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Thoracic artificial lungs (TALs) have been proposed as a bridge to transplant in patients with end-stage lung disease. Systemic embolic complications can occur following TAL attachment in the pulmonary artery to left atrium (PA-LA) configuration. Therefore, we evaluated the function of a compliant TAL (cTAL) attached via the proximal PA to distal main PA configuration.
The cTAL was attached to five (63 ± 0.9 kg) sheep in the PA-PA configuration. Device function and animal hemodynamics were assessed at baseline and with approximately 60%, 75%, and 90% of CO diverted to the cTAL. At each condition, dobutamine (0 and 5 mcg · kg−1 · min−1) was used to simulate rest and exercise conditions.
At rest, CO decreased from 6.20 ± 0.53 L/min at baseline to 5.40 ± 0.43, 4.66 ± 0.31, and 4.05 ± 0.27 L/min with 50, 75, and 90% of CO to the cTAL (p<0.01 for each flow diversion vs. baseline). During exercise, CO decreased from 7.85 ± 0.70 L/min at baseline to 7.46 ± 0.55, 6.93 ± 0.51, and 5.96 ± 0.44 L/min (p=0.82, 0.19, and p<0.01 with respect to baseline) with 50, 75, and 90% of CO to the cTAL. The cTAL resistance averaged 0.46 ± 0.02 mmHg/(L/min) and did not vary significantly with cTAL blood flow rate.
Use of a cTAL may be feasible in the PA-PA setting if cTAL blood flow is held at < 75% of CO. To ensure a drop in CO < 10%, a cTAL flow rate < 60% of CO is advised.
Lung transplantation provides the possibility of substantially increased survival for patients with end-stage pulmonary disease. Unfortunately, the demand for donor organs continues to exceed the current supply. Although changes in the donor organ allocation system have decreased waiting list mortality, there were still 266 waiting list deaths in 2008.1 To address this issue thoracic artificial lungs (TALs) have been proposed as a bridge to lung transplantation.
Numerous case reports have shown that long-term extracorporeal membranous oxygenation (ECMO) can be used to bridge patients to lung transplantation.2–5 However, cannulation and the ECMO circuit could make pre-transplant rehabilitation more difficult when compared to TAL use. ECMO is also associated with blood element activation, hemolysis, and platelet consumption which can lead to increased transfusions, systemic inflammatory response, and organ system failure.6
Use of a paracorporeal, pumpless TAL could help to enhance patient mobility preoperatively, cause fewer hematologic derangements, and expedite post-transplant recovery in patients that are bridged to lung transplantation. A previous study of the Biolung TAL (MC3, Ann Arbor, MI) in normal sheep has shown that this device is capable of providing respiratory support for a 30 day period when used in the pulmonary artery to left atrium (PA-LA) configuration.7 Moreover, these studies demonstrated stable platelet counts and no evidence of hemolysis, suggesting better biocompatibility compared to ECMO.7 There is no purposely designed TAL available clinically. However, six patients have been bridged to transplant using a Novalung ILA (Hechingen, Germany)) in a PA-LA configuration.8–10 The PA-LA configuration can decrease the workload of the right ventricle (RV) by providing an alternate pathway for blood flow. However, potentially catastrophic systemic embolic complications such as stroke could occur.9,10
An alternative configuration, the proximal PA to distal PA (PA-PA) configuration has a low risk for systemic embolic events. This approach is limited by the increased workload of the RV having to pump sequentially through the device and the native lungs. Therefore, presence of pulmonary hypertension (PH) would be a relative contraindication to this attachment configuration. However, a significant subset of lung transplant candidates with chronic respiratory insufficiency do not have pulmonary hypertension (mean PA pressure > 25 mmHg), including 69% of candidates with idiopathic pulmonary fibrosis,11 50% with chronic obstructive pulmonary disease,12 and 37% with cystic fibrosis.13
Nonetheless, the TAL must have a stable, low resistance in order for this approach to be feasible. In the current study, a new compliant thoracic lung (cTAL) design is examined for this setting. The cTAL utilizes a compliant housing with a gradual inlet in an attempt to achieve ultra-low device resistance (0.5 mmHg/(L/min)) at all relevant ranges of blood flow through the device. We hypothesized that this ultra-low resistance device could be attached in the PA-PA configuration and maintain normal CO at high device flow rates. If true, this would decrease adverse events from systemic emboli in patients being bridged to lung transplantation. Thus, the current study examines the hemodynamic effect of PA-PA attachment under various percentages of CO diverted through the cTAL and under simulated rest and exercise conditions.
