The Low-Pressure Rocking

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1 The Low-Pressure Rocking Membrane Oxygenator An Infant Model Arthur S. Palmer, M.D., Richard E. Clark, M.D., and Mitchell Mills, M.D. T he use of membrane oxygenators promises to facilitate long-term extracorporeal support through the elimination of a blood-gas interface and attendant blood protein damage [6, 101. Although a number of workers have developed membrane units that have functioned well for them clinically, these units have not gained general acceptance because of problems such as leaks, low rates of gas transfer, or tedious assembly. In a search for a method of long-term extracorporeal support for infants with respiratory distress due to reversible cardiac or pulmonary disease, we have had occasion to study a commercially available membrane oxygenator.* THEORETICAL CONSIDERATIONS The limitation governing the rate of gas exchange in membrane oxygenators is imposed by the combined rates of two interrelated gas transport processes. These are the gas transport through the membrane and the gas transport away from the membrane-blood interface into the blood phase. In the case of oxygen, the gas must first diffuse across the membrane. The rate at which this occurs is determined by the membrane thickness, the partial pressure gradient, and the solubility and diffusion coefficients of oxygen in the membrane material. The oxygen must then be carried away from the membrane-blood interface. This may occur either by diffusion further into the blood pool, or through the actual physical motion of the oxygenated blood away from this area. If oxygen is allowed to build up at this interface, the partial pressure gradient across the membrane will decrease, thereby decreasing transfer across From the Thoracic and Cardiovascular Surgical Service, Naval Hospital, National Naval Medical Center, Bethesda, Md. The opinions or assertions contained herein do not necessarily reflect the views of the Navy Department or the naval service at large. Accepted for publication July 29, Address reprint requests to Dr. Palmer, Department of Surgery, Veterans Administration Research Hospital, 333 East Huron Street, Chicago, Ill 'Medical Monitors (infant model). The Waters Co., Rochester, Minn.

2 PALMER, CLARK, AND MILLS the membrane and setting a practical limit on overall oxygen transport. Unfortunately, the rate of diffusion of oxygen into a layer of deoxygenated blood is very slow relative to the rate of diffusion through available membranes [l 11. This transport of oxygen away from the membrane-blood interface is thus the factor that tends to limit oxygen exchange. With extremely thin blood films, as in the sandwich [12] and capillary [5] types of membrane oxygenators, this slow rate of diffusion is tolerable. These thin blood films, however, have required high membrane perfusion pressures and have introduced complex problems in design and fabrication. The alternate approach, that of causing the oxygenated blood to physically flow away from the membrane-blood interface, allows for low perfusion pressures and has inspired a number of membrane oxygenator designs [4, 8, 9, 131. These usually employ a relatively thick film of blood flowing parallel to the membrane. In this situation there exists a boundary layer of blood immediately adjacent to the membrane which tends to stagnate on the membrane surface. The thickness of this boundary layer is a complex function of many variables, including flow rate, viscosity, and surface roughness. Oxygen still must diffuse passively through this boundary layer before it can participate in any induced mixing process. Efforts to decrease boundary layer thickness, and thereby its influence on oxygen transfer rate, have involved methods for rapid refilming of the blood across a roughened membrane surface, using some form of agitation. In the case of carbon dioxide, the rate of diffusion through a layer of blood is rapid. The driving partial pressure gradient across the membrane, however, is only about one-twelfth that of oxygen (assuming a normal venous PO, and $0, and 100% oxygen in the gas phase). The silicone polymer membranes presently in use are about six times more permeable to carbon dioxide than to oxygen. Thus, if the oxygen transport problems in the blood are overcome, carbon dioxide will transfer through the membrane only half as rapidly as oxygen, and the amount of blood a given membrane area will arterialize would be determined by the rate of carbon dioxide transfer through the membrane. From the above considerations, it follows that the total membrane area necessary is a function of the required rate of carbon dioxide transfer, and the actual design of the membrane oxygenator, with respect to blood film thickness and mechanisms of agitation, is a function of the required rate of oxygen transfer. A PPA RA T US The low-pressure, thick blood-film unit studied uses a membrane of M mil silicone rubber on a Dacron net. The rough net appears on the blood side of the membrane to aid in agitation. The membrane is formed into envelopes with a 31 cm. by 32 cm. exchange surface on each side, or 0.2 square meter membrane 14 THE ANNALS OF THORACIC SURGERY

Rocking Membrane Oxygenator area per envelope. Either two or four of these membrane envelopes may be fastened to each of two expanded metal supporting screens.

