Hemocompatibility Evaluation of a Novel Ambulatory Pulmonary Assist System Using a Lightweight Axial-Flow Pump.

The Pulmonary Assist System (PAS) is currently under development as a wearable respiratory assist system. In this study, the hemocompatibility of the PAS's axial-flow mechanical pump (AFP) was compared to other contemporary mechanical pumps in an acute ovine model. The PAS was attached to a normal sheep in a venovenous configuration using one of three pumps: 1) AFP, 2) ReliantHeart HeartAssist 5 (control), or 3) Abbott Pedimag (control) (n = 5 each). Each sheep was supported on the PAS for 12 hours with two L/minute of blood flow and four L/minute of sweep gas. Hemolysis, coagulation, inflammation, and platelet activation and loss were compared among the groups. In this study, the plasma-free hemoglobin (pfHb) was less than 10 mg/dl in all groups. The pfHb was significantly lower in the AFP group compared to other groups. There was no significant clot formation in the pumps and oxygenators in all groups. Furthermore, no significant differences in coagulation (oxygenator resistance, fibrinopeptide A), inflammation (white blood cell counts, IL-8), and platelet activation and loss (p-selectin, platelet counts) were observed among the groups (all, p > 0.05). This study demonstrates equivalent hemocompatibility of the PAS's AFP to other contemporary mechanical pumps with a reduced level of hemolysis on startup.

Pilot Testing of a Lightweight, Pulmonary Assist System in an Ambulatory Sheep Model of Destination Therapy Respiratory Support.

A new, lightweight (2.3 kg), ambulatory pulmonary assist system (PAS) underwent preliminary evaluation in ambulatory sheep. The PAS was purposefully designed for long-term extracorporeal respiratory support for chronic lung disease and utilizes a novel, small (0.9 m 2 surface area) gas exchanger, the pulmonary assist device, with a modified Heart Assist 5 pump fitting in a small wearable pack. Prototype PAS were attached to two sheep in venovenous configuration for 7 and 14 days, evaluating ability to remain thrombus free; maintain gas exchange and blood flow resistance; avoid biocompatibility-related complications while allowing safe ambulation. The PAS achieved 1.56 L/min of flow at 10.8 kRPM with a 24 Fr cannula in sheep one and 2.0 L/min at 10.5 kRPM with a 28 Fr cannula in sheep 2 without significant change. Both sheep walked freely, demonstrating the first application of truly ambulatory ECMO in sheep. While in vitro testing evaluated PAS oxygen transfer rates of 104.6 ml/min at 2 L/min blood flow, oxygen transfer rates averaged 60.6 ml/min and 70.6 ml/min in studies 1 and 2, due to average hemoglobin concentrations lower than humans (8.9 and 10.5 g/dl, respectively). The presented cases support uncomplicated ambulation using the PAS.

Ambulatory 7-day mechanical circulatory support in sheep model of pulmonary hypertension and right heart failure.

BACKGROUND: Right heart failure is the major cause of death in pulmonary hypertension. Lung transplantation is the only long-term treatment option for patients who fail medical therapy. Due to the scarcity of donor lungs, there is a critical need to develop durable mechanical support for the failing right heart. A major design goal for durable support is to reduce the size and complexity of devices to facilitate ambulation. Toward this end, we sought to deploy wearable mechanical support technology in a sheep disease model of chronic right heart failure. METHODS: In 6 sheep with chronic right heart failure, a mechanical support system consisting of an extracorporeal blood pump coupled with a gas exchange unit was attached in a right atrium-to-left atrium configuration for up to 7 days. Circuit performance, hematologic parameters, and animal hemodynamics were analyzed. RESULTS: Six subjects underwent the chronic disease model for 56 to 71 days. Three of the subjects survived to the 7-day end-point for circulatory support. The circuit provided 2.8 (0.5) liter/min of flow compared to the native pulmonary blood flow of 3.5 (1.1) liter/min. The animals maintained physiologically balanced blood gas profile with a sweep flow of 1.2 (1.0) liter/min. Two animals freely ambulated while wearing the circuit. CONCLUSIONS: Our novel mechanical support system provided physiologic support for a large animal model of pulmonary hypertension with right heart failure. The small footprint of the circuit and the low sweep requirement demonstrate the feasibility of this technology to enable mobile ambulatory applications.

