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A Long-term Partial Bypass Oxygenation System
A Long-term Partial Bypass Oxygenation System William J. Dorson, Jr., Ph.D., Earl Baker, M.D., Hugh Hull, M.D., Marian Molthan, M.D., Belton Meyer, M.D., Ralph Fargotstein, M.D., and Melvin L. Cohen, M.D.
A
n adequate membrane blood oxygenator should aid in the clinical support of infants suffering from respiratory distress, congenital heart disease, and respiratory burns. An oxygenator designed for such use must allow for minimal priming volume, extracorporeal transit time, exposed surface area, and trauma to the body and blood. T h e first and last criteria preclude the use of oxygenators that rely on the direct contact of blood with the oxygen gas phase (bubble, disc, screen, or centrifugal). Existing membrane oxygenators are designed primarily for adult heart-lung bypass [l, 21. They have not achieved clinical prominence, partly because of their complexity and their early stage of development. Although membrane oxygenators have proved to be much less damaging to the blood [3], the large models available cannot be adapted easily to patients who are in their first two years of life (1 to 16 kg. body weight). In addition, certain basic designs, such as individually stacked flat membranes, do not have the potential for low priming volume or transit time necessary for neonatal use. Several research groups have concentrated on developing a miniature oxygenator for infant use, and in general, new design concepts have been employed to achieve this goal. Typical reported priming volumes within the oxygenator have been between 40 ml. for partial bypass [6] and 75 ml. for total bypass [8]. The present design effort has concentrated on the use of multiple parallel silicone tubes which, for partial bypass, results in a priming volume of 5.8 ml. per kilogram of body weight within the oxygenating section, to which must be added From the Engineering Center, Arizona State University, Tempe, Ariz.; the Experimental Laboratory, St. Luke’s Hospital, Phoenix, Ariz.; and Good Samaritan Hospital and St. Joseph’s Hospital, Phoenix, Ariz. Presented at the Fifth Annual Meeting of The Society of Thoracic Surgeons, San Diego, Calif., Jan. 27-29, 1969. Supported by grants from the Tuberculosis and Respiratory Disease Associations of Arizona and Greater Maricopa, Arizona State University, and St. Luke’s Hospital. Address reprint requests to Dr. Dorson, Engineering Center, Arizona State University, Tempe, Ariz. 85281.
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the volume in the distributing plenums and connecting lines (10 to 16 ml.). Several of the projected clinical applications would require longterm perfusion in order to aid the body in overcoming the diseased state. Hyaline membrane disease and respiratory burns in infants are in this category. Partial perfusion to augment the compromised respiration may be of help in extending life during this critical period. Since pumping of blood in a perfusion circuit presumably increases trauma, the oxygenator should have minimal flow resistance to allow bypass under the driving force of the arteriovenous pressure differential. The same criteria for long-term perfusion can be applied with benefit in performing heart surgery on infants, especially during the neonatal period. Congenital heart disease requiring immediate surgical correction is commonly associated with hypoxia. Partial perfusion may be of value in improving the subject’s preoperative state, providing pumped oxygenated blood to vital organs during operation and aiding in the postoperative recovery. In addition, an oxygenator system that demonstrates long-term perfusion capabilities can be employed to provide relatively safe total bypass during open-heart surgery. It may be possible to correct congenital heart defects in small infants for whom present perfusion techniques are unsatisfactory. DESIGN
The basic oxygenator design consists of a parallel arrangement of multiple silicone tubes with blood flowing through the inner lumen. These tubes are encased in an outer shell and held in position by a system of baffles. Oxygen passes through the shell on the outside of the silicone tubes with its path continuously directed perpendicular to the silicone tubes by means of the same support baffles. Figure 1 shows an early test prototype utilizing straight tubes. Early work [4] demonstrated that the total transfer of cubic centimeters of oxygen per minute was relatively independent of tube diameter, but varied with the number and length of tubes, the blood-flow rate, and the inlet saturation. This meant that the tube diameter, and therefore the priming volume, surface area, and blood transit time, could be made as small as practical. As the tube diameter is diminished, however, the silicone tubing becomes difficult to handle and more susceptible to clotting. Silicone tubing with an inside diameter of 0.08 cm. was used to minimize priming volume. Pure dimethyl silicone has the highest O2 and COz permeability of any
FIG. 1. Straight tube oxygenator prototype.
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Long-term Partial Bypass available synthetic membrane and has a minimal index of blood trauma. All surfaces in contact with blood within this oxygenator are silicone. Disadvantages of silicone include poor mechanical strength and a tendency to stick to itself and other surfaces. A tubular cross section provides maximum strength, while the baffle supports hold the tubing in a separated position. Once an oxygen (and CO,) transfer rate and a blood-flow rate are specified, the product of the tube length and number of tubes are determined by theoretical, and verified, methods. The decision between many short tubes and a few long tubes depends upon the application. With an external pump, fewer tubes of longer length would be chosen for simplicity, especially for total heart-lung bypass. A partial bypass system designed for infants should be adaptable to use either with or without a pump, depending on clinical need. For unassisted bypass, many tubes of shorter length must be used because of the rheological properties of blood 14, 51. Because the neonate is hypercythemic, the unit was designed to have a pressure drop of 25 mm. Hg for each 60 ml. of blood flow per kilogram of body weight. The simultaneous satisfaction of blood flow and oxygenation requirements led to the elimination of straight-tube designs for pumpless application. As the number of tubes increases to satisfy the hemodynamics, the blood flow per tube decreases. This reduced blood flow results in a decrease in oxygenation rate per tube. In silicone tubes at low flow rates, the major barrier to oxygen transfer is within the blood itself, rather than within the tube wall, and this factor determines oxygenator size. Physical mixing of the blood to disrupt laminar flow removes saturated blood from the tube wall, permitting further oxygen transfer. Mixing is promoted by arranging the tubing in a tight helix similar to the thread pattern on a screw, providing a swirling action to the blood cells. An extremely tight helix would hold a theoretical advantage but would result in kinking of the silicone tubing. An oxygenator designed for partial bypass of an infant weighing 1 kg. is shown in Figure 2. Increased metabolic oxygen requirement related to larger weights is met by using combinations of the basic unit in parallel. Tests were performed to determine blood-flow resistance and rates of gas transfer. It was concluded that this design is best adapted to provide subbasal oxygen requirements when consideration is given to the limitations of the infant’s arteriovenous pressure difference as a driving force, and when the relationship of the oxygenator volume to the infant’s vascular volume also is considered. Some blood resistance to oxygen transfer remains; however, this residual resistance is an advantage, in that the introduction of severely deoxygenated blood will result in a higher oxygen transfer rate than will, for example, 75% saturated blood. Conversely, oxygen transfer rates are limited when arterialized blood flows into the oxygenator. These results are summarized in Figure 3.
