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Bio-design and manufacturing 5(1), 141-152 (2022). doi:10.1007/s42242-021-00139-2 special issue: "Smart bioelectronics and biomedical devices", Published by Springer Singapore, Singapore

Although lung transplantation can be used to treat lung failure, limited donor organ availability creates a pressing need for improved artificial lung technology. This review discusses recent developments and future research pathways for respiratory assist devices and regenerative therapies intended to treat advanced lung disease. Hollow fiber membrane gas exchangers can be used to bridge lung failure patients to transplantation. Engineering improvements to such devices are on the verge of enabling longer term wearable systems that simplify and improve support. Progress with microchannel-based devices provides hope of smaller, more biomimetic devices that may even enable implantation; however, further development and testing are needed. Advances in cell-based technologies and tissue engineering have enabled early proof of concept of bioartificial lungs with properties similar to the native organ. Recent progress with artificial lungs has enabled better treatment as a bridge therapy. Continued advances in both engineering and biology will be necessary to achieve a truly implantable artificial lung capable of destination therapy.

Gas transfer through hollow fiber membranes (HFM) can be increased via fiber oscillation. Prior work, however, does not directly translate to present-day, full-scale artificial lungs. This in vitro study characterized the effects of HFM oscillations on oxygenation and hemolysis for a pediatric-sized HFM bundle. Effects of oscillation stroke length (2–10 mm) and frequency (1–25 Hz) on oxygen transfer were measured according to established standards. The normalized index of hemolysis was measured for select conditions. All measurements were performed at a 2.5 L min(−1) blood flow rate. A lumped parameter model was used to predict oscillation-induced blood flow and elucidate the effects of system parameters on oxygenation. Oxygen transfer increased during oscillations, reaching a maximum oxygenation efficiency of 510 mL min(−1) m(−2) (97% enhancement relative to no oscillation). Enhancement magnitudes matched well with model-predicted trends and were dependent on stroke length, frequency, and physical system parameters. A 40% oxygenation enhancement was achieved without significant hemolysis increase. At a constant enhancement magnitude, a larger oscillation frequency resulted in increased hemolysis. In conclusion, HFM oscillation is a feasible approach to increasing artificial lung gas transfer efficiency. The optimal design for maximizing efficiency at small fiber displacements should minimize bundle resistance and housing compliance.

Identifying patients who are ready for weaning and liberation from veno-venous extracorporeal membrane oxygenation (ECMO) is challenging in clinical practice. Compared to the several trials addressing the safety and efficacy of ECMO in severe ARDS [1–4], the body of literature regarding ECMO weaning is remarkably scarce. Therefore, this essential component of the management of patients on ECMO is highly variable and often lacks of a systematic approach [5], analogously to the weaning protocols and spontaneous breathing trials used for liberation from mechanical ventilation [6]. The trajectory from ECMO cannulation to lung recovery and ECMO decannulation consists in the transition from a phase in which ECMO is essential to meet the patient’s metabolic needs (i.e. metabolic oxygen consumption and CO2 production) to a phase in which the native lung function has recovered to satisfy completely the metabolic demands, even if with a degree of ventilatory support considered “safe”. In between these two phases is a continuum of lung healing, during which lung function becomes sufficient to maintain a gas exchange compatible with life, but at the expenses of a high respiratory drive and large swings in transpulmonary pressures. In these conditions, ECMO has the role of maintaining lung protection partially contributing to the patient’s gas exchange [5]. In the effort to track the progress of an individual patient along this imaginary line, it is necessary to measure the relative contribution of the membrane and native lungs in terms of gas exchange, as well as the response of the patient’s respiratory drive and mechanics to the variation in ECMO settings. We propose a physiology-based assessment protocol, which combines an objective assessment of the native and artificial lung function and quantifies the patient’s response to a standardised weaning trial.

