Keith E. Cook

A polymethylpentene fiber gas exchanger for long-term extracorporeal life support

A polymethylpentene (PMP) fiber gas exchange device was evaluated in healthy sheep (35–42 kg) to characterize its performance and potential use in clinical extracorporeal life support (ECLS). Five PMP devices (1.3 m2) were compared with five silicone rubber membrane lung (SRML) devices (1.5 m2) that were supported on venovenous ECLS for 72 hours. The two device groups were compared for differences in gas exchange, device pressure gradient, hematology, blood biochemistry, and pathology. The results showed superiority in the PMP devices in both oxygen and CO2 exchange when compared at similar blood flow rates. Platelet consumption and the device pressure gradient were significantly less when using the PMP device. The device pressure gradient across the PMP devices was <20 mm Hg as compared with >150 mm Hg for the SRML devices at all blood flow rates. Changes in plasma hemoglobin levels, leukocyte counts, blood chemistry results, and pathologic findings were not significantly different between the two device groups. Plasma leakage or device failure did not occur in any of the test devices. These data support the use of the PMP device for extended circulatory support. Patients may fare better because of improved preservation of platelets, and the low resistance may allow for wider use of centrifugal-style pumps or the use of the device in a pumpless arteriovenous mode.

Development of an implantable artificial lung : Challenges and progress

Unlike dialysis, which functions as a bridge to renal transplantation, or a ventricular assist device, which serves as a bridge to cardiac transplantation, no suitable bridge to lung transplantation exists. Our goal is to design and build an ambulatory artificial lung that can be perfused entirely by the right ventricle and completely support the metabolic O2 and CO2 requirements of an adult. Such a device could realize a substantial clinical impact as a bridge to lung transplantation, as a support device immediately post-lung transplant, and as a rescue and/or supplement to mechanical ventilation during the treatment of severe respiratory failure. Research on the artificial lung has focused on the design, mode of attachment to the pulmonary circulation, and intracorporeal versus paracorporeal placement of the device.

Hemodynamic effects of attachment modes and device design of a thoracic artificial lung.

A thoracic artificial lung (TAL) was designed to treat respiratory insufficiency, acting as a temporary assist device in acute cases or as a bridge to transplant in chronic cases. We developed a computational model of the pulmonary circulatory system with the TAL inserted. The model was employed to investigate the effects of parameter values and flow distributions on power generated by the right ventricle, pulsatility in the pulmonary system, inlet flow to the left atrium, and input impedance. The ratio of right ventricle (RV) power to cardiac output ranges between 0.05 and 0.10 W/(L/min) from implantation configurations of low impedance to those of high impedance, with a control value of 0.04 W/(L/min). Addition of an inlet compliance to the TAL reduces right heart power (RHP) and impedance. A compliant TAL housing reduces flow pulsatility in the fiber bundle, thus affecting oxygen transfer rates. An elevated bundle resistance reduces flow pulsatility in the bundle, but at the expense of increased right heart power. The hybrid implantation mode, with inflow to the TAL from the proximal pulmonary artery (PA), outflow branches to the distal PA and the left atrium (LA), a band around the PA between the two anastomoses, and a band around the outlet graft to the LA, is the best compromise between hemodynamic performance and preservation of some portion of the nonpulmonary functions of the natural lungs.

Hemodynamic and gas transfer properties of a compliant thoracic artificial lung

A compliant thoracic artificial lung (TAL) has been developed for acute respiratory failure or as a bridge to transplantation. The development goal was to increase TAL compliance, lower TAL impedance, and improve right ventricular function during use. Prototypes were tested in vitro and in vivo in eight pigs between 67 and 79 kg to determine hemodynamic and gas transfer properties. The in vitro compliance was 16.2 ± 4.4 ml/mm Hg at pressures < 7.8 mm Hg and 4.3 ± 1.1 ml/mm Hg above 7.8 mm Hg. In vivo, this compliance significantly reduced blood flow pulsatility from 1.7 at the inlet to 0.36 at the outlet. Device resistance was 1.9 and 1.8 mm Hg/(L/min) at a flow rate of 4 L/min in vitro and in vivo, respectively. Approximately 75% of the resistance was at the inlet and outlet. In vivo TAL O2 and CO2 transfer rates were 188 and 186 ml/min, respectively, at 4 L/min of blood and gas flow, and average outlet O2 saturations exceeded 98% for average flow rates up to and including the maximum tested, 5.3 L/min. The new design has a markedly improved compliance and excellent gas transfer but also possesses inlet and outlet resistances that must be reduced in future designs.

Use of venovenous extracorporeal membrane oxygenation and an atrial septostomy for pulmonary and right ventricular failure.