FIG. 2. One-kilogram infant oxygenator. VOL.
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EXPERIMENTAL METHODS Following the technical development of the neonatal oxygenator, long-term test perfusions were performed to evaluate in vivo compatibility and to establish technique. Small (1.5 to 4.7 kg.) mongrel puppies were chosen as preclinical subjects. Inlet to the oxygenator was provided from bilateral femoral artery polypropylene cannulas," and return was established through femoral vein cannulas. The Y-connectors joining either arterial or venous lines to the oxygenator inlet or outlet contained a pressure monitoring and sample port. Excessive flow in Subject 4 was controlled by an external screw clamp. An in-line ultrasonic Doppler flowmeter was developed to measure total arterial flow and to provide a simultaneous audible signal. Oxygen at 0.5 to 3 liters per minute was passed through a heated humidifier to the oxygenator. The exit gas temperature from the oxygenator was maintained between 37" and 38OC. Rectal and skin temperatures were monitored. During arterial-to-venous experiments, 5% CO, in O2 was used in the oxygenator.
E X P E R I M E N T A L SERIES Seven puppies were used in the preclinical series. The first 4 underwent A-V partial bypass with no pump but with varying cannulas and maintenance regimens. The fifth and seventh underwent A-V partial bypass with a pump at equivalent flow rates. The sixth underwent short-term closed-system V-A partial bypass with pump. *Aloe Medical, Medicut sizes 14-16, Brunswick Corporation, St. Louis, Mo.
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Long-term Partial Bypass T h e oxygenator was primed with modified Ringer's lactate solution. Sedation usually was accomplished with sodium pentobarbital. Initial metabolic acidosis following cannulation was corrected with sodium bicarbonate. Heparin was given a t 6 mg. per kilogram of body weight prior to bypass, 3 mg. per kilogram of body weight for the second hour, and 1.5 mg. per kilogram of body weight each hour thereafter. After 10 hours a dosage of 3 mg. per kilogram of body weight per hour was required to maintain a capillary clotting time i n excess of 20 minutes. I n Experiments 1, 4, 5, and 7 the subjects underwent long-term A-V partial bypass for 21 to 24.6 hours, both with and without external pumping. Each subject was sacrificed 2 to 3 days after perfusion, and a complete autopsy was performed. T h e second experiment was scheduled to terminate prior to the need for a blood transfusion. This subject died 8 hours postperfusion as a result of ligation of the abdominal aorta. T h e third subject died during perfusion from peritoneal extravasation of blood and urine. T h e pump experiments were performed with a modified low-perfusion occlusive roller pump." These experiments required additional tubing (0.476 cm. ID) which added 28 ml. of priming volume to the system. A 1-kg.-sizedoxygenator was used for the first six experiments. A 2-kg. oxygenator was tested in Experiment 7. No filter was employed. T h e bypass flow was unmodified in the first three experiments, controlled with an external screw clamp a t 65 ml. per minute per kilogram of body weight in the fourth experiment, and set at 65 to 67 ml. per minute per kilogram of body weight during the A-V pump experiments. I n all experiments, blood and urine samples were collected periodically for analysis. Data from the experimental series are summarized in Table 1. T h e initial and final values listed were both taken during bypass. Specific data for Experiments 4 (no pump) and 5 (with pump) are presented i n Figures 4 and 5, respectively. Initial and final blood volumes (both on bypass) were 190 ml. and 203 ml., respectively, during Experiment 4, 295 ml. and 360 ml. during Experiment 5, and 305 ml. and 380 ml. during Experiment 7. T h e platelet count during all long-term perfusions rose initially to levels between 230,000 and 340,000, then decreased and finally leveled off at values usually between 130,000 and 180,000. T h e average pC0, for each arteriovenous experiment was between 21 and 26 mm. Hg. I n the veno-arterial experiment the pCOz average was 47 mm. Hg. Prior to bypass, all puppies had hematocrit values between 27 and 34 and were in a moderately dehydrated state. During perfusion without pump the hematocrit values continually decreased with no evidence of significant blood damage. T h e volume of sample withdrawal and blood loss did not account for the decrease i n hematocrit values during perfusion. Blood transfusions were used to maintain the hematocrit values a t acceptable levels. T h e rate of decrease of hematocrit values was noticeably reduced during bypass with a pump; however, once during each pump experiment, blood transfusions were necessary when arterial and venous pressures significantly decreased. Except o n these two occasions, arterial pressures were well maintained. Plasma hemoglobin levels were higher with a pump-oxygenator system than with a n oxygenator alone. None of the values were excessive, and frequently the highest values were obtained prior to perfusion. High intravenous rates (50 to 80 ml. per hour) were necessary to maintain urinary flow i n these anemic subjects [7]. At the end of perfusion the puppies were alert, active, and hungry. Recovery in all four of the long-term perfusion studies was uneventful. Dogs were sacrificed by succinylcholine injection, which may have resulted i n terminal pulmonary vascular congestion and hyperemia. Gross and microscopic study of all subjects revealed no pathological findings directly attributable to the oxygenator. Flow measurements (Fig. 6) were taken either *Sarns Inc., Ann Arbor, Mich.
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from the Doppler flowmeter or by occlusive pump calibration, except in the first experiment, where flow was estimated from the pressure drop across the oxygenator. T h e veno-arterial bypass was technically unsatisfactory i n Experiment 6. CLINICAL APPLICATION
A twin girl of 34 weeks gestation and weighing 1.16 kg. was delivered in St. Joseph's Hospital. T h e Apgar score was 4 at both 1 and 5 minutes after birth. Immediate intubation was required with positive-pressure ventilation at 100% oxygen. T h e infant was admitted to the Intensive Care Nursery, where her condition was diagnosed as severe hyaline membrane disease. She continued to deteriorate despite all appropriate therapy. At 3.6 hours after birth, nasotracheal intubation and respirator" ventilation with 100% O2 at 50 cm. H20 pressure were required. At 50 hours, seizures and bradycardia occurred. O n cerebral ventricular puncture, blood was present. *Bennett PR-2, Puritan-Bennett Company, Kansas City, Mo.