A cTAL, consisting of a compliant Biospan (DSM PTG, Berkeley, CA) housing and polypropylene fiber bundle, was used in this study (Fig 1). This device was designed and constructed by our research group at the University of Michigan.14 In this device, blood flows into the inlet conduit, expands into the inlet manifold, flows through the fiber bundle, travels through the outlet manifold, and exits through the outlet conduit. To create the fiber bundle, woven mats of polypropylene fibers with a fiber diameter of 210 µm were wound into compact bundles with porosity, path length, frontal area, and surface area of 0.75, 0.038 m, 0.013 m2, and 2.4 m2 respectively.
Five male sheep averaging 63 ± 0.9 kg were used in this study. Animal numbers were based on similar previous studies.14 All sheep received humane care in compliance with the “Guide for the Care and Use of Laboratory Animals” and all methods were approved by the University of Michigan Committee for the Use and Care of Animals. Anesthesia was induced and mechanical ventilation was performed according to previous published methods.14 A carotid arterial line and left jugular venous line were placed and then connected to fluid coupled pressure transducers (ICU Medical, Inc., San Clemente, CA) for the continuous monitoring of arterial and central venous pressures (MAP and CVP).
A muscle sparing left anterolateral thoracotomy was performed and the fourth rib was removed. The left lung was packed laterally and the pericardium was incised. The pulmonary artery was then identified. Dacron vascular grafts (18mm, Terumo Medical Corporation, Ann Arbor, MI) were solvent bonded to 5/8” inner diameter PVC tubing (Fisher Scientific, Pittsburgh, PA) and used as conduits for artificial lung attachment. An end-to-side anastomosis was performed between the device outlet conduit and the distal PA near the bifurcation. The device inlet end-to-side anastomosis was then performed on the proximal PA. An ultrasonic perivascular flow probe (Transonic 24AX, Transonic Systems, Inc., Ithaca, NY) was placed around the PA, proximal to the device inlet graft for measurement (T400, Transonic Systems, Ithaca, NY) of mean PA flow or cardiac output (CO). A pressure catheter (Becton Dickinson and Co., Franklin Lakes, NJ) was then inserted at the proximal PA and connected to a transducer for the display and recording of the proximal PA pressure (pP AP). A Rummel tourniquet was placed around the PA between the inlet and outlet grafts to allow for the adjustment of flow through the cTAL. Pressure catheters were inserted into the distal PA near the bifurcation and into the left atrium to allow for the recording of the distal PA pressure (dPAP) and the left atrial pressure (LAP). Prior to device attachment, 1g of methylprednisolone (Solu-Medrol, Pfizer, New York, NY) was administered, and the animal was anticoagulated with 100 IU/kg of intravenous sodium heparin (Baxter Healthcare Corp., Deerfield, IL) to maintain active clotting times of above 300 seconds.
The cTAL was primed with heparinized saline (10 U/mL) and then connected to the proximal PA (device inlet) and distal PA (device outlet) grafts (Figure 2). An ultrasonic flow probe (Transonic 14PXL, Transonic Systems, Inc., Ithaca, NY) was placed around the inflow conduit in order to measure (T400, Transonic Systems Inc., Ithaca, NY) device flow (QcTAL). The cTAL inlet and outlet pressures (Pin and Pout) were measured by fluid-coupled pressure transducers. A suction line was attached to the cTAL gas outlet and 95:5% O2:CO2 with vaporized isoflurane (1–3%) was used as the sweep gas through the gas inlet. Sweep gas flow was adjusted during cTAL use to maintain PaCO2 between 35 and 45 mmHg. A Hoffmann clamp was placed around the cTAL outlet conduit to restrict flow through the device. After cTAL attachment, a full data set was taken (see below), clamps on the cTAL inlet and outlet conduits were removed, and the Hoffmann clamp was loosened until 1 L/min flow to the cTAL was achieved. This flow was maintained for 10 minutes for equilibration of fluid volumes and any inflammatory response. Flow to the cTAL was then stopped briefly, and up to 500 mL of hetastarch and 500 mL of crystalloid were administered to restore CVP back to pre-cTAL values, if required.
Rest and exercise conditions were then simulated using a continuous dobutamine (Hospira Inc., Lake Forest, IL) infusion of 0 and 5 mcg · kg−1 · min−1, respectively. At each dose, a data set was acquired at baseline, with no flow to the device. Thereafter, clamps were removed from the cTAL and the Rummel tourniquet was tightened to divert 60, 75, and 90% of CO to the cTAL. At each condition, 10 minutes were allowed for equilibration before data was taken. A data set consisted of recording the average values of all blood pressures and flows. In addition, arterial and device inlet and outlet blood samples were taken and assayed for pH, pCO2, pO2 using an ABL 725 blood gas analyzer (Radiometer Copenhagen Copenhagen, DK).