Background There is increasing evidence demonstrating the value of partial extracorporeal CO2 removal (ECCO2R) for the treatment of hypercapnia in patients with acute exacerbations of chronic obstructive pulmonary disease and acute respiratory distress syndrome. Mechanical ventilation has traditionally been used to treat hypercapnia in these patients, however, it has been well-established that aggressive ventilator settings can lead to ventilator-induced lung injury. ECCO2R removes CO2 independently of the lungs and has been used to permit lung protective ventilation to prevent ventilator-induced lung injury, prevent intubation, and aid in ventilator weaning. The Low-Flow Pittsburgh Ambulatory Lung (LF-PAL) is a low-flow ECCO2R device that integrates the fiber bundle (0.65 m2) and centrifugal pump into a compact unit to permit patient ambulation. Methods A blood analog was used to evaluate the performance of the pump at various impeller rotation rates. In vitro CO2 removal tested under normocapnic conditions and 6-h hemolysis testing were completed using bovine blood. Computational fluid dynamics and a mass-transfer model were also used to evaluate the performance of the LF-PAL. Results The integrated pump was able to generate flows up to 700 mL/min against the Hemolung 15.5 Fr dual lumen catheter. The maximum vCO2 of 105 mL/min was achieved at a blood flow rate of 700 mL/min. The therapeutic index of hemolysis was 0.080 g/(100 min). The normalized index of hemolysis was 0.158 g/(100 L). Conclusions The LF-PAL met pumping, CO2 removal, and hemolysis design targets and has the potential to enable ambulation while on ECCO2R.

Microfabrication techniques are attractive for constructing artificial lungs due to the ability to create features similar in size to those in the natural lung. However, a simple and intuitive mathematical model capable of accurately predicting the gas exchange performance of microchannel artificial lungs does not currently exist. Such a model is critical to understanding and optimizing these devices. Here, we describe a simple, closed-form mathematical model for gas exchange in microchannel artificial lungs and qualify it through application to experimental data from several research groups. We utilize lumped parameters and several assumptions to obtain a closed-form set of equations that describe gas exchange. This work is intended to augment computational models by providing a more intuitive, albeit potentially less accurate, understanding of the operation and trade-offs inherent in microchannel artificial lung devices.

Current thoracic artificial lungs (TALs) possess blood flow impedances greater than the natural lungs, resulting in abnormal pulmonary hemodynamics when implanted. This study sought to reduce TAL impedance using computational fluid dynamics (CFD). CFD was performed on TAL models with inlet and outlet expansion and contraction angles, θ, of 15°, 45°, and 90°. Pulsatile blood flow was simulated for flow rates of 2-6 L/min, heart rates of 80 and 100 beats/min, and inlet pulsatilities of 3.75 and 2. Pressure and flow data were used to calculate the zeroth and first harmonic impedance moduli, Z(0) and Z(1), respectively. The 45° and 90° models were also tested in vitro under similar conditions. CFD results indicate Z(0) increases as stroke volume and θ increase. At 4 L/min, 100 beats/min, and a pulsatility of 3.75, Z(0) was 0.47, 0.61, and 0.79 mmHg/(L/min) for the 15°, 45°, and 90° devices, respectively. Velocity band and vector plots also indicate better flow patterns in the 45° device. At the same conditions, in vitro Z (0) were 0.69 ± 0.13 and 0.79 ± 0.10 mmHg/(L/min), respectively, for the 45° and 90° models. These Z(0) are 65% smaller than previous TAL designs. In vitro, Z(1) increased with flow rate but was small and unlikely to significantly affect hemodynamics. The optimal design for flow patterns and low impedance was the 45° model.

One of the principal challenges in artificial lung technology has been the ability to provide levels of oxygen and carbon dioxide exchange that rival those of the natural human lung, while mitigating the deleterious interaction between blood and the surface of the synthetic gas exchange membrane. This interaction is exacerbated by the large oxygenator surface area required to achieve sufficient levels of gas transfer. In an effort to address this challenge, microfluidics-based artificial lung technologies comprising stacked microchannel networks have been explored by several groups. Here we report the design, fabrication and initial testing of a parallel plate multilayered silicone-based microfluidic construct containing ultrathin gas exchange membranes, aimed at maximizing gas transfer efficiency while minimizing membrane-blood contact area. The device comprises a branched microvascular network that provides controlled wall shear stress and uniform blood flow, and is designed to minimize blood damage, thrombosis and inflammatory responses seen in current oxygenators. Initial testing indicates that flow distribution through the multilayer structure is uniform and that the thin membrane can withstand pressures equivalent to those expected during operation. Oxygen transfer using phosphate buffered saline as the carrier fluid has also been assessed, demonstrating a sharp increase in oxygen transfer as membrane thickness is reduced, consistent with the expected values of oxygen permeance for thin silicone membranes.

The purpose of this study was to investigate the effect of multiple mechanical forces in gas exchange and hemolysis in an intravascular lung assist device (IVLAD). Specific focus was given to the effect of membrane vibration. We designed the oscillatory type artificial lung assist device attached with a polyvinylidene fluoride sensor and a lead zirconate titanate (PZT) actuator (vibrator). Maximum oxygen transfer occurred at a frequency of 7 Hz for bovine blood and 35 Hz for distilled water. The normalized index of hemolysis oxygenator values for the circuit was 0.0014 g/mL for excitation of the PZT actuator with a sinusoidal 10-V wave and 0.0018 g/mL for a 50-V wave. The experiment results indicate effective performance in enhancing the gas transfer of the IVLAD. This novel hollow membrane filter IVLAD design demonstrates an acceptable level of gas exchange performance with an acceptable level of blood compatibility, and so it has potential as an implantable lung assist device for patients with acute respiratory distress syndrome.