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At 33.3 hours the infant was heparinized (3 mg. per kilogram of body weight) and started on partial arteriovenous perfusion employing the preplaced conventional umbilical catheters, the occlusive roller pump, and a 2-kg. oxygenator. The priming volume was 50 ml. of modified Ringer's lactate solution. A flow rate of 70 ml. per minute was maintained throughout the perfusion, and after 2 hours the 100% oxygen flow to the oxygenator was changed to 95% oxygen and 5% GOz. Heparin was given at 1.5 mg. per kilogram of body weight per hour. Within 30 minutes after bypass the infant was pink. Heart rate was constant at 180 to 200 until 39 hours of age. Reduction in respirator oxygen concentration to avoid oxygen toxicity was attempted on two occasions, but reduction was not tolerated. At 39 hours, 5 ml. of blood was removed from the left subdural space and 18 ml. from the left lateral ventricle, An indwelling cannula was placed in the left cerebral ventricle, and active bleeding continued. During the last 4 hours of bypass, without transfusion, and when ventricular drainage was 1 ml. per hour or less, the decrease in hematocrit value was only from 39 to 35. During the final 9 hours of bypass, metabolic acidosis was not present, pCOz fell progressively until it became necessary to introduce dead space into the airway system, and oxygen saturation became normal. Vital signs, color, and indications of peripheral perfusion remained stable for the duration of the infant's
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life until age 53.9 hours, 20.6 hours after initiation of partial bypass perfusion, when the heartbeat suddenly ceased, and the infant died. Blood-gas data are shown in Figure 7. Plasma hemoglobin ranged from 3.1 to 7.1 mg. per 100 ml. of plasma; platelet count ranged from 43,000 to 332,000 per cubic millimeter of blood. Autopsy revealed the probable cause of death to be hemorrhage and edema of the brain. COMMENT
The preclinical pathological findings summarized in Table 1 show isolated organ damage which may have been caused by the maintenance of surgical procedures. Renal infarcts were observed only in the first experiment, in which heparinization and fluid administration were inadequate. This was the only subject demonstrating microthrombi in the lungs. In the second experiment liver necrosis resulted from poor technical procedure. Because of the A-V flow path, tissue damage should be demonstrated in the lungs if the oxygenator system has produced major trauma. Since this was not the case, and all other organs except those mentioned were normal on both gross and microscopic examination, it was concluded that there was no contraindication to clinical application of the oxygenator. T h e oxygenator system provided stable perfusion with minimum maintenance. The most significant results were (1) maintenance of a 306
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physiological platelet level during all perfusions; (2) decrease in hematocrit value during bypass without a pump (Fig. 4); (3) ability to perform long-term perfusion with an external pump; and (4) slower decline in hematocrit value (Fig. 5) during pump operation. The longterm pump potential is important to neonatal application because many candidates for direct blood oxygenation have depressed arterial pressures that initially would preclude pumpless application. With improved oxygenation of the blood, the arterial pressure may rise, and pump assist could then be discontinued. The oxygenator system, therefore, should have the potential for use with or without a pump. In addition, the use of an atraumatic infant membrane oxygenator should allow for an improved survival in the performance of cardiac surgery. Neonatal application can best be accomplished with short, tapered umbilical catheters. T h e primary objective is to minimize flow resistance. This requires flexible catheters that are larger and thinner-walled than those usually used. These large catheters can be inserted during the immediate postnatal period. Femoral cannulation may be used as an alternate technique when umbilical catheterization is inadequate or impossible. VOL.
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The initial human application was accomplished on a neonate known to have cerebral ventricular hemorrhage and severe hyaline membrane disease. Conventional preplaced catheters were used in this emergency application, and the long, narrow lumen of these catheters produced a high pressure within the oxygenator. Blood-gas analyses after 13 hours of perfusion with sustained appearance of adequate peripheral circulation indicate an increase in both the effective alveolar ventilation and respiration processes. Thus, it is possible that lung function was improved during partial bypass perfusion. Decrease in the respirator-administered oxygen concentration was poorly tolerated, however, and the respirator was continued at 100% oxygen to the time of death. In this first clinical application, pump-oxygenator partial bypass with low plasma hemoglobin was maintained for 20.6 hours. This is thought to confirm that minimal blood trauma is associated with this oxygenator system. SUMMARY
A membrane oxygenator has been developed for long-term partial arteriovenous perfusion in neonates with severe respiratory distress or cyanotic congenital heart disease. Its characteristics are minimal fluidpriming volume and exposed surface area, short extracorporeal transit time, and minimal trauma to the blood. The oxygenator utilizes multiple coiled silicone tubes of small diameter, which results in low flow resistance. Partial bypass units have the capability of being used either with or without a pump when the A-V pressure differential is within normal limits. The oxygenating capacity of this design concept was established initially with both laboratory and animal bypass experiments. The long-term physiological effects of partial bypass were studied in a series of 7 mongrel puppies. Bypass was performed on 4 puppies for 21 to 24.6 hours with and without an extracorporeal pump. These subjects all exhibited excellent postperfusion survival. No major pathological findings attributable to the oxygenator application were found. The first clinical application was made on a terminal premature infant. Blood gases and all vital signs were improved, and the neonate was sustained for 20.6 hours. Despite indications of improved total effective lung function during this procedure, the infant died of massive cerebral hemorrhage. REFERENCES
1. Bramson, M. L., Osborn, J. J., Main, F. B., O’Brien, M. F., Wright, J. S., and Gerbode, F. A new disposable membrane oxygenator with integral heat exchange. J. Thorac. Cardiovasc. Surg. 50:391, 1965. 308
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Long-term Partial Bypass 2. Clowes, G. H. A., Jr., Hopkins, A. L., and Neville, W. E. An artificial lung dependent upon diffusion of oxygen and carbon dioxide through plastic membranes. J . Thorac. Surg. 32:630, 1956. 3. Dobell, A. R. C., Mitri, M., Galva, R., Sarkozy, E., and Murphy, D. R. Biological evaluation of blood after prolonged recirculation through film and membrane oxygenators. Ann. Surg. 161:617, 1965. 4. Dorson, W., Jr., Baker, E., and Hull, H. A shell and tube odygenator. Trans. Amer. Soc. Artif. Intern. Organs 14:242, 1968. 5. Dorson, W. J., Jr., and Hershey, D. Analytical and experimental description of blood flow. Digest of the Seventh International Conference of Medical and Biological Engineering, Stockholm, 1967. P. 374. 6. Kolobow, T., Zapol, W., Pierce, J. E., Keeley, A. F., Replogle, R. L., and Haller, A. Partial extracorporeal gas exchange in alert newborn lambs with a membrane artificial lung perfused via an A-V shunt for periods up to 96 hours. Trans. Amer. SOC. Artif. Intern. Organs. 14:328, 1968. 7. Michalski, A. H., Lowenstein, E., Austen, W. G., Buckley, M. J., and Laver, M. B. Patterns of oxygenation and cardiovascular adjustment to acute, transient normovolemic anemia. A n n . Surg. 168:946, 1968. 