increase gas exchange, a PA band could be used. The ideal percentage of flow to the TAL is likely dependent on the severity of respiratory dysfunction and the degree of pulmonary hypertension. This change will likely have two opposite effects on the duration of device use. The first is that a patient with chronic lung disease will be less tolerant of device deterioration. As TAL resistance increases and the percentage of blood flow to the TAL decreases, blood gases will experience a significant deterioration, unlike in this study. Conversely, higher blood flow rates through the device will likely decrease clot formation by decreasing surface concentrations of activated coagulation factors.

Finally, device replacement may prove more challenging in these patients. Blood gases will undoubtedly deteriorate more rapidly during replacement, and thus replacement should be performed while the patient is breathing pure oxygen. The duration of replacement is less than 5 minutes, however, and should be feasible without complications.

In conclusion, the MC3 Biolung is fully capable of 30 days of respiratory support in the in parallel, PA-to-LA attachment mode. Sheep hemodynamics, blood gases, and organ function did not deteriorate during the course of the month. Device biocompatibility was not a significant cause of morbidity or mortality over 30 days, but a more biocompatible TAL is warranted to extend the useful life of each device past 9.5 days as well as reduce the risk of organ dysfunction during several months of support. Further studies should examine the ideal pharmacologic intervention to control coagulation at the fiber surface. Finally, testing of the Biolung should continue in models of chronic lung disease before clinical use.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR JOSEPH B. ZWISCHENBERGER (Galveston, TX): Once again we are indebted to Dr Bartlett and his group for their innovative approach to extracorporeal gas exchange. This particular approach, with a PA-to-LA approach, is unique among those centers investigating total artificial lung technology. The Achilles’ heel of this technique is it is totally dependent on the right ventricle for contractility and flow and the variable resistance of the lung, and as you could see, there was considerable variation in flow through the devices throughout the course of these animals, requiring frequent device change out due to thrombosis. In fact, this group has presented in their previous literature and appears confirmed by this literature that there is a variation in flow from 10% to 90% of the cardiac output as the interplay between the right ventricle, the lungs, and the device all determine variable flow.

The results are clear that this variation in flow can result in thrombosis and systemic emboli. Therefore, despite the gargantuan effort it takes to do a 30-day study in a sheep to get survival, I have to ask, in a condition of disease where the right ventricular dysfunction and variable pulmonary resistance is predictable, how would this approach appear practical in treatment of disease?

Once again, I thank Dr Bartlett and his group for their innovation.

DR SATO: Thank you, Dr Zwischenberger. We are testing with the PA-LA configuration, and this configuration has the advantage to unload the right ventricle, and after unloading the right ventricle, it improves right ventricular function. In the patient suffering from chronic lung disease, they have high pulmonary vascular resistance. So if we can attach the device in such a patient, we can increase the flow to the device. We can improve the thrombogenicity. And also we know that we found a lot of clot formation in the device, so we need to improve the biocompatibility of the device. We believe the PA-LA attachment is feasible because the VA ECMO is feasible. So we believe some biocompatibility improvement and some combination of pharmacological intervention helps to attach our device in the patients.

DR BARTLEY GRIFFITH (Baltimore, MD): Thank you very much for bringing us up to date on really what I consider to be excellent animal work and bioengineering. The problem in introducing an artificial lung is its inherent blood incompatibility.

Surgeons every day can work with devices that exchange oxygen and carbon dioxide, but how can we translate that into the clinical realm of bridge to transplant or even chronic use? You mentioned frequently in your paper that the average number of devices per animal was four. Clearly with an ACT running close to 250 seconds, we need better surface biocompatibility. So my question is where are you going with your surfaces? Is it nitric oxide application, is it heparin, albumin, or some combination?

And finally I just really wanted to say very much thank you to your mentor, Robert Bartlett, who has done so much for all of us interested in this field.

DR SATO: Thank you for the questions. I would like to answer them. Definitely we need to do some surface coating on the device. Nitric oxide should work on the device as a device coating. In the article we can find long-term ECMO testing in animals with a heparin-coated surface device. So surface coating should help long-term for the bypass circuit.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
This work was supported by a grant from the National Institutes of Health (RO1 HL69420).


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

  1. Sato H, McGillicuddy JW, Griffith GW, et al. Effects of artificial lung compliance on in vivo pulmonary system hemodynamics ASAIO J 2006;52:248-256.[Medline]
  2. Perlman CE, Cook KE, Seipelt R, Mavroudis C, Backer CL, Mockros LF. Hemodynamic consequences of artificial lung attachment in an in vivo porcine model ASAIO J 2005;51:412-425.[Medline]
  3. McGillicuddy JW, Chambers SD, Galligan DT, Hirschl RB, Bartlett RH, Cook KE. In vitro, fluid mechanical effects of thoracic artificial lung compliance ASAIO J 2005;51:789-794.[Medline]
  4. Sato H, Griffith GW, Hall CM, et al. Seven-day artificial lung testing in an in-parallel configuration Ann Thorac Surg 2007;84:988-994.[Abstract/Free Full Text]
  5. Cook KE, Perlman CE, Seipelt R, Backer CL, Mavroudis C, Mockros LF. Hemodynamic and gas transfer properties of a compliant thoracic artificial lung ASAIO J 2005;51:404-411.[Medline]
  6. Eya K, Tatsumi E, Taenaka Y, et al. Importance of metabolic function of the natural lung evaluated by prolonged exclusion of the pulmonary circulation ASAIO J 1996;42:M805-M809.[Medline]
  7. Cook KE, Maxhimer J, Leonard DJ, Mavroudis C, Backer CL, Mockros LF. Platelet and leukocyte activation and design consequences for thoracic artificial lungs ASAIO J 2002;48:620-630.[Medline]
  8. Cook KE, Mockros LF. Biocompatibility of artificial lungsIn: Vaslef SN, Anderson RW, editors. The artificial lung. Austin, TX: Landes Bioscience; 2002.




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