Extracorporeal membrane oxygenation (ECMO) has been successful as a rescue therapy for infants with respiratory failure with some diagnoses such as meconium aspiration syndrome (MAS) having a survival rate of more than 94%. New therapies have allowed many infants who would have required ECMO to be kept off ECMO, but at what cost. The survival rate for the neonatal ECMO patient has dropped over the years, whereas the time of ECMO has increased, indicating that the new therapies are keeping the less ill infants off ECMO. The major cause of non-survival in this population remains intraventricular hemorrhage. The primary risk factors related to this are thought to be pre-ECMO events, such as hypoxia and/or ischemia either prenatally or post-delivery. ECMO events that may complicate this are heparinization that is required while on ECMO and concern for the effect of shear stress and blood flow pattern changes created by the ECMO pump with venoarterial ECMO, although these changes are not seen in venovenous ECMO, the more common form of ECMO. Newer low-resistant microporous artificial lungs and miniaturized pumping systems may allow ECMO to be performed using less blood and safer equipment. The smaller low-resistant artificial lungs provide the ability to consider giving extracorporeal life support using only this membrane with flow provided by an arterial-venous shunt, thus eliminating the pumping system all together. Trials are ongoing in adults and, if effective, may direct further research into using this technique in newborns where the umbilical artery and vein could be used as the arterial-venous shunt.

Surface-coated cardiopulmonary bypass (CPB) has been shown to have excellent biocompatibility during cardiac surgery in adults, but there have been only a few reports demonstrating the efficacy of this coating for congenital cardiac surgery. We tested the efficacy of poly-2-methoxyethylacrylate (PMEA) coating for CPB circuits in congenital cardiac surgery. Eleven operative cases of ventricular septal defect were studied: group C (control: no coating, n = 5) and group P (PMEA coating, n = 6). The platelet count and beta-thromboglobulin (beta TG), fibrinogen (FBG), thrombin-antithrombin complex (TAT), and neutrophil elastase levels were measured during the operation. Postoperative chest tube drainage was analyzed and the surface of the artificial lung was observed with an electron microscope. Elevation of TAT and neutrophil elastase was suppressed in group P (P0.05). Observation of the artificial lung surface using an electron microscope clearly revealed fewer blood cells were adherent to the surface in group P. The FBG level and postoperative bleeding were relatively lower in group P, but there were no significant differences between groups. The platelet count and beta TG level were the same in both groups. We concluded that the PMEA-coated circuit reduces activation of the coagulation system and the inflammatory reaction in pediatric cardiac surgery.

We have utilized soft lithography techniques to create three-dimensional arrays of blood microchannels and gas pathways in poly(dimethylsiloxane) (PDMS) that approach the microvascular scale of the natural lung. The blood microchannels were lined with endothelial cells in an effort to provide a non-thrombogenic surface that might ultimately reduce the need for systemic anticoagulation. A novel design and fabrication method were developed to create prototype modules for gas permeance and cell culture testing. The gas permeance modules contained 6 layers, four gas and two blood, while the modules for cell culture testing contained two layers of blood channels. The gas permeance of the modules was examined and maximum values of 9.16 x 10(-6) and 3.55 x 10(-5) mL/s/cm(2)/cmHg, for O(2) and CO(2) respectively, were obtained. Finally, endothelial cells were seeded and dynamically cultured in prototype cell culture modules. Confluent and viable cell monolayers were achieved after 10 days of perfusion.

This article describes recent progress in the field of artificial lungs, centering on the current state and trends in clinical use and research and development. Trends in the recent clinical use in Japan can be found in shipment-number-based surveys as well as in the questionnaire surveys for clinical extracorporeal membrane oxygenation (ECMO) and percutaneous cardiopulmonary support (PCPS). It is likely that the use of artificial lungs for open-heart surgery has peaked, and this can be attributed to the rapid expansion and popularization of off-pump coronary artery bypass grafting surgery. In contrast, the increase in the number of artificial lungs used in assisted circulation cases is showing significant growth. Along with such clinical trends, research and development toward next-generation systems is active in the field of assisted circulation, focusing on emergency or long-term use of PCPS or ECMO. Approaches include enhancing the performance of conventional systems in terms of long-term durability and hemocompatibility, developing a novel device by integrating the oxygenator with the blood pump, and developing an implantable type of artificial lung such as an intravenous oxygenator. Next-generation devices not only will benefit a multitude of patients but also represent an important target with the prospect for expansion of the market for artificial lungs. In the future, further expansion of research and development in this field, as well as progress in practical and clinical applications of innovative devices, is expected.