BACKGROUND Right ventricular failure is a major contributor to morbidity and mortality on the lung transplant waiting list. This study was designed to evaluate the effectiveness of an atrial septostomy with venovenous extracorporeal membrane oxygenation (VV-ECMO) as a novel potential bridge to transplantation. METHODS Adult sheep (58±3 kg; n=12) underwent a clamshell thoracotomy and instrumentation to measure all relevant pressures and cardiac output (CO). Sheep with tricuspid insufficiency (TI [n=5]) and without tricuspid insufficiency (ØTI [n=7]) were examined. After creation of a 1-cm atrial septal defect and initiating VV-ECMO, the pulmonary artery (PA) was banded to allow progressive reduction of pulmonary blood flow, and data were collected. RESULTS The CO in both groups remained unchanged from baseline at all pulmonary blood flow conditions. With TI, the CO was 5.1±1.2 L/min at baseline versus 5.1±1.2 L/min with a fully occluded PA (p=0.99). For ØTI, the CO was 4.5±1.4 L/min at baseline versus 4.5±1.2 L/min with no pulmonary blood flow (p=0.99). Furthermore, CO was not affected by the presence of TI (p=0.76). Mean right ventricular pressures were significantly lower in the TI group (TI=20.2±11 mm Hg versus ØTI=29.9±8.9 mm Hg; p<0.00001). Right and left atrial mean arterial pressures were not different between both groups (p>0.5). Lastly, VV-ECMO maintained normal blood gases, with mean O2 saturations of 99% ± 4.1% in both groups. CONCLUSIONS Right to left atrial shunting of oxygenated blood with VV-ECMO is capable of maintaining normal systemic hemodynamics and normal arterial blood gases during high right ventricular afterload dysfunction.

Achieving One-Step Surface Coating of Highly Hydrophilic Poly(Carboxybetaine Methacrylate) Polymers on Hydrophobic and Hydrophilic Surfaces

It is highly desirable to develop a universal nonfouling coating via a simple one-step dip-coating method. Developing such a universal coating method for a hydrophilic polymer onto a variety of surfaces with hydrophobic and hydrophilic properties is very challenging. This work demonstrates a versatile and simple method to attach zwitterionic poly(carboxybetaine methacrylate) (PCB), one of the most hydrophilic polymers, onto both hydrophobic and hydrophilic surfaces to render them nonfouling. This is achieved by the coating of a catechol chain end carboxybetaine methacrylate polymer (DOPA-PCB) assisted by dopamine. The coating process was carried out in water. Water miscible solvents such as methanol and tetrahydrofuran (THF) are added to the coatings if surface wettability is an issue, as for certain hydrophobic surfaces. This versatile coating method was applied to several types of surfaces such as polypropylene (PP), polydimethyl siloxane (PDMS), Teflon, polystyrene (PS), polymethylmethacrylate (PMMA), polyvinyl chloride (PVC) and also on metal oxides such as silicon dioxide.

Development of an artificial placenta I: pumpless arterio-venous extracorporeal life support in a neonatal sheep model

PURPOSE Effective treatment of respiratory failure in premature infants remains an unsolved problem. The development of an artificial placenta, in the form of a pumpless arteriovenous extracorporeal life support (AV-ECLS) circuit that maintains fetal circulation, is an appealing alternative. METHODS A near-term (140 d/term = 145 days) neonatal lamb model was used (n = 7). Fetuses were exposed by hysterotomy, and flow probes were placed on the ductus arteriosus, aorta, and carotid artery. Catheters were placed into the umbilical vessels, and pumpless AV-ECLS was initiated. Fetuses were submerged in a warm saline bath, and support was maintained for up to 4 hours. RESULTS Mean initial device flow was 383 mL/min but steadily declined to 177 mL/min at 4 hours. Mean initial pO(2) was 24 mm Hg and 18 mm Hg at 4 hours. Initial mean pCO(2) was 60 mm Hg and declined to 42 mm Hg at 4 hours. Mean arterial pressure was initially 43 mm Hg and decreased to 34 mm Hg at 4 hours. Flow in the ductus arteriosus was maintained for 4 hours. Of 7 fetuses, 5 survived 4 hours of support. CONCLUSIONS Pumpless AV-ECLS can support gas exchange and maintain fetal circulation in a neonatal lamb model for a 4-hour period. Prolonged support (>4 hours) is hampered by high cannula resistance and declining device flow.

Large animal model of chronic pulmonary hypertension.

