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Development of an implantable artificial lung
Development of an implantable artificial lung A. S. Palmer, M.D. (by invitation), J. Collins, M.S. (by invitation), and L. R. Head, M.D., Chicago, Ill.
Chronic lung diseases such as emphysema and pneumoconiosis, which lead to progressive respiratory insufficiency, are commonly encountered in clinical practice. Present treatment is entirely for control of symptoms and can only slow or occasionally arrest the progression. When the lungs can no longer deliver sufficient oxygen for survival, augmentation with a transplanted or artificial lung would be desirable. As transplants are presently plagued with the problems of availability and rejection, an implantable membrane oxygenator which functions as an artificial lung is under development. Membrane oxygenators for extracorporeal support are commercially available and have been shown to be clinically useful over short-term periods.' An implantable unit, however, must possess characteristics not found in the extracorporeal type. The maximum size and shape are limited to those of the pleural cavity. The required inlet pressure must not exceed that generated by the right ventricle, and thrombosis must be prevented in the prosthesis without the use of systemic heparinization.
membrane surface. The inside and outside diameters are 0.030 and 0.063 em., respectively, with the tubing cut into 16 em. lengths. These are joined at their ends in parallel into modules of circular cross-section containing twenty-two tubes each. The modules are then manifolded into rectangular groups containing 2,288 to 6,270 individual capillary tubes with spacers of open cell, polyurethan mesh inserted between modules to aid in distribution of ventilating gas. Silastic inflow and outflow tubes are connected to the manifolds to complete the blood pathway. Silastic cannulas for blood sampling, pressure measurement, and drug infusion are connected to the inflow and outflow tubes. All tubing comprising the blood pathway is then enclosed in a ventilating envelope of Silastic sheeting. A Silastic bronchus is connected to the envelope. The details of construction are schematically depicted in Fig. 1. Fig. 2 is a photograph of a completed artificial lung. Specifications of the lungs with this general design that were tested are shown in Table I.
Design
Implantation
Blood flow is through Silastic* capillary tubing which functions as the exchange
Eight units of this design were implanted in 10 dogs. Each new unit of this series was improved or enlarged on the basis of information obtained from implantation of the previous unit. Prior to implantation each artificial lung was tested in vitro to determine pressure-flow characteristics and gas transfer rates. All implantations were performed in fe-
From the Departments of Surgery, Northwestern University and Northwestern Memorial Hospital-Wesley Pavilion, Chicago, Ill. 606 I I. Supported by the John A. Hartford Foundation, Inc. Read at the Fifty-third Annual Meeting of The American Association for Thoracic Surgery, Dallas, Texas, April 16, 17, and 18, 1973. "Dow Corning Corporation, Midland, Mich.
521
The Journal of
522
Palmer, Collins, Head
Thoracic and Cardiovascular Surgery
ventilating envelope
cut-away view of artificial lung
Fig. 1. Schematic representation of artificial lung construction; see text for description.
male mongrel dogs weighing 15 to 20 kilograms. Anesthesia was induced and maintained with intermittent intravenous Surital, * and positive-pressure endotracheal ventilation was established. Through a left anterior thoracotomy incision, a left pneumonectomy was performed. In our earlier experience we then sutured the artificial bronchus to the left main-stem bronchus. Subsequently, we began closing the left main-stem bronchus and bringing the artificial bronchus directly through a stab wound in the left chest wall (Fig. 3). The inlet of the artificial lung was then connected to the left pulmonary artery and the outlet to the left atrium via the left atrial appendage. The cannulas for blood sampling and pressure measurement were brought through the chest wall, and the chest was closed in the usual fashion. The dogs were then allowed to awaken and breathe spontaneously. The normal motion of the chest and diaphragm induced the ventilating envelope of the artificial lung to move air in and out of the artificial bronchus. 'Parke, Davis & Co., Detroit, Mich. (sodium thiamylal ) ,
Regional heparinization was used to prevent clotting in the prosthesis. Heparin was directed via the Silastic cannula into the inlet of the artificial lung by means of a small infusion pump at a rate of 2,000 to 3,000 units per hour. Protamine was simultaneously directed into the outlet of the artificial lung at a rate of 200 to 300 mg. per hour. During the initial infusion adjustments, clotting was monitored by means of the activated partial thromboplastin time. Results
The artificial lungs fit easily into the left hemithorax of the dogs and occupied less than one third of the available space. As soon as the dogs were allowed to breathe spontaneously with the chest closed, the ventilating envelopes began to move air in and out of the artificial bronchus. The tidal volume of the artificial lung varied with the size and respiratory effort of the dog but was generally one fourth to one third that of the remaining right lung. The regional heparinization was rather easy to manage. We found a good correla-
Volume 66
Implantable artificial lung
Number 4
523
October, 1973
Fig. 2. Completed artificial lung with a portion of the ventilating envelope cut away to expose the blood pathway.