We have extended our model of the ovine pulmonary circulation to include a model of a paracorporeal artificial lung (AL) and its attachments to the natural pulmonary circulation in two configurations: in series and in parallel. Our model of the natural lung (NL) circulation is first shown to be in agreement with hemodynamic and input impedance data from the open literature. We then study design efficacy of the AL in terms of its housing and attachments. A sensitivity analysis of the modified pulmonary circulation model reveals that there are three key parameters: inlet graft length (IGL) and the compliances of the inlet compliance chamber (CC) and housing of the artificial lung. Based on literature reports, we assume the right ventricle is well-matched to the impedance of the natural pulmonary circulation and adjust the parameters of the modeled AL circuit to achieve the best least-squares fit to natural pulmonary input impedance data. Best-fit parameters produce impedance curves that fit natural impedance well, particularly below 3 Hz, where both compliance and graft length have their largest effects. Of these parameters, the impedance profile is most sensitive to IGL. However, the compliances are important, as well, particularly at low frequencies.

The artificial lung was first developed in 1939 and transformed from a research project to a commercial product in the 1970s. The commercial product is called an oxygenator. Driven by a market desire and market growth in conjunction with the growth of cardiac surgery, many companies developed competitive oxygenators. After a couple of decades of competitive development, oxygenator technology has improved drastically. As the oxygenator market has matured, it has become less profitable and now shows a low growth rate. Because of this, industry has reduced the development effort for future oxygenators. However, thanks to these developments, we now have a significant technology base to apply to the artificial lung. Now it is time to go to the next step toward a true artificial lung. To achieve this, the most important thing to understand is the market needs.

Zusammenfassung Trotz anhaltender Diskussion ist die extrakorporale Membranoxygenierung (extracorporeal membrane oxygenation, ECMO) auch bei erwachsenen Patienten zu einem festen Bestandteil der therapeutischen Optionen in der Behandlung des akuten Lungenversagens (ARDS, acute respiratory distress syndrome) geworden. Die beiden bislang durchgeführten randomisierten Vergleichsstudien konnten allerdings keinen Vorteil im Hinblick auf die Letalität verglichen mit konventioneller Beatmungstherapie belegen. In der Konsequenz resultierte aus beiden Studien keine Empfehlung für die ECMO-Therapie (1–3). Mittlerweile liegen weitreichende weltweite Erfahrungen (Gesamtzahl der therapierten erwachsenen Patienten Ende 2001 ca. 1000) vor. Wachsende Erfahrung und verbesserte Technik haben die Rate technischer Komplikationen der extrakorporalen Lungenersatztherapie deutlich reduziert. Aus einer Reihe von Gründen ist in der jüngsten Zeit die Inzidenz des Einsatzes von ECMO dennoch deutlich rückläufig. Einzelne Ein- und Ausschlusskriterien variieren zwischen den verschiedenen ECMO-Zentren. Potentielle Reversibilität der aktuellen Lungenschädigung und bei ausgeschöpfter konventioneller Therapie Fortbestand einer lebensbedrohlichen Gasaustauschstörung stellen jedoch übereinstimmende Grundvoraussetzung für die Durchführung einer ECMO-Therapie dar. Gebräuchliche Kriterien sind ein Murray lung injury score >3,5 (Röntgen-Befund, PaO2/FiO2 Ratio, statische Compliance=Cstat, PEEP) eine Morel-Klassifikation >3 (Röntgen-Befund, AaDO2/FiO2-Index, Cstat, PEEP), eine AaDO2 >600mmHg, ein intrapulmonaler Shunt QS/QT >30% und eine Erhöhung des extravaskulären Lungenwassers auf >15ml/kg KG. In manchen Zentren stellt darüber hinaus die Dauer der maschinellen Beatmung (2 Erythrozytenkonzentrate pro h), Alter >60 Jahre und – besonders in den USA – die Dauer der vorausgehenden invasiven Beatmung. Nach unserer Erfahrung optimiert ein frühzeitiger Kontakt zu einem ECMO-Referenzzentrum die Identifikation von Patienten die von einer ECMO-Therapie profitieren, die Gesamttherapie, den Transport und das Outcome. Auf Grund der hohen apparativen und personellen Anforderungen bei gleichzeitig sinkender Inzidenz sollte ECMO im Erwachsenensektor auf eine kleine Zahl Referenzzentren mit großer Erfahrung begrenzt bleiben. Damit lässt sich gleichzeitig eine ausreichende Routine aufrechterhalten. In Zeiten sich wandelnder ökonomischer Rahmenbedingungen kommt einer kritischen Indikationsstellung und hochqualifizierten Durchführung der ECMO-Therapie eine besondere Bedeutung zu.