3 Rocking Membrane Oxygenator area per envelope. Either two or four of these membrane envelopes may be fastened to each of two expanded metal supporting screens. The screens slope three degrees down from the horizontal. They can be rocked around a central axis through an arc of 45 degrees in each direction at a rate ranging from 0 to 80 oscillations per minute. The screens, with attached membranes, are enclosed in a stainless-steel frame covered with a transparent Mylar hood. When in use, venous blood drains into the venous reservoir and is distributed via a manifold to each of the membrane envelopes. As it drains through the membrane envelopes to the arterial reservoir, it is constantly refilmed over the rough membrane surface by the rocking action of the supporting screens. This refilming can be observed visually. Warm humidified oxygen is directed between and around the membrane envelopes. METHODS GAS TRANSFER The unit was assembled using two membrane envelopes per screen. It was connected in series with a disc oxygenator which was set up to deoxygenate blood (Figure). The system was primed with 21-day-old human bank blood of a single ABO and Rh type. Heparin and sufficient sodium bicarbonate were added to maintain a base excess of zero, as determined with a Siggaard-Andersen nomogram [141. Blood temperature was maintained at 57 C. with a Gebauer heat exchanger. Blood drained by gravity from the disc deoxygenator through a Biotronex electromagnetic flow probe into the venous reservoir of the membrane oxygenator. Following oxygenation in the membrane envelopes, the blood was returned from the arterial reservoir to the disc deoxygenator with a single-head roller pump. Nitrogen, oxygen, and carbon dioxide were supplied to the deoxygenator at flow rates that reduced the PO, to venous levels. Blood flow was started at 100 ml. per minute and increased by increments of 100 ml. per minute to 800 ml. per minute. After stabilization at each flow rate, arterial and venous samples were drawn. An Instrumentation Laboratory apparatus was used to determine ph, p02, and pcoz, and saturations were determined with an 4 HE./ Schematic representation of the circuit used for in vitro gas exchange studies. DD = disc deoxygenator, TP = thermistor probe, RP = roller pump, AR = arterial reseruoir, MO = membrane oxygenator, VR = venous reservoir, FP = electromagnetic flowmeter probe, SC = screw clamp, HE = water lines to heat exchanger.

PALMER, CLARK, AND MILLS American Optical reflective oximeter. This series was then repeated with the membranes rocking at 25, 35, 45, 55, and 65 oscillations per minute.

4 PALMER, CLARK, AND MILLS American Optical reflective oximeter. This series was then repeated with the membranes rocking at 25, 35, 45, 55, and 65 oscillations per minute. All results were duplicated during three separate runs, using a new blood prime and new membranes for each run. HEMOLYSIS The unit was assembled with a set of two new membrane envelopes on each screen. The pulsatile arterial pump supplied with the unit was used to recirculate blood from the arterial to the venous reservoir after it had flowed through the membrane envelopes. The system was primed with 800 ml. of freshly drawn heparinized dog blood. Blood flow was started at the rated capacity of 800 ml. per minute. Rocking speed was set at 55 oscillations per minute, and oxygen flow was 4 liters per minute. Samples were taken at hourly intervals for plasma hemoglobin determination by the Beau method [3]. To determine what portion of plasma hemoglobin was contributed by the pump and fittings alone, the membrane envelopes were removed and replaced by lengths of quarter-inch Tygon tubing. The experiment was then repeated using a new fresh blood prime. ANIMAL PERFUSIONS The unit was assembled with the maximum of four membrane envelopes on each screen, using the manifolds and reservoirs supplied with the envelopes; 1,000 ml. of Ringer s lactate solution and 500 ml. of heparinized dog blood were added as prime and recirculated until the system was devoid of visible air. Beagle dogs weighing approximately 8 kg. were anesthetized with sodium pentobarbital (22 mg. per kilogram of body weight) and intubated. Large venous cannulas were placed in the superior and inferior venae cavae via a femoral and jugular vein. An arterial cannula was placed in a femoral artery, and partial bypass was instituted. Total cardiopulmonary bypass was accomplished through the induction of ventricular fibrillation with an A.C. fibrillator. RESULTS Each membrane envelope provided 0.2 square meter of membrane surface. Thus, there was a total of 0.8 square meter with two envelopes per screen and 1.6 square meters with four. A few representative data points obtained with the unit in series with the deoxygenator are shown in Table 1. The rate of oxygen transfer was consistently 15 to 24 cc. per minute in the clinically useful range of poz. The average was 20 cc. per minute, or 25 cc. per minute per square meter. As shown in the table, higher rates of transfer could be obtained by markedly decreasing venous saturation; however, the membranes were then no longer able to arterialize fully the blood presented to them. The rates of oxygen transfer as calculated from the three separate runs were easily reproducible for each data point. Carbon dioxide was handled well, as reflected in an arterial pc0- consistently below 45 mm. Hg and usually below 40 mm. Hg. Variation of the membrane rocking speed between 35 and 65 oscillations per minute produced no change in the rate of oxygen transfer. Below 35 or over 65 oscillations per minute there was visible channeling of the blood, and the oxygen transfer rate dropped markedly. Variation in the rate of oxygen supply had no observable effect on oxygen transfer rate, provided that the flow was sufficient to distend slightly the membrane envelopes. The amount of free plasma hemoglobin generated by the pump and fittings used in the hemolysis test circuit was 10 mg. per hour over a four-hour period. With the rocking membrane envelopes in the circuit, this amount was increased to 46 mg. per hour. The membrane envelopes thus contributed 36 mg. per hour. In our initial animal perfusions, we found that with eight membrane 16 THE ANNALS OF THORACIC SURGERY