Average blood flows and pressures were used to calculate all resistances. The cardiac output, CO, is equal to the average PA flow rate. cTAL resistance, RcTAL, was calculated using the formula:
The PVR of the native lungs was calculated by the following formula:
The resistance of the graft anastomoses, Ra, was calculated by analyzing all the resistive elements in the experimental pulmonary system setup (Figure 2). Total pulmonary system resistance, RT, is defined as the resistance of combined artificial and natural lung system from the proximal pulmonary artery to the left atrium, and is thus calculated as:
Shunt resistance, Rs, is defined as the resistance of the section of the main pulmonary artery containing the artificial lung and its anastomoses which is in series with the natural lungs. It was thus calculated as:
The sum of the anastomoses resistances, Ra, are assumed to be in series with the cTAL resistance, giving the following relationship:
In which f is the fraction of CO diverted to the cTAL. The values of RT, Rs, and Ra were thus calculated at each flow condition.
Statistical analyses were performed using SPSS 19 (SPSS, Chicago, IL). The analysis of baseline PVR before and after TAL attachment was conducted using a paired two-tailed student’s t-test assuming equal variances. To examine if cTAL resistance varied significantly with flow rate, a one-way ANOVA was performed. For comparisons of mean values of all other dependent variables, linear models with correlated error structures (given the repeated measures) were fitted to the observed data. Separate models were fitted for the 0 and 5 mcg/kg/min of dobutamine data. Each model included fixed effects of flow diversion in order to examine differences between baseline and 60%, 75%, and 90% is flow diversion. Alternative covariance structures were compared using information criteria (e.g., AIC, BIC). In most cases, an autoregressive covariance structure was found to have the best fit. However, Toeplitz and diagonal covariance structures were used for PVR and mPAP, respectively. A Bonferroni correction was applied to the contrasts to prevent increases in Type I error rates. All data is reported as the mean ± the standard error, and a p-value of 0.05 or less was considered statistically significant.
The resistance of the cTAL did not change significantly with flow rate (p = 0.16), averaging 0.46 ± 0.02 mmHg/(L · min−1) over the entire range of flows. Due to relatively high venous saturations (83.1 ± 1.3%) and lower hemoglobin (6.11 ± 0.17 g/dL), the gas transfer function of the lung was never challenged. Arterial blood gas hemoglobin oxygen saturations were maintained at 99% for all of the conditions. Finally, all of the devices functioned without a noticeable decrease in gas exchange or increase in resistance. There was no noticeable clot formation within the device at the conclusion of the experiment.
During the early equilibration period, there was an event due to blood contact with the artificial lung featuring increased PVR and decreased MAP and CO. This is common to blood bearing artificial circuits and is normally attributed to inflammation.6 During this event, PVR increased from 1.61 ± 0.32 to 3.13 ± 0.17 mmHg/(L/min) (p=0.01), CO decreased from 6.58 ± 0.56 L/min to 6.20 ± 0.53 L/min, and MAP decreased from 87.6 ± 6.2 to 80.9 ± 3.9.
Thereafter, CO was 6.20 ± 0.53 L/min at the experimental baseline and decreased 13% to 5.40 ± 0.34 L/min at 60% flow to the cTAL (p<0.01), 25% to 4.66 ± 0.31 L/min at 75% flow to the cTAL (p<0.01), and 35% to 4.05 ± 0.27 L/min at 90 %flow to the cTAL (p<0.01) (Figure 3a). After starting dobutamine at 5 mcg · kg−1 · min−1, CO increased to 7.85 ± 0.70 L/min at baseline with no flow to the cTAL. Once again, CO decreased with increasing flows to the cTAL, dropping 5% to 7.46 ± 0.55 L/min (p=0.82), 12% to 6.93 ± 0.51 L/min (p=0.19), and 24% to 5.96 ± 0.44 L/min (p<0.01) with 60, 75%, and 90% of CO going through the cTAL, respectively. Other measures of RV dysfunction varied only slightly and were not as sensitive as CO. The CVP was between 11.4 and 12.5 mmHg under all conditions and did not change significantly with attachment mode at 0 or 5 mcg/kg/min of dobutamine (p = 0.08 and p = 0.59). Lactate was within normal ranges for the duration of the experiment (0.8–1.4 mmol/L). The only statistically significant change was a decrease in lactate with increasing flow the cTAL with 0 dobutamine (p<0.01 vs. baseline).