In the 1970s, the use of cardiopulmonary bypass at the bedside for critically ill patients with respiratory failure began and was termed extracorporeal membrane oxygenation (ECMO). Later, in the 1980s, applications for extracorporeal technology expanded, and included oxygenation, CO2 removal, and hemodynamic support. However, early studies regarding the use of ECMO for acute lung failure provided less than optimistic results. Today, recent research has created a renewed interest in such technology. There have been progressive advancements in artificial lung technology, and ECMO serves as a form of life support and as a bridge to transplantation for critically ill patients when traditional supportive care is no longer effective. These progressive advancements in artificial lung technology provide another tool in the critical care physician’s arsenal to combat this often fatal injury.

Intravascular oxygenation and carbon dioxide removal remains a potentially attractive means for respiratory support in patients with acute or chronic respiratory failure. Our group has been developing an intravascular hollow fiber artificial lung that uses a pulsating balloon located within the fiber bundle to augment gas transfer. We previously reported on a simple compartmental model for simulating O2 exchange in pulsating intravascular artificial lungs. In this study we evaluate the O2 exchange model with gas exchange and PO2 measurements performed on an idealized intravascular artificial lung (IIVAL) tested in a water perfusion loop. The IIVAL has well-defined bundle geometry and can be operated in balloon pulsation mode, or a steady perfusion mode for determining the mass transfer correlation required by the model. The O2 exchange rates and compartmental O2 tensions measured with balloon pulsation in the IIVAL are within 10% of model predictions for flow and pulsation conditions relevant to intravascular oxygenation. The experiments confirmed that a significant buildup of PO2 occurs within the fiber bundle, which reduces the O2 exchange rate. The agreement between experiments and predictions suggests that the model captures the cardinal processes dictating gas transfer in pulsating intravascular artificial lungs. © 2000 Biomedical Engineering Society. PAC00: 8780-y, 8710+e

Acute respiratory distress syndrome (ARDS) is a pulmonary edemic condition which reduces respiratory exchange in 150,000 people per year in the United States. The currently available therapies of mechanical ventilation and extracorporeal membrane oxygenation are associated with high mortality rates, so intravenous oxygenation represents an attractive, alternative support modality. We are developing an intravenous membrane oxygenator (IMO) device intended to provide 50% of basal oxygen and carbon dioxide exchange requirements for ARDS patients. A unique aspect of the IMO is its use of an integral balloon to provide active mixing. This paper describes a mathematical model which was developed to quantify and optimize the gas exchange performance of the IMO. The model focuses on balloon activated mixing, uses a lumped compartment approach, and approximates the blood-side mass transfer coefficients with cross-flow correlations. IMO gas exchange was simulated in water and blood, for a variety of device geometries and balloon pulsation rates. The modeling predicts the following: (1) gas exchange efficiency is reduced by a buildup of oxygen in the fluid near the fibers; (2) the IMO gas exchange rate in blood is normally about twice that in water under comparable conditions; (3) a balloon diameter of about 1.5 cm leads to optimal gas exchange performance; and (4) in vivo positioning can affect gas exchange rates. The numerically predicted gas transfer rates correlate closely with those experimentally measured in vitro for current IMO prototypes. © 1998 Biomedical Engineering Society.

The results of the present testing of the PEPR as an executive element of distributive system of ALV devices revealed the static and dynamic characteristics of the PEPR to meet the requirements for devices of this class. Multifunctional properties of the PEPR allow its direct use, without additional modification, in different types of ALV devices. Electric control of the PEPR allows effective incorporation of microprocessor controllers in the design of even portable ALV devices, facilitating unification of ALV devices designed for different fields of application.