5 Rocking Membrane Oxygenator TABLE 1. IN VITRO GAS EXCHANGE DATA USING FOUR MEMBRANE ENVELOPES AT A ROCKING RATE OF 55 OSCILLATIONS PER MINUTE Oxygen Oxygen Blood Satura- PCOZ Oxygen Transfer tion (%) (mm. Hg) Flow Transfer (cc./ (ml./min.) Venous Arterial Venous Arterial (cc./min.) min./m2) envelopes we could not arterialize twice the blood flow we had arterialized with four membrane envelopes in the in vitro circuit. We observed the cause of this to be unequal distribution of the blood from the venous reservoir to each of the eight membrane envelopes. A few envelopes receiving very small blood flows contributed negligible amounts to total oxygen transfer. Those receiving large flows were overwhelmed and were discharging only partially oxygenated blood into the arterial reservoir. Attempts to correct this by readjusting the membranes on the screens and carefully adjusting the tension of each individual envelope were unsuccessful. Owing to this unequal blood distribution, the arterial p02 consistently fell below 60 mm. Hg in our first few animal experiments, as shown in Table 2. We therefore abandoned the eight-membrane system as well as further animal perfusions with this unit. COMMENT The preparation of this membrane oxygenator for perfusion was easy and rapid. The membranes and lines were all preassembled at the factory and needed only to be fastened to the machine after sterilization. Occasional pinhole leaks were encountered in a membrane, but because of the low operating pressures these were not significant with respect to blood loss. The rate of oxygen transfer we obtained is about the same as that reported by Shepherd et al. [13] using a similar machine. With four membranes in place, this provides for oxygen transfer of only 15 to 24 cc. per minute, which will arterialize a blood flow of about 500 ml. per minute. This provides inadequate reserve for complete cardiopulmonary bypass, even in infants. Attempts to increase membrane surface area with eight membrane envelopes were unsuccessful, probably because of uneven membrane tension, and the animal perfusions with this unit were abandoned because of inadequate oxygenation. A more practical method of increasing membrane area might be simply to use larger membrane

6 $ 2 8 TABLE 2. PERFUSION DATA USING EIGHT MEMBRANE ENVELOPES AND A DOG WEIGHING 8 KILOGRAMS T a n vl Blood PO2 pco2 Base (mm. Hg) (mm. Hg) s Time Flow PH Excess Mode of m 6 (min.) (ml./min.) Venous Arterial Venous Arterial Venous Arterial (meq/liter) Bypass Partial 30 1, Total 45 1, Total 60 1, Total Partial

Rocking Membrane Oxygenator envelopes on a larger machine. Crystal et al. [4] have studied a similar machine, designed for adults, with envelopes three times as large as those reported here.