Large animal preclinical investigation into the optimal extracorporeal life support configuration for pulmonary hypertension and right ventricular failure.

INTRODUCTION: Right ventricular failure (RVF) is a major cause of mortality in pulmonary hypertension (PH). Mechanical circulatory support holds promise for patients with medically refractory PH, but there are no clinical devices for long-term right ventricular (RV) support. Investigations into optimal device parameters and circuit configurations for PH-induced RVF (PH-RVF) are needed. METHODS: Eleven sheep underwent previously published chronic PH model. We then evaluated a low-profile, ventricular assist device (VAD)-quality pump combined with a novel low-resistance membrane oxygenator (Pulmonary Assist Device, PAD) under one of four central cannulation strategies: right atrium-to-left atrium (RA-LA, N = 3), RA-to-pulmonary artery (RA-PA, N=3), pumpless pulmonary artery-to-left atrium (PA-LA, N = 2), and RA-to-ascending aorta (RA-Ao, N = 3). Acute-on-chronic RVF (AoC RVF) was induced, and mechanical support was provided for up to 6 hours at blood flow rates of 1 to 3 liter/min. Circuit parameters, physiologic, hemodynamic, and echocardiography data were collected. RESULTS: The RA-LA configuration achieved blood flow of 3 liter/min. Meanwhile, RA-PA and RA-Ao faced challenges maintaining 3 liter/min of flow due to higher circuit afterload. Pumpless PA-LA was flow-limited due to anatomical limitations inherent to this animal model. RA-LA and RA-Ao demonstrated serial RV unloading with increasing circuit flow, while RA-PA did not. RA-LA also improved left ventricular (LV) and septal geometry by echocardiographic assessment and had the lowest inotropic dependence. CONCLUSION: RA-LA and RA-Ao configurations unload the RV, while RA-LA also lowers pump speed and inotropic requirements, and improves LV mechanics. RA-PA provide inferior support for PH-RVF, while an alternate animal model is needed to evaluate PA-LA.

72-Hour in vivo evaluation of nitric oxide generating artificial lung gas exchange fibers in sheep.

The large, densely packed artificial surface area of artificial lungs results in rapid clotting and device failure. Surface generated nitric oxide (NO) can be used to reduce platelet activation and coagulation on gas exchange fibers, while not inducing patient bleeding due to its short half-life in blood. To generate NO, artificial lungs can be manufactured with PDMS hollow fibers embedded with copper nanoparticles (Cu NP) and supplied with an infusion of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP). The SNAP reacts with Cu NP to generate NO. This study investigates clot formation and gas exchange performance of artificial lungs with either NO-generating Cu-PDMS or standard polymethylpentene (PMP) fibers. One miniature artificial lung (MAL) made with 10 wt% Cu-PDMS hollow fibers and one PMP control MAL were attached to sheep in parallel in a veno-venous extracorporeal membrane oxygenation circuit (n = 8). Blood flow through each device was set at 300 mL/min, and each device received a SNAP infusion of 0.12 µmol/min. The ACT was between 110 and 180 s in all cases. Blood flow resistance was calculated as a measure of clot formation on the fiber bundle. Gas exchange experiments comparing the two groups were conducted every 24 h at blood flow rates of 300 and 600 mL/min. Devices were removed once the resistance reached 3x baseline (failure) or following 72 h. All devices were imaged using scanning electron microscopy (SEM) at the inlet, outlet, and middle of the fiber bundle. The Cu-PDMS NO generating MALs had a significantly smaller increase in resistance compared to the control devices. Resistance rose from 26 ±â€¯8 and 23 ±â€¯5 in the control and Cu-PDMS devices, respectively, to 35 ±â€¯8 mmHg/(mL/min) and 72 ±â€¯23 mmHg/(mL/min) at the end of each experiment. The resistance and SEM imaging of fiber surfaces demonstrate lower clot formation on Cu-PDMS fibers. Although not statistically significant, oxygen transfer for the Cu-PDMS MALs was 13.3% less than the control at 600 mL/min blood flow rate. Future in vivo studies with larger Cu-PDMS devices are needed to define gas exchange capabilities and anticoagulant activity over a long-term study at clinically relevant ACTs. STATEMENT OF SIGNIFICANCE: In artificial lungs, the large, densely-packed blood contacting surface area of the hollow fiber bundle is critical for gas exchange but also creates rapid, surface-generated clot requiring significant anticoagulation. Monitoring of anticoagulation, thrombosis, and resultant complications has kept permanent respiratory support from becoming a clinical reality. In this study, we use a hollow fiber material that generates nitric oxide (NO) to prevent platelet activation at the blood contacting surface. This material is tested in vivo in a miniature artificial lung and compared against the clinical standard. Results indicated significantly reduced clot formation. Surface-focused anticoagulation like this should reduce complication rates and allow for permanent respiratory support by extending the functional lifespan of artificial lungs and can further be applied to other medical devices.