Five different artificial organs or tissues are selected from our studies to show how membranes are used as biomaterials. They are artificial kidney, artificial lung, artificial skin, artificial pancreas, and artificial cornea. The membranes in these artificial organs are mostly employed to allow the selective permeation of some substances, similar to those in industrial applications. However, biocompatibility is additionally required in the medical applications of these membranes. It is shown that coupling of poly(ethylene glycol) onto the cellulose membrane used for hemodialysis greatly improves the blood compatibility, while graft polymerization of acrylamide onto a silicone membrane used for extracorporeal membrane oxygenation largely reduces clot formation on the surface. The silicone membrane is shown to be effective also for protection of damaged skin, when used with a porous collagen sheet. It is further demonstrated that poly(vinyl alcohol) membranes without and with immobilized collagen can be used for the entrapment of Langerhans islets and for the repair of damaged corneal tissue, respectively.

We modified a Bain circuit by placing the circuit into the Y piece of a standard carbon dioxide absorber circle, connecting the fresh gas hose on the anesthetic machine to the Bain's fresh gas inlet, and occluding the circle's fresh gas inlet. This circle-modified Bain breathing circuit was studied to evaluate whether it reduces fresh gas flow requirements. The Bain and modified Bain steady states were analyzed by mechanical and computer modeling. The mechanical model consisted of an artificial lung ventilated to steady state. Carbon dioxide was measured with capnography. Computer modeling was by compartmental analysis calculated with spread-sheet software. Steady-state solutions were obtained by numeric analysis. The circle-modified Bain greatly reduced retention of carbon dioxide. For example, with 1-liter tidal volumes, 10-liter minute volumes (10 breaths per minute), and a 2.1 L/min fresh gas flow, the steady-state end-tidal carbon dioxide values of the Bain and modified Bain were 9.3 and 4.6%, respectively, in the physical model (carbon dioxide inflow of 230 ml/min). Results from the mechanical model helped validate the computer model.

The effect of hyperbaric oxygen (HBO) on the growth of anaplastic carcinoma colonies in rat lungs after intravenous tumor cell injection was studied. From the first day after tumor cell injection, the rats were exposed to HBO for 16-21 days, 90 min per day. Oxygen at a pressure of 300 kPa (3.0 ATA) significantly decreased the number of lung tumor colonies and increased the survival of tumor-bearing rats, whereas the application of oxygen at a pressure of 100 kPa had no effect. An oxygen-nitrogen normoxic mixture balanced with nitrogen to 300 kPa (3.0 ATA) did not affect the number of colonies, suggesting that the effect was specific for oxygen and not for the increased pressure itself. A 6-day application of oxygen at a 300 kPa pressure suppressed the growth of lung tumor colonies when applied on days 1-6 and 7-12 after intravenous tumor cell injection, but had no effect when applied on days 13-18. In contrast to dramatic effects of HBO on the development of artificial lung metastases, the oxygen at the same 300 kPa pressure had no effect on the growth of tumor cells injected in the hind foot. Thus it appears that the suppression of lung tumor colonies by HBO was due to local oxygen effects in the lungs.

The goal of this work is to design and build an impiantatile artificial lung that can be inserted as a whole into a large vein in the body with the least effect on cardiovascular hemodynamics. The experimental results demonstrate that the pressure drop is not entirely related to viscosity effects. The friction factor decreases with an increase in the number of tied-hollow fibers at a constant Reynolds number. A uniform flow pattern without stagnation is observed at all numbers of tied hollow fibers tested. The tied hollow fiber module, built in this study with 3 cm of outer diameter of module, 380 m of outer diameter of tied hollow fiber, and 700 number of tied hollow fiber with length of 60 cm, which shows a pressure drop of 13–16 mmHg, satisfies the required pressure drop qualifying 15 mmHg as an intravascular artificial lung.

Introduction: Accurate measurement of airway pressures (Paw) are crucial during mechanical ventilation. Intratracheal pulmonary ventilation(ITPV) utilizes a reverse thruster device to deliver a continuous flow of gas at the level of the carina, thereby generating a different carinal Paw than conventional ventilation (CV). This study compares the proximal and carinal Paw during CV and ITPV, in both an artificial lung an in a rabbit model.

In 1988 a heat moisture exchanger (HME) was introduced for neonatal use. We tested this in the laboratory for efficiency of heat and moisture retention at typical neonatal ventilator settings. Methods: A manifold was built which contained the HME with either side, a thermistor, pressure transducer and relative humidity (RH) sensor. All six probes were connected to a computerised monitoring system that continuously displayed the variables. Results: The HME increased the dead space of the circuit by 1.2 mls. 1 hour experiments showed a temperature gradient of 4°C and a RH gradient of 90% with no significant alteration at flow rates between 2-10 L/min. There was no pressure gradient and the airway pressure rise time did not increase when the HME was present. 16 hour experiments showed no significant water loss from the water saturated artificial lung used in the tests. Conclusion: The HME is highly efficient in this system and would be useful at least in situations where infants are ventilated with unhumidified gas (eg. transportation).