Fig. 3. Technique of lung implantation. a, Pulmonary artery connector. b, Left atrial connector. C, Cannulas for drug infusion, blood sampling, and pressure measurement. d, Artificial bronchus.
Table I. Specifications A rtificial lung
Tubing No.
Membrane surface area (sq. M.)
Dry weight (Gm.)
1 2 3 4 5 6 7 8
2,288 2,420 2,420 2,420 3,212 3,212 3,212 6.270
0.35 0.37 0.37 0.37 0.49 0.49 0.49 0.95
311 292 280
tion between the Lee-White clotting time and the activated partial thromboplastin time in this situation. The results of the activated partial thromboplastin times were available in minutes, and the infusion of heparin and protamine could be promptly readjusted on the basis of these results. The initial adjustments were usually completed within 15 minutes of implantation and provided for a clotting time in the artificial lung which was over an hour and a clotting time in the dog which was normal. The requirements for heparin and protamine then remained remarkably constant; only minimal readjustment was necessary. The maximum blood flow through the lung was 145 c.c. per minute. The range is shown in Table I. When ventilated with oxygen in vivo, the unit completely satu-
22')
304 360 380 500
IPriming
volume (c.c.) 50 50 40 40 50 60 48 80
Blood [low
(c.c.rmin.t 90 80 100 120 40 60 130 145
rated the venous blood. Oxygen transfer rate was therefore dependent on venous saturation and rate of blood flow; it ranged from 15 to 23 ml. per minute per square meter of membrane surface. Po, Pco, and pH remained in the normal range. This was selfregulated by the dogs as they were 'breathing spontaneously. Four dogs died within 5 hours of implantation. All of these deaths could be related to technical problems such as bleeding at an anastomosis or kinking of a major vessel. In the other 6 dogs, function of the artificial lung was maintained from 7 to 35 hours after implantation. At autopsy, no clots were seen in any component of any artificial lung. There was a minimal buildup of a white, fibrin-like material along the inlet tube and manifold
The Journal of
524
Palmer, Collins, Head
Thoracic ond Cardiovascular Surgery
of some implants. This was not extensive enough to have affected the flow rate and was not quantitatively related to the duration of function of the artificial lung. Discussion The use of capillary tubing eliminates the need for the rigid supports and spacers required by most oxygenators in which flat sheets are used as a membrane surface. This unit can therefore confrom to the shape of the chest and maintain enough flexibility to allow for implantation through a thoracotomy incision. As the ventilating envelope actually changes size and moves the capillary tubes during each breath, the distribution of ventilating gas is quite efficient. This is evidenced by the lack of shunting of unoxygenated blood through the lung. These units are limited in capacity, but their total volume is also quite small. The modular aspect of the design should provide for scaling up to larger capacities quite easily. Improvements in manifolding techniques have resulted in better volume-tocapacity ratios than were present in the earlier models reported from this laboratory.": 3 A major problem is prevention of intravascular coagulation in the artificial lung. Regional heparinization was used successfully in this series, but the technique has obvious and serious limitations. In addition, the systemic effects of protamine infusion are poorly understood, and there is evidence that it may be particularly detrimental to pulmonary tissue.' Other methods for the prevention of clotting in artificial organs involve the treatment of all blood-contacting surfaces with a heparin-binding agent. 5 We are currently investigating the applicability of these methods to this artificial lung. Summary Artificial lungs were implanted in the left hemithorax of 10 dogs following left pneumonectomy. The dogs recovered from the operation and resumed spontaneous respi-
ration. Ventilation of the artificial lung was achieved through the normal motion of the chest, and perfusion was obtained from the left pulmonary artery. Oxygen transfer ranged from 15 to 23 mI. per minute per square meter of membrane surface. A major problem is prevention of clotting in the prosthesis. In addition to regional heparinization, antithrombogenic surface treatments are under investigation. The assistance of Anthony J. Formolo, Michael P. Huber, and William O'Brien is gratefully acknowledged.