8. Zingg, W. Membrane oxygenator for infants. Trans. Amer. Soc. Artif. Intern. Organs 13:334, 1967. DISCUSSION DR. RALPHDETERLINC (Boston, Mass.): I wish to thank the authors for the opportunity to review their manuscript before this meeting. I wish to emphasize the fact that Dr. Dorson is an engineer, so consequently my remarks will reflect the opinions of our own engineer, Cliff Birtwell, and of Don Billig, who now is in charge of our pediatric thoracic and cardiac surgery. There is a distinct clinical need for a system such as that developed by the authors, especially in light of the serious complications that can result from prolonged use of a respirator unit. There seems to be some doubt, however, as to the safety of this system for total extracorporeal circulation. A very satisfactory low priming volume of 50 ml. was achieved with this particular equipment for respiratory support, but one would prefer a larger priming volume for cardiopulmonary bypass should the venous return fall off or early technical problems arise. For optimal gas exchange, the choice of dimethyl silicone is very appropriate, and a short tube design also helps meet requirements of low resistance, short transit time, and modest turbulence. The falling hematocrit value that was observed by the authors during partial long-term bypass perfusion in the infant also has been noted by John Fisher in our own department at Tufts University, Alex Haller, and some others. Blood loss obviously was not a complete explanation. It would be of importance to determine what role was played by red cell sequestration, shifts of intracellular and extracellular fluid, and hemodilution from water loading, as was done in the animal experiments. T h e puppies were given a large amount of intravenous fluid to maintain not only blood pressure but also urine output. Intracellular and extracellular fluid shifts, if significant, could alter the intracellular and extracellular potassium-ion concentration which, in turn, is related to digitalis toxicity and cardiac rhythm, as shown in the paper by Dr. Callaghan’s group. I should like to see a standardized protocol developed for studying additional animals, with a few long-term survivors. It is understandable that in their 7 puppies the authors had to vary some of the maintenance regimens; however, there are too many variables in the small series to draw very firm conclusions, and the use of the long, narrow lumen umbilical tubes in the child prevented this from providing an optimal trial of the system. I do not believe that succinylcholine should be used for sacrificing the pup-
DORSON E T AL. pies in future experiments. The authors assumed that the pulmonary congestion and hyperemia found at autopsy were a result of this drug and not of the bypass or extra fluid administration. This is important, especially in a situation where respiratory assistance is the primary objective of the study. I do wish to congratulate them, however, for contributing materially to an area that needs more attention. This is an example of the creativity and specialized use of materials and design that may result when an engineer and a clinician work closely together. I certainly look forward to seeing further reports from this group. DR. LEWISH. BOSHER, JR. (Richmond, Va.): For the past two years I have had the privilege of working with T. Leigh Williams, a chemical engineer, in the development of a tube membrane oxygenator that Dr. Williams has called the hollow filament fabric oxygenator. The fabric oxygenator differs from the oxygenator described by Dr. Dorson in three important ways: (1) the individual filaments or tubes are much smaller than the tubes described by Dr. Dorson, having an inside diameter of 42 p and a wall thickness of 11 p, i.e., a wall thickness slightly less than 4(L mil; (2) the tubes are woven together in the form of a fabric; (3) oxygen is passed through the tubes, and blood flows around the tubes. The oxygenator is composed of a stack of these fabric sheets so gasketed that gas enters along two adjacent sides and leaves along the opposite two sides of the stack. Blood flows through the stack perpendicular to and around the tubes. Thus far, the only hollow filaments available to us in the preferred size have been made from polyethylene, a polymer that transports oxygen and carbon dioxide poorly. Two hundred sheets with a cross-sectional area of 12.2 square inches yield a membrane area of 8 square meters but a priming volume of only 280 ml. With blood flow of 1,500 ml. per minute and a total oxygen flow of 7 liters per minute, 66 cc. of oxygen per minute, or 8.3 cc. of oxygen per square meter of membrane surface per minute has been transported. The transport of carbon dioxide has been very poor at physiological gas pressures. The pressure gradient across the stack at 1,500 ml. blood flow per minute is less than 25 mm. Hg, so that gravity flow suffices. Polymers far more permeable than Polyethylene are known, and Dr. Williams is working with industry to obtain filaments of the proper size made from such polymers with characteristics that permit weaving into fabric. We hope to take a major step forward in the near future with a polymer eight times more permeable than polyethylene. DR. DORSON: I would like to thank Dr. Deterling and Dr. Bosher for their comments and suggestions. The priming volume with connection tubing is on the order of 20 ml. When we use the pump, that extra line contributes about 30 ml. more, so the total prime is about 50 ml. We have alluded to the possible use of this type of system in total bypass; however, we have not considered this application in detail, and certainly we would have to put in some means of immediate volume control such as a reservoir, which would add to the prime. The hematocrit histories in the animal experiments are complicated by the high intravenous rates. In the infant we did not require such a high intravenous rate, and there was no large hematocrit loss during the stable period (last 9 hours). The animal studies obviously were designed to prove clinical safety, and we do plan to do more rigidly controlled tests. The hematocrit difference with and without the pump was significant. The blood volume as given in the paper increased with the pump bypass experiments, and the hemoglobin loss was less. Any explanation would be speculative; however, it does confirm that there is minimal trauma with this system. We did have unassisted bypass both at a higher flow and at about the same flow as the pump experiments. This tends to eliminate flow rate differences as a reason for the lower hematocrit loss with the pump.
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Long-term Partial Bypass I agree completely with Dr. Deterling about the use of succinylcholine for sacrifice, and I thank him for his suggestions. I would like to point out that pulmonary hemorrhage and edema, when present, were mild. The excellent survival status of these puppies-they would get up off the table in most cases and eat and drink with abandon after a 24-hour experiment-agrees with the minimal pathological findings. Concerning extra fluid administration, the need for a high intravenous rate in anemic canines has been reported by Michalski et al. (Ann. Surg. 168:946, 1968). We did this to maintain adequate systemic pressures and urinary output. Finally, Dr. Bosher, the only comparison I can make quickly is that our membrane area exposed to the blood is not in the square meter region. It is down to .06 square meter per kilogram, so that on the gas transfer flux we have a considerably higher oxygenation efficiency than you do with your design. This, however, must be modified by the fact that you do not have optimal fiber materials.
NOTICE FROM THE BOARD OF THORACIC SURGERY The 1970 spring examinations will be given as follows: Written Examination. T o be held at various centers throughout the country on February 6 , 1970. Final date for filing applications is December 1, 1969. Oral Examination. T o be given in April, 1970, in Washington, D.C. Final date for filing applications is December 1, 1969. Please address all communications to the Board of Thoracic Surgery, Inc., 1151 Taylor Ave., Detroit, Mich. 48202.