Intravenous infusions of perfluorochemical emulsions, combined with administration of inspired oxygen or carbogen have been found to improve tumor oxygenation and increase the response of solid tumors in animals to radiotherapy. Fluosol-DA 20 per cent, the only perfluorochemical emulsion currently approved for testing in humans in the United States, has recently entered clinical trials as an adjunct to radiotherapy in the treatment of head and neck carcinoma. The studies reported here were undertaken as part of our laboratory evaluation of the safety and clinical potential of this oxygen-transport fluid as an adjunct to cancer therapy; they asked whether single or multiple treatments with Fluosol and an oxygen-enriched atmosphere produced immunologic perturbations, pulmonary damage, or other effects which altered the development of artificial lung metastases in experimental animals. Neither single nor multiple treatments with clinically relevant regimens of Fluosol and carbogen (95 per cent O2/5 per cent CO2) had any effect on the development of lung nodules from intravenously injected EMT6 tumor cells.

Anin vitro evaluation of an experimental membrane blood oxygenator was conducted. Blood in the oxygenator was mixed by an oscillating metal rod, which led to a considerable reduction in the diffusional resistance to oxygen transfer. Nevertheless, membrane limited performance was not experimentally realised. Computer simulation of a mathematical model of boundary-layer gas exchange revealed that the oxygen uptake in red cells is controlled by the length of the diffusion path. There was almost no difference in the calculated saturation times using either finite or instantaneous reaction kinetics. These considerations are used to explain the performance of the oxygenator.

By means of ultrasonic method used in acute experiments on cats with open chest under artificial lung ventilation the authors studied the blood flow in low-lobar pulmonary artery and the vein, the blood pressure in pulmonary artery as well as the balance between output of right and left ventricles in experimental pulmonary edemas caused by intravenous infusion of mixture fatty acids. It was shown, that acute injury of lungs vessels produces redistribution of blood flow to the lesser circulation, increases the pressure in pulmonary artery. The pattern of pulsating blood flow in lobar artery and vein changes. The authors assume that in situation, when lung vessels permeability is already deranged redistribution of the blood to the lesser circulation aggravates the degree of edema.

An overall design analysis is presented for oxygenators with sheet-membrane blood channels. Those types considered are clear channels without and with transverse mixing and woven-mesh filled channels with thick and thin membranes. The analysis accounts for oxygen-transfer rates and increased flow resistance produced by the screens and for such fabrication variables as blood header length, header-thickness-to-channel-height ratio, and blood-screen void volume. For reasonable priming volumes, practical channel lengths and total widths, oxygenators having screen-filled channels with thick membranes or clear channels without mixing are only suitable for partial adult or neonatal support. Adult total bypass is feasible with screen-filled channel designs using thin or highly permeable membranes. Since the configuration of existing clear channel devices with secondary mixing (e.g. Couette or Taylor-vortex types) usually involves a single and relatively thick channel, they are restricted to neonatal or partial bypass applications despite their inherent high transfer efficiencies.

Treatment of severe acute respiratory failure with extracorporeal gas exchange necessitating near complete systemic anticoagulation requires a delicate balance to be maintained between disseminated intravascular coagulation and hemorrhagic complications. The present study describes our first experience using a heparin coated extracorporeal artificial lung and circuitry during clinical extracorporeal CO2 removal. In spite of a partial thromboplastin time and activated clotting time within or close to the normal range, neither laboratory evidence for disseminated intravascular coagulation induced by the extracorporeal circuit nor thrombi in the pulmonary vasculature were found. Scanning electron microscopy of the heparin coated hollow fiber gas exchanger demonstrated only minor deposits on the surface. Use of a heparin coated artificial lung may enhance the margin of safety of extracorporeal gas exchange and ultimately broaden its indications.

Extracorporeal CO2-removal promises to be an efficient alternative to the conservative treatment of advanced lung diseases. Extracorporeal CO2-removal is achieved in a veno-venous bypass in combination with low frequency ventilation. Positive clinical results in the treatment of adult respiratory distress syndrome (ARDS) are encouraging. In order to prove the applicability of this method to different kinds of respiratory insufficiency, physiological studies using animal models are necessary. We report here on experiments with dogs and sheep undergoing a veno-venous bypass employing a CO2-eliminator. The experimental results are compared with theoretical values which predict the important relationships between blood flow rate of the extracorporeal circulation (ECC), the CO2-elimination capacity of the CO2-eliminator and the low ventilation rate (down to apnea for 5 h) of the natural lung. It was shown that the blood gas data as well as acid base status could be maintained within physiological ranges.