REFERENCES
2 3
4
5
Lande, A. J., Edwards, M. L., Bloch, J. H., Carlson, R. G., Subramanian, V. A., Ascheim, R. S., Scheidt, S. S., Fillmore, S., Killip, T., and Lillehei, C. W.: Clinical Experience With Emergency Use of Prolonged Cardiopulmonary Bypass With a Membrane Pump Oxygenator, Ann. Thorac. Surg. 10: 409, 1970. Bodell, B. R., Head, J. M., Head, L. R., and Formolo, A. J.: An Implantable Artificial Lung, J. A. M. A. 191: 225, 1967. Shah-Mirany, J., Head, L. R., Ghetzler, R., Formolo, A. J., Palmer, A. S., and Bodell, B. R.: An Implantable Artificial Lung, Ann. Thorac. Surg. 13: 381, 1972. Radegran, R., and McAslan, C.: Circulatory and Ventilatory Effects of Induced Platelet Aggregation and Their Inhibition by Acetylsalicylic Acid, Acta Anaesth. Scand. 16: 76, 1972. Rea, W. J., Whitley, D., and Eberle, J. W.: Long-Term Membrane Oxygenation Without Systemic Heparinization, Trans. Am. Soc. Artif. Intern. Organs 18: 316,1972.
Discussion DR. HEAD (Closing) An electromagnetic flow probe, not shown in the schematic drawing, is included with the catheter lines and brought out through the chest. Also, the retrograde flow through the pressuremonitoring cannula on the atrial side has been correlated with in vitro lung flow rates. This measurement correlates with the other parameters of flow. It is simple to use. We have done quite extensive work on ventilating envelopes placed in the chest as dead space ventilation. These have been implanted
Volume 66 Number 4 October, 1973
for periods up to 9 months. If they are constructed properly, they maintain their tidal volume. If the elasticity of the envelope is greater than the collapse of the chest wall, there is a tendency for fluid to form fluid and for a thick layer of
Implantable artificial lung
5 25
fibrin to build up around the lung. This constricts the tidal volume of the lung. If the envelopes are constructed and fitted in the chest properly, fluid does not accumulate and a very thin membrane is laid down around the lung which does not reduce its tidal volume.
Introductory abstracts
Beginning in January, 1974, it is requested that each article begin with a brief abstract. Authors submitting articles on or after September 1, 1973, should supply an abstract of 150 words or less.
Chronic lung diseases such as emphysema and pneumoconiosis, which lead to progressive respiratory insufficiency, are commonly encountered in clinical practice. Present treatment is entirely for control of symptoms and can only slow or occasionally arrest the progression. When the lungs can no longer deliver sufficient oxygen for survival, augmentation with a transplanted or artificial lung would be desirable. As transplants are presently plagued with the problems of availability and rejection, an implantable membrane oxygenator which functions as an artificial lung is under development. Membrane oxygenators for extracorporeal support are commercially available and have been shown to be clinically useful over short-term periods.' An implantable unit, however, must possess characteristics not found in the extracorporeal type. The maximum size and shape are limited to those of the pleural cavity. The required inlet pressure must not exceed that generated by the right ventricle, and thrombosis must be prevented in the prosthesis without the use of systemic heparinization.
membrane surface. The inside and outside diameters are 0.030 and 0.063 em., respectively, with the tubing cut into 16 em. lengths. These are joined at their ends in parallel into modules of circular cross-section containing twenty-two tubes each. The modules are then manifolded into rectangular groups containing 2,288 to 6,270 individual capillary tubes with spacers of open cell, polyurethan mesh inserted between modules to aid in distribution of ventilating gas. Silastic inflow and outflow tubes are connected to the manifolds to complete the blood pathway. Silastic cannulas for blood sampling, pressure measurement, and drug infusion are connected to the inflow and outflow tubes. All tubing comprising the blood pathway is then enclosed in a ventilating envelope of Silastic sheeting. A Silastic bronchus is connected to the envelope. The details of construction are schematically depicted in Fig. 1. Fig. 2 is a photograph of a completed artificial lung. Specifications of the lungs with this general design that were tested are shown in Table I.
Design
Implantation
Blood flow is through Silastic* capillary tubing which functions as the exchange
Eight units of this design were implanted in 10 dogs. Each new unit of this series was improved or enlarged on the basis of information obtained from implantation of the previous unit. Prior to implantation each artificial lung was tested in vitro to determine pressure-flow characteristics and gas transfer rates. All implantations were performed in fe-
From the Departments of Surgery, Northwestern University and Northwestern Memorial Hospital-Wesley Pavilion, Chicago, Ill. 606 I I. Supported by the John A. Hartford Foundation, Inc. Read at the Fifty-third Annual Meeting of The American Association for Thoracic Surgery, Dallas, Texas, April 16, 17, and 18, 1973. "Dow Corning Corporation, Midland, Mich.