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n adequate membrane blood oxygenator should aid in the clinical support of infants suffering from respiratory distress, congenital heart disease, and respiratory burns. An oxygenator designed for such use must allow for minimal priming volume, extracorporeal transit time, exposed surface area, and trauma to the body and blood. T h e first and last criteria preclude the use of oxygenators that rely on the direct contact of blood with the oxygen gas phase (bubble, disc, screen, or centrifugal). Existing membrane oxygenators are designed primarily for adult heart-lung bypass [l, 21. They have not achieved clinical prominence, partly because of their complexity and their early stage of development. Although membrane oxygenators have proved to be much less damaging to the blood [3], the large models available cannot be adapted easily to patients who are in their first two years of life (1 to 16 kg. body weight). In addition, certain basic designs, such as individually stacked flat membranes, do not have the potential for low priming volume or transit time necessary for neonatal use. Several research groups have concentrated on developing a miniature oxygenator for infant use, and in general, new design concepts have been employed to achieve this goal. Typical reported priming volumes within the oxygenator have been between 40 ml. for partial bypass [6] and 75 ml. for total bypass [8]. The present design effort has concentrated on the use of multiple parallel silicone tubes which, for partial bypass, results in a priming volume of 5.8 ml. per kilogram of body weight within the oxygenating section, to which must be added From the Engineering Center, Arizona State University, Tempe, Ariz.; the Experimental Laboratory, St. Luke’s Hospital, Phoenix, Ariz.; and Good Samaritan Hospital and St. Joseph’s Hospital, Phoenix, Ariz. Presented at the Fifth Annual Meeting of The Society of Thoracic Surgeons, San Diego, Calif., Jan. 27-29, 1969. Supported by grants from the Tuberculosis and Respiratory Disease Associations of Arizona and Greater Maricopa, Arizona State University, and St. Luke’s Hospital. Address reprint requests to Dr. Dorson, Engineering Center, Arizona State University, Tempe, Ariz. 85281.
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the volume in the distributing plenums and connecting lines (10 to 16 ml.). Several of the projected clinical applications would require longterm perfusion in order to aid the body in overcoming the diseased state. Hyaline membrane disease and respiratory burns in infants are in this category. Partial perfusion to augment the compromised respiration may be of help in extending life during this critical period. Since pumping of blood in a perfusion circuit presumably increases trauma, the oxygenator should have minimal flow resistance to allow bypass under the driving force of the arteriovenous pressure differential. The same criteria for long-term perfusion can be applied with benefit in performing heart surgery on infants, especially during the neonatal period. Congenital heart disease requiring immediate surgical correction is commonly associated with hypoxia. Partial perfusion may be of value in improving the subject’s preoperative state, providing pumped oxygenated blood to vital organs during operation and aiding in the postoperative recovery. In addition, an oxygenator system that demonstrates long-term perfusion capabilities can be employed to provide relatively safe total bypass during open-heart surgery. It may be possible to correct congenital heart defects in small infants for whom present perfusion techniques are unsatisfactory. DESIGN
The basic oxygenator design consists of a parallel arrangement of multiple silicone tubes with blood flowing through the inner lumen. These tubes are encased in an outer shell and held in position by a system of baffles. Oxygen passes through the shell on the outside of the silicone tubes with its path continuously directed perpendicular to the silicone tubes by means of the same support baffles. Figure 1 shows an early test prototype utilizing straight tubes. Early work [4] demonstrated that the total transfer of cubic centimeters of oxygen per minute was relatively independent of tube diameter, but varied with the number and length of tubes, the blood-flow rate, and the inlet saturation. This meant that the tube diameter, and therefore the priming volume, surface area, and blood transit time, could be made as small as practical. As the tube diameter is diminished, however, the silicone tubing becomes difficult to handle and more susceptible to clotting. Silicone tubing with an inside diameter of 0.08 cm. was used to minimize priming volume. Pure dimethyl silicone has the highest O2 and COz permeability of any
FIG. 1. Straight tube oxygenator prototype.
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Long-term Partial Bypass available synthetic membrane and has a minimal index of blood trauma. All surfaces in contact with blood within this oxygenator are silicone. Disadvantages of silicone include poor mechanical strength and a tendency to stick to itself and other surfaces. A tubular cross section provides maximum strength, while the baffle supports hold the tubing in a separated position. Once an oxygen (and CO,) transfer rate and a blood-flow rate are specified, the product of the tube length and number of tubes are determined by theoretical, and verified, methods. The decision between many short tubes and a few long tubes depends upon the application. With an external pump, fewer tubes of longer length would be chosen for simplicity, especially for total heart-lung bypass. A partial bypass system designed for infants should be adaptable to use either with or without a pump, depending on clinical need. For unassisted bypass, many tubes of shorter length must be used because of the rheological properties of blood 14, 51. Because the neonate is hypercythemic, the unit was designed to have a pressure drop of 25 mm. Hg for each 60 ml. of blood flow per kilogram of body weight. The simultaneous satisfaction of blood flow and oxygenation requirements led to the elimination of straight-tube designs for pumpless application. As the number of tubes increases to satisfy the hemodynamics, the blood flow per tube decreases. This reduced blood flow results in a decrease in oxygenation rate per tube. In silicone tubes at low flow rates, the major barrier to oxygen transfer is within the blood itself, rather than within the tube wall, and this factor determines oxygenator size. Physical mixing of the blood to disrupt laminar flow removes saturated blood from the tube wall, permitting further oxygen transfer. Mixing is promoted by arranging the tubing in a tight helix similar to the thread pattern on a screw, providing a swirling action to the blood cells. An extremely tight helix would hold a theoretical advantage but would result in kinking of the silicone tubing. An oxygenator designed for partial bypass of an infant weighing 1 kg. is shown in Figure 2. Increased metabolic oxygen requirement related to larger weights is met by using combinations of the basic unit in parallel. Tests were performed to determine blood-flow resistance and rates of gas transfer. It was concluded that this design is best adapted to provide subbasal oxygen requirements when consideration is given to the limitations of the infant’s arteriovenous pressure difference as a driving force, and when the relationship of the oxygenator volume to the infant’s vascular volume also is considered. Some blood resistance to oxygen transfer remains; however, this residual resistance is an advantage, in that the introduction of severely deoxygenated blood will result in a higher oxygen transfer rate than will, for example, 75% saturated blood. Conversely, oxygen transfer rates are limited when arterialized blood flows into the oxygenator. These results are summarized in Figure 3.