A semi-empirical graphical method to predict the performance of oxygenators using straight and parallel capillary tubes has been developed from a mathematical model and an extensive amount ofin vitro data obtained under precisely controlled conditions. This graphical technique predicts the performance of a given oxygenator for exchange of both oxygen and carbon dioxide for a wide range of blood flows and input-blood conditions, and greatly simplifies the analysis of data taken in evaluation procedures where precise control of test conditions is not achieved. Performance predictions for capillary-tube oxygenators obtained by this method are supported by preliminaryin vivo data, as well as by extensivein vitro data. The calculation also provides a simple means of designing or selecting a capillary oxygenator for application under known operating conditions. This method has indicated that, for the same blood flow rate, oxygenators staged in series are significantly more effective than when connected in parallel. This prediction has also been verified in the laboratory.

1. A special oxygenator-deoxygenator system is proposed for estimating the characteristics of new and commercially manufactured oxygenators.

Experiments designed to investigate concomitant enhancement of tumor growth in the lungs of tumor-bearing mice are reported. When a fibrosarcoma (NFSA)3 that had arisen spontaneously in a C3Hf/Bu mouse was transplanted into the hind legs of syngeneic mice 2 weeks prior to IV tumor challenge, the tumor-bearing mice developed more lung colonies than did normal controls. Paradoxically, the same mice demonstrated concomitant resistance to an IM tumor challenge. Animals bearing the tumor for only 1 week and those from which the tumor had been excised after 2 weeks' growth showed neither enhancement nor resistance to lung colony growth. Enhancement in mice bearing the tumor for 2 weeks was shown not to be due to metastases seeded from the primary tumor. Tumor-bearing animals receiving whole-body irradiation (WBI) 1 day before or 12 days after tumor transplantation showed no enhancement compared with nontumor-bearing WBI controls. Mice receiving partial body radiation with the thorax shielded also failed to show concomitant enhancement. Adult thymectomy alone did not affect the enhancement, while thymectomy followed by whole-body irradiation and bone marrow-cell reconstitution abolished it. Although apparently dependent upon relatively long-lived T cells, enhancement was not tumor-specific; mice bearing another fibrosarcoma (FSA), which does not cross react immunologically with NFSA, also showed enhancement when challenged IV with NFSA. Treatment of tumor-bearing mice with C. parvum prior to IV challenge prevented the enhancement phenomenon.

The capacity of IV injected fibrosarcoma cells to form metastatic nodules in the lungs of corresponding syngeneic CBA mice was enhanced by pretreatment of tumor cell recipients with cyclophosphamide. The effet depended upon the dose but not upon the injection route of cyclophosphamide. The enhancement of lung-colony formation lasted for about 10 days after injection of the drug, with its maximum at day 1. Cyclophosphamide was also effective in whole body-irradiated and TIR mice. Its effect, however, was abolished to a great extent by reconstituting mice with nonseparated or nonadherent spleen and bone marrow cells from either normal or TIR mice. Lymphoid cells from CY-treated mice, however, had no such reconstitutive capacity. These observations imply that the cyclophosphamide-induced enhancement of tumor metastasis formation was partly due to nonimmunologic factors and partly due to suppression of non-T lymphocytes.

Top of pageAbstract Extracorporeal techniques for respiratory support in the newborn are feasible and established as neonatal extracorporeal membrane oxygenation (ECMO). It has been shown however, that even in severly damaged lungs, sufficient oxygenation (apneic oxygenation) can be maintained by only removing CO2 with an artificial lung, a technique called extracorporeal CO2-removal (ECCO2R). During routine acetate hemodialysis in 22 patients with end stage renal disease an overall CO2-removal of 79.1 +/- 15.1 ml was measured, at least one third of the entire metabolic CO2-production. For total metabolic CO2-removal, acetate dialysate (22mmol/l) was modified with phosphate buffer (2mmol/l), lactate (5mmol/l) and sodium hydroxide (7mmol/l) to compensate for the bicarbonate loss. In 6 sheep, apneic oxygenation could be achieved with blood flow rates as low as 10-15 ml/kg/min for 4-6 hours. These data suggest that a hemodialysis procedure for bicarbonate and CO2elimination (ecBICCO2R) is an efficient method for CO2-removal necessitating much lower blood flow rates than other techniques presently used. An other advantage of this technique is the maintainence of acid-base, electrolyte and fluid balance as well as renal replacement in multiple organ failure.