521
The Journal of
522
Palmer, Collins, Head
Thoracic and Cardiovascular Surgery
ventilating envelope
cut-away view of artificial lung
Fig. 1. Schematic representation of artificial lung construction; see text for description.
male mongrel dogs weighing 15 to 20 kilograms. Anesthesia was induced and maintained with intermittent intravenous Surital, * and positive-pressure endotracheal ventilation was established. Through a left anterior thoracotomy incision, a left pneumonectomy was performed. In our earlier experience we then sutured the artificial bronchus to the left main-stem bronchus. Subsequently, we began closing the left main-stem bronchus and bringing the artificial bronchus directly through a stab wound in the left chest wall (Fig. 3). The inlet of the artificial lung was then connected to the left pulmonary artery and the outlet to the left atrium via the left atrial appendage. The cannulas for blood sampling and pressure measurement were brought through the chest wall, and the chest was closed in the usual fashion. The dogs were then allowed to awaken and breathe spontaneously. The normal motion of the chest and diaphragm induced the ventilating envelope of the artificial lung to move air in and out of the artificial bronchus. 'Parke, Davis & Co., Detroit, Mich. (sodium thiamylal ) ,
Regional heparinization was used to prevent clotting in the prosthesis. Heparin was directed via the Silastic cannula into the inlet of the artificial lung by means of a small infusion pump at a rate of 2,000 to 3,000 units per hour. Protamine was simultaneously directed into the outlet of the artificial lung at a rate of 200 to 300 mg. per hour. During the initial infusion adjustments, clotting was monitored by means of the activated partial thromboplastin time. Results
The artificial lungs fit easily into the left hemithorax of the dogs and occupied less than one third of the available space. As soon as the dogs were allowed to breathe spontaneously with the chest closed, the ventilating envelopes began to move air in and out of the artificial bronchus. The tidal volume of the artificial lung varied with the size and respiratory effort of the dog but was generally one fourth to one third that of the remaining right lung. The regional heparinization was rather easy to manage. We found a good correla-
Volume 66
Implantable artificial lung
Number 4
523
October, 1973
Fig. 2. Completed artificial lung with a portion of the ventilating envelope cut away to expose the blood pathway.
Fig. 3. Technique of lung implantation. a, Pulmonary artery connector. b, Left atrial connector. C, Cannulas for drug infusion, blood sampling, and pressure measurement. d, Artificial bronchus.
Table I. Specifications A rtificial lung
Tubing No.
Membrane surface area (sq. M.)
Dry weight (Gm.)
1 2 3 4 5 6 7 8
2,288 2,420 2,420 2,420 3,212 3,212 3,212 6.270
0.35 0.37 0.37 0.37 0.49 0.49 0.49 0.95
311 292 280
tion between the Lee-White clotting time and the activated partial thromboplastin time in this situation. The results of the activated partial thromboplastin times were available in minutes, and the infusion of heparin and protamine could be promptly readjusted on the basis of these results. The initial adjustments were usually completed within 15 minutes of implantation and provided for a clotting time in the artificial lung which was over an hour and a clotting time in the dog which was normal. The requirements for heparin and protamine then remained remarkably constant; only minimal readjustment was necessary. The maximum blood flow through the lung was 145 c.c. per minute. The range is shown in Table I. When ventilated with oxygen in vivo, the unit completely satu-
22')
304 360 380 500
IPriming
volume (c.c.) 50 50 40 40 50 60 48 80
Blood [low
(c.c.rmin.t 90 80 100 120 40 60 130 145
rated the venous blood. Oxygen transfer rate was therefore dependent on venous saturation and rate of blood flow; it ranged from 15 to 23 ml. per minute per square meter of membrane surface. Po, Pco, and pH remained in the normal range. This was selfregulated by the dogs as they were 'breathing spontaneously. Four dogs died within 5 hours of implantation. All of these deaths could be related to technical problems such as bleeding at an anastomosis or kinking of a major vessel. In the other 6 dogs, function of the artificial lung was maintained from 7 to 35 hours after implantation. At autopsy, no clots were seen in any component of any artificial lung. There was a minimal buildup of a white, fibrin-like material along the inlet tube and manifold
The Journal of
524
Palmer, Collins, Head
Thoracic ond Cardiovascular Surgery