FIG. 2. One-kilogram infant oxygenator. VOL.
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EXPERIMENTAL METHODS Following the technical development of the neonatal oxygenator, long-term test perfusions were performed to evaluate in vivo compatibility and to establish technique. Small (1.5 to 4.7 kg.) mongrel puppies were chosen as preclinical subjects. Inlet to the oxygenator was provided from bilateral femoral artery polypropylene cannulas," and return was established through femoral vein cannulas. The Y-connectors joining either arterial or venous lines to the oxygenator inlet or outlet contained a pressure monitoring and sample port. Excessive flow in Subject 4 was controlled by an external screw clamp. An in-line ultrasonic Doppler flowmeter was developed to measure total arterial flow and to provide a simultaneous audible signal. Oxygen at 0.5 to 3 liters per minute was passed through a heated humidifier to the oxygenator. The exit gas temperature from the oxygenator was maintained between 37" and 38OC. Rectal and skin temperatures were monitored. During arterial-to-venous experiments, 5% CO, in O2 was used in the oxygenator.
E X P E R I M E N T A L SERIES Seven puppies were used in the preclinical series. The first 4 underwent A-V partial bypass with no pump but with varying cannulas and maintenance regimens. The fifth and seventh underwent A-V partial bypass with a pump at equivalent flow rates. The sixth underwent short-term closed-system V-A partial bypass with pump. *Aloe Medical, Medicut sizes 14-16, Brunswick Corporation, St. Louis, Mo.
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Long-term Partial Bypass T h e oxygenator was primed with modified Ringer's lactate solution. Sedation usually was accomplished with sodium pentobarbital. Initial metabolic acidosis following cannulation was corrected with sodium bicarbonate. Heparin was given a t 6 mg. per kilogram of body weight prior to bypass, 3 mg. per kilogram of body weight for the second hour, and 1.5 mg. per kilogram of body weight each hour thereafter. After 10 hours a dosage of 3 mg. per kilogram of body weight per hour was required to maintain a capillary clotting time i n excess of 20 minutes. I n Experiments 1, 4, 5, and 7 the subjects underwent long-term A-V partial bypass for 21 to 24.6 hours, both with and without external pumping. Each subject was sacrificed 2 to 3 days after perfusion, and a complete autopsy was performed. T h e second experiment was scheduled to terminate prior to the need for a blood transfusion. This subject died 8 hours postperfusion as a result of ligation of the abdominal aorta. T h e third subject died during perfusion from peritoneal extravasation of blood and urine. T h e pump experiments were performed with a modified low-perfusion occlusive roller pump." These experiments required additional tubing (0.476 cm. ID) which added 28 ml. of priming volume to the system. A 1-kg.-sizedoxygenator was used for the first six experiments. A 2-kg. oxygenator was tested in Experiment 7. No filter was employed. T h e bypass flow was unmodified in the first three experiments, controlled with an external screw clamp a t 65 ml. per minute per kilogram of body weight in the fourth experiment, and set at 65 to 67 ml. per minute per kilogram of body weight during the A-V pump experiments. I n all experiments, blood and urine samples were collected periodically for analysis. Data from the experimental series are summarized in Table 1. T h e initial and final values listed were both taken during bypass. Specific data for Experiments 4 (no pump) and 5 (with pump) are presented i n Figures 4 and 5, respectively. Initial and final blood volumes (both on bypass) were 190 ml. and 203 ml., respectively, during Experiment 4, 295 ml. and 360 ml. during Experiment 5, and 305 ml. and 380 ml. during Experiment 7. T h e platelet count during all long-term perfusions rose initially to levels between 230,000 and 340,000, then decreased and finally leveled off at values usually between 130,000 and 180,000. T h e average pC0, for each arteriovenous experiment was between 21 and 26 mm. Hg. I n the veno-arterial experiment the pCOz average was 47 mm. Hg. Prior to bypass, all puppies had hematocrit values between 27 and 34 and were in a moderately dehydrated state. During perfusion without pump the hematocrit values continually decreased with no evidence of significant blood damage. T h e volume of sample withdrawal and blood loss did not account for the decrease i n hematocrit values during perfusion. Blood transfusions were used to maintain the hematocrit values a t acceptable levels. T h e rate of decrease of hematocrit values was noticeably reduced during bypass with a pump; however, once during each pump experiment, blood transfusions were necessary when arterial and venous pressures significantly decreased. Except o n these two occasions, arterial pressures were well maintained. Plasma hemoglobin levels were higher with a pump-oxygenator system than with a n oxygenator alone. None of the values were excessive, and frequently the highest values were obtained prior to perfusion. High intravenous rates (50 to 80 ml. per hour) were necessary to maintain urinary flow i n these anemic subjects [7]. At the end of perfusion the puppies were alert, active, and hungry. Recovery in all four of the long-term perfusion studies was uneventful. Dogs were sacrificed by succinylcholine injection, which may have resulted i n terminal pulmonary vascular congestion and hyperemia. Gross and microscopic study of all subjects revealed no pathological findings directly attributable to the oxygenator. Flow measurements (Fig. 6) were taken either *Sarns Inc., Ann Arbor, Mich.
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from the Doppler flowmeter or by occlusive pump calibration, except in the first experiment, where flow was estimated from the pressure drop across the oxygenator. T h e veno-arterial bypass was technically unsatisfactory i n Experiment 6. CLINICAL APPLICATION
A twin girl of 34 weeks gestation and weighing 1.16 kg. was delivered in St. Joseph's Hospital. T h e Apgar score was 4 at both 1 and 5 minutes after birth. Immediate intubation was required with positive-pressure ventilation at 100% oxygen. T h e infant was admitted to the Intensive Care Nursery, where her condition was diagnosed as severe hyaline membrane disease. She continued to deteriorate despite all appropriate therapy. At 3.6 hours after birth, nasotracheal intubation and respirator" ventilation with 100% O2 at 50 cm. H20 pressure were required. At 50 hours, seizures and bradycardia occurred. O n cerebral ventricular puncture, blood was present. *Bennett PR-2, Puritan-Bennett Company, Kansas City, Mo.