Like CO, MAP decreased with increasing flow to the TAL (Figure 3b). The baseline MAP was 81 ± 4.0 mmHg and it increased slightly to 83 ± 5.7 mmHg at 60% of cTAL flow (p=0.99) before decreasing to 76 ± 6.1 mmHg (p=0.88) and 67 ± 5.0 mmHg (p<0.05) under 75% and 90% cTAL flow conditions, respectively. Under the simulated exercise condition, the baseline MAP was 84 ± 5.3 mmHg. This decreased to 80 ± 6.9 mmHg at 60% cTAL flow (p=0.99), 69 ± 2.8 mmHg at 75% flow to the cTAL (p<0.05) and 60 ± 1.3 mmHg at 90% flow to the cTAL (p<0.01).
The cause of diminishing CO and MAP with increasing flow diversion to the cTAL is increasing RV afterload. Figure 4 shows the total pulmonary system resistance, RT, and its two subsections, shunt resistance, Rs, and PVR. As blood flow is diverted to the cTAL, RT increases linearly at both 0 and 5 mcg/kg/min of dobutamine from 3.39 ± 0.38 and 3.01 ± 0.28 mmHg/(L/min) at BL to 6.50 ± 0.14 and 5.10 ± 0.57 mmHg/(L/min) at 90% flow to the cTAL. The PVR does not change significantly with flow diversion (p=0.21, 0.99, and 0.99 with increasing cTAL flow in the 0 dobutamine conditions and p=0.35, 0.59, and 0.99 during the 5 mcg/kg/min of dobutamine conditions). However, as the PA is banded, blood flows increasingly through the higher resistance circuit with the TAL and its anastomoses. As a result, Rs increases from 0.26 ± 0.34 and 0.78 ± 0.22 at baseline to 3.18 ± 0.32 and 3.04 ± 0.35 mmHg/(L/min) with 90% of CO going to the TAL with 0 and 5 mcg/kg/min, respectively. Finally, the increased resistance was due to increased flow through this high resistance circuit and not due to changes in the resistances themselves. Neither RcTAL nor Ra change significantly with increasing flow diversion (p=0.42 and p=0.11 at 0 mcg/kg/min dobutamine and p=0.42 and p=0.35 at 5 mcg/kg/min dobutamine for RcTAL and Ra, respectively). The Ra was 2.63 ± 0.43, 2.39 ± 0.17, and 3.06 ± 0.37 mmHg/(L/min) at 60, 75 and 90% diversion at 0 mcg/kg/min of dobutamine and 2.25 ± 0.54, 2.60 ± 0.63 mmHg/(L/min), and 2.88 ± 0.39 mmHg/(L/min) with 60%, 75%, and 90% diversion at 5 mcg/kg/min of dobutamine.
Due to offsetting changes in CO and RT, PPAP increased only a small amount with increasing flow diversion (Figure 5). Baseline PPAP was 28 ± 2.0 mmHg and increased by a statistically insignificant amount (p=0.16) to 33 ± 2.5 mmHg at 90% flow to the cTAL with 0 mcg/kg/min of dobutamine. In a similar fashion, the baseline PPAP of 32 ± 4.8 mmHg increased insignificantly (p=0.98) to 38 ± 0.6 mmHg at 90% flow to the cTAL with 5 mcg/kg/min of dobutamine.
Several previous studies have examined TAL use in a PA-PA setting. Lick et al. utilized an early prototype of the MC3 Biolung (Ann Arbor, MI) in conscious, normal sheep with 100% flow diversion, resulting in poor heart function, including a 50% incidence of right heart failure.17 In surviving sheep, however, heart function improved over the 7-day study. Thereafter, the Biolung was redesigned to reduce blood flow impedance. The result was a device with an average blood flow resistance of approximately 1.8 mmHg/(L/min) under simulated blood flow conditions.18 Subsequently, this device was tested in conscious sheep with ARDS, again with 100% diversion. This study demonstrated an approximate 20% decrease in CO, followed by accommodation and normalization of CO.19 Sato et al, tested the MC3 Biolung in anesthetized sheep and found a 25% decrease in CO with 100% flow diversion.18 Perlman et al. also tested an early cTAL prototype in two groups of anesthetized pigs with either 42% or 100% flow diversion.20 This device had an average blood flow resistance of 1.9 mmHg/(L/min) under the same conditions as the Biolung.21 In this setting CO decreased by 12 and 42%, respectively.