7 Rocking Membrane Oxygenator envelopes on a larger machine. Crystal et al. [4] have studied a similar machine, designed for adults, with envelopes three times as large as those reported here. They reported an oxygen transfer rate of 29 cc. per minute per square meter, with a potential membrane area of 8.4 square meters. This provides for a maximum transfer rate as high as 245 cc. per minute. It is interesting to note that Crystal and his coworkers obtained a rate of oxygen transfer per square meter very similar to ours while using 1/2 mil Teflon membranes, which are much less permeable to oxygen than the silicone type on our machine. This demonstrates the dependence of oxygen transfer rate on oxygenator design with respect to adequate blood agitation, rather than on membrane permeability. Katsuhara et al. [8], using a rocking membrane oxygenator based on the same principle but of an apparently more efficient design, reported an oxygen transfer rate of 92 cc. per minute per square meter. This is more than three times the rate encountered by Shepherd, Crystal, and ourselves using the design reported here. The observed rate of hemolysis appears surprisingly high for a membrane oxygenator. A high rate of hemolysis was observed by Frater et al. [7] using a similar machine, but they reported no definite figures. The fact that there was a small circulating volume in the test circuit contributes to the rapid rise in plasma hemoglobin concentration but will not change the hemolytic index [l]. The hemolytic index of 0.37 mg. per 100 ml. calculated for this unit compares favorably with that of 3.5 mg. per 100 ml. for a 17-inch disc oxygenator and 1.22 mg. per 100 ml. for an adult Temptrol bubble oxygenator, calculated from data obtained in a similar circuit [2], but it is certainly higher than expected. SUMMARY AND CONCLUSIONS Theoretical considerations concerning gas exchange in membrane oxygenators reveal that the rate of carbon dioxide transfer is a function of membrane area, while oxygen transfer rate is dependent on oxygenator design. A commercially available infant membrane oxygenator was evaluated. In the clinically useful range of hemoglobin saturation, the oxygen transfer rate averaged 20 cc. per minute or 25 cc. per minute per square meter. Carbon dioxide transfer was adequate at maximum blood flows. The hemolytic index for the rocking membranes was 0.37 mg. per 100 ml. The findings of this study suggest the following conclusions: 1. The rocking membrane concept permits membrane oxygenator designs that are dependable and that can be assembled rapidly and easily. These oxygenators operate at low pressures, and thus leaks are not a problem. VOL. 9, NO. 1, JANUARY,

8 PALMER, CLARK, AND MILLS 2. This model transferred oxygen at a rate insufficient for total extracorporeal support in infants. Other designs, using this same concept, have been reported to transfer sufficient quantities of oxygen for total extracorporeal support in both infants and adults. 3. Carbon dioxide transfer was adequate. 4. Hemolysis due to membrane agitation results in a hemolytic index in this model which is slightly higher than in most extracorporeal pumps, but much lower than in disc or bubble oxygenators. REFERENCES 1. Allen, J. G. (Ed.). Extracorporeal Circulation. Springfield, 111.: Thomas, P Andersen, M. N., and Kuchiba, K. Blood trauma produced by pump oxygenators. J. Thorac. Cardiovasc. Surg. 57:238, Beau, A. F. A method for hemoglobin in serum and urine. Amer. J. Clin. Path. 38:111, Crystal, D. K., Day, S. W., Wagner, C. L., Martinis, A. J., Owen, J. J., and Walker, P. E. A gravity-flow membrane oxygenator. Arch. Surg. (Chicago) 88: 122, De Filippi, R. P., Tompkins, J. R., and Porter, J. H. The capillary membrane blood oxygenator: In vitro and in vivo gas exchange measurements. Trans. Amer. SOC. Artif. Intern. Organs 14:236, Dobell, A. R. C., Mitri, M., Galva, R., Sarkozy, E., and Murphy, D. R. Biologic evaluation of blood after prolonged recirculation through film and membrane oxygenators. Ann. Surg. 161:617, Frater, R. W. M., Wexler, H., and Amirana, M. Arteriovenous shunt through a membrane oxygenator for pulmonary support. J. Cardiovasc. Surg. (Torino) 10: 147, Katsuhara, K., Yokosuka, T., and Sakakibara, S. The swing type membrane oxygenator: Gas exchange performance of the swing motion system. J. Surg. Res. 8:245, Kylstra, J. A., Moulopoulos, S. D., and Kolff, W. J. Further development of an ultra-thin Teflon membrane gas exchanger. Trans. Amer. SOC. Artif. Intern. Organs 7:355, Lee, W. H., Jr., Krumhaar, D., Fonkalsrud, E. W., Schjeide, 0. A., and Maloney, J. F., Jr. Denaturation of plasma proteins as a cause of morbidity and death after intracardiac operations. Surgery 50:29, Marx, T. I., Snyder, W. E., St. John, A. D., and Moeller, C. E. Diffusion of oxygen into a film of whole blood. J. Appl. Physiol. 15:1123, Peirce, E. C., 11. A new concept in membrane support for artificial lungs. Trans. Amer. SOC. Artif. Zn.tern. Organs 12:334, Shepherd, M. P., Zingg, W., and Mustard, W. T. Membrane oxygenation: Assessment of three suitable membranes and an appraisal of a commercially available infant membrane oxygenator. Canad. J. Surg. 10:489, Siggaard-Andersen, 0. Blood acid-base alignment nomogram. Scand. J. Clin. Lab. Invest. 15:211, THE ANNALS OF THORACIC SURGERY

Development of a Practical Membrane Lung System

Development of a Practical Membrane Lung System W. C. Helton, M.D., F. W. Johnson, M.D., J. B. Howe, F. B. Freedman, Ph.D., W. G. Lindsay, M.D., and D. M. Nicoloff, M.D., Ph.D. ABSTRACT The purpose of