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At 33.3 hours the infant was heparinized (3 mg. per kilogram of body weight) and started on partial arteriovenous perfusion employing the preplaced conventional umbilical catheters, the occlusive roller pump, and a 2-kg. oxygenator. The priming volume was 50 ml. of modified Ringer's lactate solution. A flow rate of 70 ml. per minute was maintained throughout the perfusion, and after 2 hours the 100% oxygen flow to the oxygenator was changed to 95% oxygen and 5% GOz. Heparin was given at 1.5 mg. per kilogram of body weight per hour. Within 30 minutes after bypass the infant was pink. Heart rate was constant at 180 to 200 until 39 hours of age. Reduction in respirator oxygen concentration to avoid oxygen toxicity was attempted on two occasions, but reduction was not tolerated. At 39 hours, 5 ml. of blood was removed from the left subdural space and 18 ml. from the left lateral ventricle, An indwelling cannula was placed in the left cerebral ventricle, and active bleeding continued. During the last 4 hours of bypass, without transfusion, and when ventricular drainage was 1 ml. per hour or less, the decrease in hematocrit value was only from 39 to 35. During the final 9 hours of bypass, metabolic acidosis was not present, pCOz fell progressively until it became necessary to introduce dead space into the airway system, and oxygen saturation became normal. Vital signs, color, and indications of peripheral perfusion remained stable for the duration of the infant's
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life until age 53.9 hours, 20.6 hours after initiation of partial bypass perfusion, when the heartbeat suddenly ceased, and the infant died. Blood-gas data are shown in Figure 7. Plasma hemoglobin ranged from 3.1 to 7.1 mg. per 100 ml. of plasma; platelet count ranged from 43,000 to 332,000 per cubic millimeter of blood. Autopsy revealed the probable cause of death to be hemorrhage and edema of the brain. COMMENT
The preclinical pathological findings summarized in Table 1 show isolated organ damage which may have been caused by the maintenance of surgical procedures. Renal infarcts were observed only in the first experiment, in which heparinization and fluid administration were inadequate. This was the only subject demonstrating microthrombi in the lungs. In the second experiment liver necrosis resulted from poor technical procedure. Because of the A-V flow path, tissue damage should be demonstrated in the lungs if the oxygenator system has produced major trauma. Since this was not the case, and all other organs except those mentioned were normal on both gross and microscopic examination, it was concluded that there was no contraindication to clinical application of the oxygenator. T h e oxygenator system provided stable perfusion with minimum maintenance. The most significant results were (1) maintenance of a 306
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physiological platelet level during all perfusions; (2) decrease in hematocrit value during bypass without a pump (Fig. 4); (3) ability to perform long-term perfusion with an external pump; and (4) slower decline in hematocrit value (Fig. 5) during pump operation. The longterm pump potential is important to neonatal application because many candidates for direct blood oxygenation have depressed arterial pressures that initially would preclude pumpless application. With improved oxygenation of the blood, the arterial pressure may rise, and pump assist could then be discontinued. The oxygenator system, therefore, should have the potential for use with or without a pump. In addition, the use of an atraumatic infant membrane oxygenator should allow for an improved survival in the performance of cardiac surgery. Neonatal application can best be accomplished with short, tapered umbilical catheters. T h e primary objective is to minimize flow resistance. This requires flexible catheters that are larger and thinner-walled than those usually used. These large catheters can be inserted during the immediate postnatal period. Femoral cannulation may be used as an alternate technique when umbilical catheterization is inadequate or impossible. VOL.
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The initial human application was accomplished on a neonate known to have cerebral ventricular hemorrhage and severe hyaline membrane disease. Conventional preplaced catheters were used in this emergency application, and the long, narrow lumen of these catheters produced a high pressure within the oxygenator. Blood-gas analyses after 13 hours of perfusion with sustained appearance of adequate peripheral circulation indicate an increase in both the effective alveolar ventilation and respiration processes. Thus, it is possible that lung function was improved during partial bypass perfusion. Decrease in the respirator-administered oxygen concentration was poorly tolerated, however, and the respirator was continued at 100% oxygen to the time of death. In this first clinical application, pump-oxygenator partial bypass with low plasma hemoglobin was maintained for 20.6 hours. This is thought to confirm that minimal blood trauma is associated with this oxygenator system. SUMMARY
A membrane oxygenator has been developed for long-term partial arteriovenous perfusion in neonates with severe respiratory distress or cyanotic congenital heart disease. Its characteristics are minimal fluidpriming volume and exposed surface area, short extracorporeal transit time, and minimal trauma to the blood. The oxygenator utilizes multiple coiled silicone tubes of small diameter, which results in low flow resistance. Partial bypass units have the capability of being used either with or without a pump when the A-V pressure differential is within normal limits. The oxygenating capacity of this design concept was established initially with both laboratory and animal bypass experiments. The long-term physiological effects of partial bypass were studied in a series of 7 mongrel puppies. Bypass was performed on 4 puppies for 21 to 24.6 hours with and without an extracorporeal pump. These subjects all exhibited excellent postperfusion survival. No major pathological findings attributable to the oxygenator application were found. The first clinical application was made on a terminal premature infant. Blood gases and all vital signs were improved, and the neonate was sustained for 20.6 hours. Despite indications of improved total effective lung function during this procedure, the infant died of massive cerebral hemorrhage. REFERENCES
1. Bramson, M. L., Osborn, J. J., Main, F. B., O’Brien, M. F., Wright, J. S., and Gerbode, F. A new disposable membrane oxygenator with integral heat exchange. J. Thorac. Cardiovasc. Surg. 50:391, 1965. 308
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Long-term Partial Bypass 2. Clowes, G. H. A., Jr., Hopkins, A. L., and Neville, W. E. An artificial lung dependent upon diffusion of oxygen and carbon dioxide through plastic membranes. J . Thorac. Surg. 32:630, 1956. 3. Dobell, A. R. C., Mitri, M., Galva, R., Sarkozy, E., and Murphy, D. R. Biological evaluation of blood after prolonged recirculation through film and membrane oxygenators. Ann. Surg. 161:617, 1965. 4. Dorson, W., Jr., Baker, E., and Hull, H. A shell and tube odygenator. Trans. Amer. Soc. Artif. Intern. Organs 14:242, 1968. 5. Dorson, W. J., Jr., and Hershey, D. Analytical and experimental description of blood flow. Digest of the Seventh International Conference of Medical and Biological Engineering, Stockholm, 1967. P. 374. 6. Kolobow, T., Zapol, W., Pierce, J. E., Keeley, A. F., Replogle, R. L., and Haller, A. Partial extracorporeal gas exchange in alert newborn lambs with a membrane artificial lung perfused via an A-V shunt for periods up to 96 hours. Trans. Amer. SOC. Artif. Intern. Organs. 14:328, 1968. 7. Michalski, A. H., Lowenstein, E., Austen, W. G., Buckley, M. J., and Laver, M. B. Patterns of oxygenation and cardiovascular adjustment to acute, transient normovolemic anemia. A n n . Surg. 168:946, 1968. 