of some implants. This was not extensive enough to have affected the flow rate and was not quantitatively related to the duration of function of the artificial lung. Discussion The use of capillary tubing eliminates the need for the rigid supports and spacers required by most oxygenators in which flat sheets are used as a membrane surface. This unit can therefore confrom to the shape of the chest and maintain enough flexibility to allow for implantation through a thoracotomy incision. As the ventilating envelope actually changes size and moves the capillary tubes during each breath, the distribution of ventilating gas is quite efficient. This is evidenced by the lack of shunting of unoxygenated blood through the lung. These units are limited in capacity, but their total volume is also quite small. The modular aspect of the design should provide for scaling up to larger capacities quite easily. Improvements in manifolding techniques have resulted in better volume-tocapacity ratios than were present in the earlier models reported from this laboratory.": 3 A major problem is prevention of intravascular coagulation in the artificial lung. Regional heparinization was used successfully in this series, but the technique has obvious and serious limitations. In addition, the systemic effects of protamine infusion are poorly understood, and there is evidence that it may be particularly detrimental to pulmonary tissue.' Other methods for the prevention of clotting in artificial organs involve the treatment of all blood-contacting surfaces with a heparin-binding agent. 5 We are currently investigating the applicability of these methods to this artificial lung. Summary Artificial lungs were implanted in the left hemithorax of 10 dogs following left pneumonectomy. The dogs recovered from the operation and resumed spontaneous respi-
ration. Ventilation of the artificial lung was achieved through the normal motion of the chest, and perfusion was obtained from the left pulmonary artery. Oxygen transfer ranged from 15 to 23 mI. per minute per square meter of membrane surface. A major problem is prevention of clotting in the prosthesis. In addition to regional heparinization, antithrombogenic surface treatments are under investigation. The assistance of Anthony J. Formolo, Michael P. Huber, and William O'Brien is gratefully acknowledged.
REFERENCES
2 3
4
5
Lande, A. J., Edwards, M. L., Bloch, J. H., Carlson, R. G., Subramanian, V. A., Ascheim, R. S., Scheidt, S. S., Fillmore, S., Killip, T., and Lillehei, C. W.: Clinical Experience With Emergency Use of Prolonged Cardiopulmonary Bypass With a Membrane Pump Oxygenator, Ann. Thorac. Surg. 10: 409, 1970. Bodell, B. R., Head, J. M., Head, L. R., and Formolo, A. J.: An Implantable Artificial Lung, J. A. M. A. 191: 225, 1967. Shah-Mirany, J., Head, L. R., Ghetzler, R., Formolo, A. J., Palmer, A. S., and Bodell, B. R.: An Implantable Artificial Lung, Ann. Thorac. Surg. 13: 381, 1972. Radegran, R., and McAslan, C.: Circulatory and Ventilatory Effects of Induced Platelet Aggregation and Their Inhibition by Acetylsalicylic Acid, Acta Anaesth. Scand. 16: 76, 1972. Rea, W. J., Whitley, D., and Eberle, J. W.: Long-Term Membrane Oxygenation Without Systemic Heparinization, Trans. Am. Soc. Artif. Intern. Organs 18: 316,1972.
Discussion DR. HEAD (Closing) An electromagnetic flow probe, not shown in the schematic drawing, is included with the catheter lines and brought out through the chest. Also, the retrograde flow through the pressuremonitoring cannula on the atrial side has been correlated with in vitro lung flow rates. This measurement correlates with the other parameters of flow. It is simple to use. We have done quite extensive work on ventilating envelopes placed in the chest as dead space ventilation. These have been implanted
Volume 66 Number 4 October, 1973
for periods up to 9 months. If they are constructed properly, they maintain their tidal volume. If the elasticity of the envelope is greater than the collapse of the chest wall, there is a tendency for fluid to form fluid and for a thick layer of
Implantable artificial lung
5 25
fibrin to build up around the lung. This constricts the tidal volume of the lung. If the envelopes are constructed and fitted in the chest properly, fluid does not accumulate and a very thin membrane is laid down around the lung which does not reduce its tidal volume.
Introductory abstracts
Beginning in January, 1974, it is requested that each article begin with a brief abstract. Authors submitting articles on or after September 1, 1973, should supply an abstract of 150 words or less.