The goal of the current study was to determine if further hemodynamic improvements in PA-PA attachment were possible using newer, ultra-low impedance TALs. In vitro studies of this device indicate that resistance is 0.53 ± 0.06 mmHg/(L/min) at blood flows of 4 L/min, and compliance was 5.21 ± 0.57 mL/mmHg.1 This resistance was less than one-third of previously published devices, and the compliance was 18% greater than previous designs.18,21,22 This study confirmed that it is possible to achieve PA-PA attachment with both significant TAL flow and minimal impact on hemodynamics. However, cardiac output dropped 25% and 12% during rest and exercise conditions at 75% diversion. As a result, diversion of 60% of CO or less appears to be a more reasonable level. At 60%, there was a 13% and 8% drop in CO at rest and exercise conditions. This is a level to which the heart could likely accommodate (see below).
The CO decrease during the present study is similar to those in Sato et al. and Perlman et al, despite lower TAL and pulmonary system resistances. Those studies demonstrated a 4 mmHg/(L/min) increase in PSR at 100% flow diversion vs. approximately 3.1 mmHg/(L/min) at 90% diversion in the current study. A PSR reduction of 0.9 mmHg/(L/min) should lead to a 5–7% increase in CO,23–24 or only 0.3–0.4 L/min. Thus, the benefits gained from even a large drop in TAL resistance are small. Ultimately, the largest resistance in the system is not the cTAL itself, but that of the anastomoses. Anastomoses resistances averaged approximately 2.6 mmHg/(L/min) in the current study, similar to that of previous studies,18,23 while the cTAL resistance is now only 0.5 mmHg/(L/min).
Despite the limited improvement in CO, minimization of TAL resistance should remain the goal to minimize RV strain. Three groups have reported on the use of the Novalung lung assist device (Novalung GmbH, Hechingen, Germany) in a PA to LA configuration in seven patients with marked pulmonary hypertension.8–10 Average device flow in these patients ranged from 2.5–3.0 L/min with a pressure drop of 25–30 mmHg across the device, or a device resistance of 10 mmHg/(L/min).10 Although this still allowed modest RV unloading in the PA-LA setting, this device would not be tolerated in a PA-PA configuration.
Despite these limitations, long-term results in conscious subjects should be significantly better. Two previous studies have indicated improved CO over 3–7 days of PA-PA support in conscious sheep with 100% flow diversion.18,19 This may be due to RV accommodation or alleviation of the effects of both anesthesia and any inflammatory response to the device. Prolonged anesthesia leads to a progressive decrease in mean arterial pressure, RV perfusion, and thus cardiac output.25,26 There was also an initial event that increased pulmonary vascular resistance and most likely a loss in cardiac function prior to the experimental period beginning.6,25 These events are common to blood contact with any blood gas exchanger, be it CPB, ECMO, or the cTAL and are typically attributed to inflammation.6 This effect typically resolves within 24 hours after initiation of ECMO,27,28 and there is no evidence of a significant systemic inflammation within 24 hours after TAL attachment.7 Thus, as arterial pressure returns to normal and the inflammation abates, cardiac function is likely to improve in awake sheep.
As stated earlier, the ability of the device to transfer oxygen was never challenged due to the use of 100% inspired oxygen and low hemoglobin. As a result, device outlet oxygen saturation was always greater than 99%. Gas exchange function for this device has recently been described elsewhere under more challenging conditions,.14,29,30 In that study, inlet blood conditions were set to those from the FDA "Guidance for Cardiopulmonary Bypass Oxygenators 510(k) Submissions" as well as the standards provided by ANSI/AAMI/ISO 7199. These were, in part, Hb = 12 ± 1 g/dL, SO2 = 65 ± 5%, and PCO2 = 45 ± 5 mmHg. With these inlet conditions, outlet oxyhemoglobin saturation was greater than 99% and PO2 at least 243 mmHg with up to 7 L/min of blood flow. The resulting oxygen transfer at 7 L/min was 395 mL/min. The CO2 transfer was not examined. However, CO2 transfer is typically excessive in these devices, requiring CO2 to be added into the sweep gas.7 This level of gas transfer is more than sufficient for this application.
In conclusion, the cTAL tested in the current study had a resistance well below previous TALs at all flow rates tested and maintained adequate gas exchange under all conditions. Despite this, flow diversion to the device should be limited to less than 60% of CO in the PA-PA setting to minimize changes in pulmonary hemodynamics. Further study is required, however, to determine the effect of PA-PA attachment in conscious sheep. Ultimately, if the cTAL can be used in the PA-PA configuration with minimal alteration in hemodynamics, systemic embolic complications could be eliminated.
Funding Sources: National Institutes of Health, R01 HL089043
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Disclosures/Conflicts of Interest: None