Fourteen Day In Vivo Testing of a Compliant Thoracic Artificial Lung.

The compliant thoracic artificial lung (cTAL) has been studied in acute in vivo and in vitro experiments. The cTAL's long-term function and potential use as a bridge to lung transplantation are assessed presently. The cTAL without anticoagulant coatings was attached to sheep (n = 5) via the pulmonary artery and left atrium for 14 days. Systemic heparin anticoagulation was used. Compliant thoracic artificial lung resistance, cTAL gas exchange, hematologic parameters, and organ function were recorded. Two sheep were euthanized for nondevice-related issues. The cTAL's resistance averaged 1.04 ± 0.05 mmHg/(L/min) with no statistically significant increases. The cTAL transferred 180 ± 8 ml/min of oxygen with 3.18 ± 0.05 L/min of blood flow. Except for transient surgical effects, organ function markers were largely unchanged. Necropsies revealed pulmonary edema and atelectasis but no other derangements. Hemoglobin levels dropped with device attachment but remained steady at 9.0 ± 0.1 g/dl thereafter. In a 14 day experiment, the cTAL without anticoagulant coatings exhibited minimal clot formation. Sheep physiology was largely unchanged except for device attachment-related hemodilution. This suggests that patients treated with the cTAL should not require multiple blood transfusions. Once tested with anticoagulant coatings and plasma resistant gas exchange fiber, the cTAL could serve as a bridge to transplantation.

Design and in vitro assessment of an improved, low-resistance compliant thoracic artificial lung.

Current thoracic artificial lungs (TALs) have blood flow impedances greater than the natural lungs, which can result in abnormal pulmonary hemodynamics. This study investigated the impedance and gas transfer performance of a compliant TAL (cTAL). Fluid-structure interaction analysis was performed using ADINA (ADINA R&D Inc., Watertown, MA) to examine the effect of the inlet and outlet expansion angle, θ, on device impedance and blood flow patterns. Based on the results, the θ = 45° model was chosen for prototyping and in vitro testing. Glycerol was pumped through this cTAL at 2, 4, and 6 L/min at 80 and 100 beats/min, and the zeroth and first harmonic impedance moduli, Z(0) and Z(1), were calculated. Gas transfer testing was conducted at blood flow rates of 3, 5, and 7 L/min. Fluid-structure interaction results indicated that the 45° model had an ideal combination of low impedance and even blood flow patterns and was thus chosen for prototyping. In vitro, Z(0) = 0.53 ± 0.06 mm Hg/(L/min) and Z(1) = 0.86 ± 0.08 mm Hg/(L/min) at 4 L/min and 100 beats/min. Outlet PO(2) and SO(2) values were above 200 mm Hg and 99.5%, respectively, at each flow rate. Thus, the cTAL had lower impedance than hard shell TALs and excellent gas transfer.