8. Zingg, W. Membrane oxygenator for infants. Trans. Amer. Soc. Artif. Intern. Organs 13:334, 1967. DISCUSSION DR. RALPHDETERLINC (Boston, Mass.): I wish to thank the authors for the opportunity to review their manuscript before this meeting. I wish to emphasize the fact that Dr. Dorson is an engineer, so consequently my remarks will reflect the opinions of our own engineer, Cliff Birtwell, and of Don Billig, who now is in charge of our pediatric thoracic and cardiac surgery. There is a distinct clinical need for a system such as that developed by the authors, especially in light of the serious complications that can result from prolonged use of a respirator unit. There seems to be some doubt, however, as to the safety of this system for total extracorporeal circulation. A very satisfactory low priming volume of 50 ml. was achieved with this particular equipment for respiratory support, but one would prefer a larger priming volume for cardiopulmonary bypass should the venous return fall off or early technical problems arise. For optimal gas exchange, the choice of dimethyl silicone is very appropriate, and a short tube design also helps meet requirements of low resistance, short transit time, and modest turbulence. The falling hematocrit value that was observed by the authors during partial long-term bypass perfusion in the infant also has been noted by John Fisher in our own department at Tufts University, Alex Haller, and some others. Blood loss obviously was not a complete explanation. It would be of importance to determine what role was played by red cell sequestration, shifts of intracellular and extracellular fluid, and hemodilution from water loading, as was done in the animal experiments. T h e puppies were given a large amount of intravenous fluid to maintain not only blood pressure but also urine output. Intracellular and extracellular fluid shifts, if significant, could alter the intracellular and extracellular potassium-ion concentration which, in turn, is related to digitalis toxicity and cardiac rhythm, as shown in the paper by Dr. Callaghan’s group. I should like to see a standardized protocol developed for studying additional animals, with a few long-term survivors. It is understandable that in their 7 puppies the authors had to vary some of the maintenance regimens; however, there are too many variables in the small series to draw very firm conclusions, and the use of the long, narrow lumen umbilical tubes in the child prevented this from providing an optimal trial of the system. I do not believe that succinylcholine should be used for sacrificing the pup-
DORSON E T AL. pies in future experiments. The authors assumed that the pulmonary congestion and hyperemia found at autopsy were a result of this drug and not of the bypass or extra fluid administration. This is important, especially in a situation where respiratory assistance is the primary objective of the study. I do wish to congratulate them, however, for contributing materially to an area that needs more attention. This is an example of the creativity and specialized use of materials and design that may result when an engineer and a clinician work closely together. I certainly look forward to seeing further reports from this group. DR. LEWISH. BOSHER, JR. (Richmond, Va.): For the past two years I have had the privilege of working with T. Leigh Williams, a chemical engineer, in the development of a tube membrane oxygenator that Dr. Williams has called the hollow filament fabric oxygenator. The fabric oxygenator differs from the oxygenator described by Dr. Dorson in three important ways: (1) the individual filaments or tubes are much smaller than the tubes described by Dr. Dorson, having an inside diameter of 42 p and a wall thickness of 11 p, i.e., a wall thickness slightly less than 4(L mil; (2) the tubes are woven together in the form of a fabric; (3) oxygen is passed through the tubes, and blood flows around the tubes. The oxygenator is composed of a stack of these fabric sheets so gasketed that gas enters along two adjacent sides and leaves along the opposite two sides of the stack. Blood flows through the stack perpendicular to and around the tubes. Thus far, the only hollow filaments available to us in the preferred size have been made from polyethylene, a polymer that transports oxygen and carbon dioxide poorly. Two hundred sheets with a cross-sectional area of 12.2 square inches yield a membrane area of 8 square meters but a priming volume of only 280 ml. With blood flow of 1,500 ml. per minute and a total oxygen flow of 7 liters per minute, 66 cc. of oxygen per minute, or 8.3 cc. of oxygen per square meter of membrane surface per minute has been transported. The transport of carbon dioxide has been very poor at physiological gas pressures. The pressure gradient across the stack at 1,500 ml. blood flow per minute is less than 25 mm. Hg, so that gravity flow suffices. Polymers far more permeable than Polyethylene are known, and Dr. Williams is working with industry to obtain filaments of the proper size made from such polymers with characteristics that permit weaving into fabric. We hope to take a major step forward in the near future with a polymer eight times more permeable than polyethylene. DR. DORSON: I would like to thank Dr. Deterling and Dr. Bosher for their comments and suggestions. The priming volume with connection tubing is on the order of 20 ml. When we use the pump, that extra line contributes about 30 ml. more, so the total prime is about 50 ml. We have alluded to the possible use of this type of system in total bypass; however, we have not considered this application in detail, and certainly we would have to put in some means of immediate volume control such as a reservoir, which would add to the prime. The hematocrit histories in the animal experiments are complicated by the high intravenous rates. In the infant we did not require such a high intravenous rate, and there was no large hematocrit loss during the stable period (last 9 hours). The animal studies obviously were designed to prove clinical safety, and we do plan to do more rigidly controlled tests. The hematocrit difference with and without the pump was significant. The blood volume as given in the paper increased with the pump bypass experiments, and the hemoglobin loss was less. Any explanation would be speculative; however, it does confirm that there is minimal trauma with this system. We did have unassisted bypass both at a higher flow and at about the same flow as the pump experiments. This tends to eliminate flow rate differences as a reason for the lower hematocrit loss with the pump.
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Long-term Partial Bypass I agree completely with Dr. Deterling about the use of succinylcholine for sacrifice, and I thank him for his suggestions. I would like to point out that pulmonary hemorrhage and edema, when present, were mild. The excellent survival status of these puppies-they would get up off the table in most cases and eat and drink with abandon after a 24-hour experiment-agrees with the minimal pathological findings. Concerning extra fluid administration, the need for a high intravenous rate in anemic canines has been reported by Michalski et al. (Ann. Surg. 168:946, 1968). We did this to maintain adequate systemic pressures and urinary output. Finally, Dr. Bosher, the only comparison I can make quickly is that our membrane area exposed to the blood is not in the square meter region. It is down to .06 square meter per kilogram, so that on the gas transfer flux we have a considerably higher oxygenation efficiency than you do with your design. This, however, must be modified by the fact that you do not have optimal fiber materials.
NOTICE FROM THE BOARD OF THORACIC SURGERY The 1970 spring examinations will be given as follows: Written Examination. T o be held at various centers throughout the country on February 6 , 1970. Final date for filing applications is December 1, 1969. Oral Examination. T o be given in April, 1970, in Washington, D.C. Final date for filing applications is December 1, 1969. Please address all communications to the Board of Thoracic Surgery, Inc., 1151 Taylor Ave., Detroit, Mich. 48202.
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