A large animal model is needed to study artificial lung attachment in a setting simulating chronic lung disease with significant pulmonary hypertension (PH). This study sought to create a sheep model that develops significant PH within 60 days with a low rate of mortality. Sephadex beads were injected in the pulmonary circulation of sheep every other day for 60 days at doses of 0.5, 0.75, and 1 g (n = 10, 10, 7). Mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were obtained every 2 weeks. In the 0.5, 0.75, and 1-g groups, 90, 70, and 14.3% of sheep completed the study, respectively, with the remainder experiencing heart failure. By the 60th day, pulmonary vascular resistance had increased (p < 0.01) from 0.89 ± 0.3 to 3.2 ± 0.9 mm Hg/(L/min) and from 0.9 ± 0.3 to 4.3 ± 3.2 mm Hg/(L/min) in the 0.5 and 0.75-g groups, respectively. Significant right ventricular hypertrophy was observed in the 0.75-g group but not in the 0.5-g group. Data from the 1-g group were insufficient for analysis due to high mortality. Thus, the 0.5 and 0.75-g groups generate significant PH, but the 0.75-g group is a better model of chronic PH in lung disease due to the development of right ventricular hypertrophy.

Testing of an Intrathoracic Artificial Lung in a Pig Model

A low input impedance, intrathoracic artificial lung is being developed for use in acute respiratory failure or as a bridge to transplantation. The device uses microporous, hollow fibers in a 0.74 void fraction, 1.83 m2 surface area bundle. The bundle is placed within a thermoformed polyethylene terephthalate glucose modified housing with a gross volume of 800 cm3. The blood inlet and outlet are 18 mm inner diameter vascular grafts. Between the inlet graft and the device is a 1 inch inner diameter, thin-walled, latex tubing compliance chamber. These devices were implanted in Yorkshire pigs via median sternotomy with an end to side anastomosis to the pulmonary artery and left atrium. The distal pulmonary artery was occluded to divert the right ventricular output to the device. Pigs 1 and 2 were supported fully for 24 hrs and then killed. Pig 3 was supported partially for 20 hrs and died from bleeding complications. The first implant, in a 55 kg male pig, transferred an average of 176 ml/min +/- 42.4 of O2 and 190 ml/min +/- 39.7 of CO2 with an average blood flow rate of 2.71/min +/- 0.46. The normalized average right ventricular output power, Pn, was 0.062 W/(L/min) +/- 0.0082, and the average device resistance, R, was 3.5 mmHg/(L/min) +/- 0.62. The second implant, in a 60 kg male pig, transferred an average of 204 ml/min +/- 22.5 of O2 and 242 ml/min +/- 17.2 of CO2 with an average blood flow rate of 3.7 L/min +/- 0.45, Pn of 0.064 W/(L/min) +/- 0.0067, and R of 4.3 mmHg/(L/min) +/- 0.89. The third implant, in an 89 kg male pig, transferred an average of 156 ml/min +/- 39.6 of O2 and 187 ml/min +/- 21.4 of CO2 with an average blood flow rate of 2.5 L/min +/- 0.49, Pn of 0.052 W/(l/min) +/- 0.0067, and R of 3.4 mmHg/(L/min) +/- 0.74. These experiments suggest that such an artificial lung can temporarily support the gas transfer requirements of adult humans without over-loading the right ventricle.

Design and evaluation of a new, low pressure loss, implantable artificial lung

The authors designed and tested an artificial lung intended for intrathoracic implantation as a bridge to lung transplantation in chronic pulmonary insufficiency or as an alternative in the treatment of advanced acute respiratory failure. The prototype devices are comprised of 380 microns outer diameter polypropylene matted fibers with a blood path length of 3.5 cm, frontal area of 128 cm2, void fraction (porosity) of 0.53, and surface area of approximately 2.2 m2. Blood flow is external and approximately perpendicular to the fiber bundle, which fits in an extruded, flexible polyethylene terephthalate housing. Inflow and outflow anastomoses are made to the pulmonary artery and the left atrium, respectively, thereby avoiding a prosthetic blood pump. Inlet and outlet gas lines exit through the chest wall. Nine in vitro experiments of oxygen (O2) transfer performance by the device, with water, initially were done. Our previously described semiempirical mathematical model of convective O2 transfer in cross-flow, hollow fiber membrane lungs was applied to the results from the water tests to predict the transfer rates at any set of blood conditions. Five in vitro blood tests were conducted using a single-pass technique to evaluate O2 and carbon dioxide (CO2) transfer rates, measure pressure losses, and compare predicted and measured O2 transfer rates. O2 transfer rates of 150-200 ml/min, and CO2 transfer rates exceeding 200 ml/min, could be achieved at blood flow rates as great as 4 l/min. Pressure drops of approximately 10-20 mmHg were observed at blood flow rates of 2-4 l/min. Preliminary results of device implantation in two pigs indicate the feasibility of achieving clinically significant O2 and CO2 transfer rates with a low blood-side pressure loss.