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Prolonged circulatory assistance in awake neonatal lambs
Prolonged circulatory assistance in awake neonatal lambs Six awake neonatal lambs have survived continuous extracorporeal circulation of 50 per cent of their blood volume for up to 4 days. Perfusion was carried out through a new silicone membrane oxygenator by means of the oscillating tube principle. Surprisingly little biochemical and hematologic change has been measured, and the results point to early clinical evaluation.
D. G. Melrose, M.A., M.RC.P., F.RC.S., * and M. P. Singh, M.B.B.S., F.RC.S.(E.),** London, England
E xtracorporeal circulation of blood is a routine matter both for renal dialysis and for open-heart surgery. Man can survive for a lifetime without kidneys provided intermittent dialysis is carried out, and it is possible to circulate the entire cardiac output through a heart-lung machine for short periods. In chronic dialysis it is common practice to pass the blood volume of the patient through the machine approximately once in 30 minutes, perhaps 24 times in all. In total body perfusion this volume is exchanged in about 2 minutes, perhaps 100 times in all. To date the latter system has proved too destructive to allow its use for more than 4 or 5 hours at a time. The advent of membrane oxygenators now offers the prospect of greatly lengthening this time scale. Several people owe their lives to devices that can be used to assist the circulation for up to a week.':" This study describes the continuous in vivo circulation of blood through an ef-
•
From the Department of Surgery, Royal Postgraduate Medical School, Ducane Road, London W12 OHS, England. This study is supported by a project grant from the Medical Research Council. Received for publication Nov. 8, 1973. • Professor of Surgical Science. • ·Consultant Paediatric Surgeon.
584
ficient membrane oxygenator system" for between 48 and 96 hours. During this time the blood volume has been circulated between 1,000 and 4,000 times. Young Iambs remained conscious, free to feed and to move about during this time, and suffered no obvious change in health. Our object was primarily to define those areas in which biological change occurs as a preliminary to an attempt to maintain the total circulation for protracted periods. Method
Six lambs between 7 and 21 days of age were used. Each was initially premedicated with acetylpromazine (0.1 mg. per kilogram) and anesthetized with halothane through a face mask. The jugular veins were then exposed at operation under sterile conditions, and into each was passed a silicone rubber T tube. One tube drained blood from the right atrium and from the head and the other returned it to the other jugular vein. T tubes were used to diminish any interference of the normal cerebral circulation. Anticoagulation was ensured by an injection of 3 mg. per kilogram into the animal followed by intermittent doses of 1 to 1.5 mg. per kilogram per hour into the circuit. After cannulation the animals were
Volume 67 Number 4
Prolonged circulatory assistance
585
April, 1974
OUT
Fig. 1. Polydimethyl siloxane circuit tubing, reservoir, heat exchanger, and membrane oxygenator.
placed in a restraining cage and connected to the extracorporeal circuit. Perfusion was adjusted to approximate half the cardiac output (calculated from the body weight) and was maintained for predetermined periods of 48 hours in 2 lambs, 72 hours in 2, and 96 hours in 2. As soon as the animal was normally awake, bottle feeding with milk was commenced. Every effort made to ensure that as normal a life as possible was allowed. Restraint was limited to preventing the lamb from rotating in its cage in order to avoid kinking of the tubes, and the animal was under observation at all times. On no occasion, nor for any reason, was it necessary to modify the protocol or to cut short
the chosen perfusion time. Blood samples from entry and exit points of the oxygenator were taken at intervals, and all urine was collected; otherwise the animals were not disturbed by additional monitoring. The extracorporeal circuit consisted of a Sarns roller pump, normally used in renal dialysis, and an oxygenator composed of twenty-four silicone tubes (2 mm. in diameter, 1.65 M. in length, and 65 p. in wall thickness) (Fig. 1). The tubes were first formed into a plait and then secured at each end into a silicone rubber manifold. Plaiting produces a self-supporting and stable configuration which has proved easy to assemble and remarkably reliable in use (Fig. 2). The internal surface area of the
The Journal of
586
Melrose and Singh
Thorac ic and Card iovascular Surgery
Fig. 2. Section of oxygenator showing twenty-four tube plait.
oxygenator was 0.22 sq. M. All circuit tubing was of silicone rubber (7 mm. internal diameter). The return tubing passed through a heat exchanger to maintain normal blood temperature. * The machine was primed with crossmatched sheep blood; in all, approximately 250 ml. of donor blood was used to prime the oxygenator and to make up losses due to sampling over the 48 to 96 hour period . No transfusion as such was given, either of blood or of electrolytes. Venous blood entered the oxygenator at a gravity head of 100 cm. of water and was pumped from there by the roller pump at a rate of between 150 and 300 ml. per minute. The roller pump speed was controlled by a microswitch, which sensed the volume of a silicone rubber reservoir and adjusted to compensate automatically for changes in venous return. A comparison of the flow rates measured with the animals standing and lying down showed a variance of approximately 20 per cent. Very little manual supervision was required. The oxygenator was oscillated at approximately 75 strokes per minute through a 30 degree angle to provide normal arterial tensions for oxygen and carbon dioxide. The gas mixture contained 90 per cent oxygen and 7 per cent carbon dioxide and entered the oxygenator humidified at a flow rate of I to 1.5 L. per minute. "Both oxygen ator and circu it tubing was made to our specific ation by Mr . John Belgian of J. G. Franklin and Sons ( Searle Gr oup), Lane End Road, High Wycombe, Bucks, En gland .
At the appropriate time the Iambs were re-anesthetized with halothane and oxygen, the tubes were removed, the veins were resutured with 6-0 Ethiflex, and continuity of flow was re-established. Ampicillin (500 mg.) was administered daily during perfusion and for 3 days postoperatively. Samples of the silicone material used in the oxygenator were taken at the end of each perfusion for histology. This necessitated a change of oxygenator after 3 experiments, and thus two were used for the series. Cleaning between perfusions was carried out by circulating for 1 hour a five per cent sodium hydroxide solution followed by rinsing with 5 per cent hydrochloric acid and then distilled water . For convenience, sterilization was effected by the circulation of a 2 per cent solution of formaldehyde followed by rinsing with sterile distilled water and sterile saline prior to priming. Each oxygenator was run for an aggregate of approximately 300 hours without any evidence of leaks or of deterioration in efficiency. Results Considerable difficulty attends presentation of the available data: Statistics on so small a sample are inadmissible, and even averaging is inadequate. However, the results from each experiment form so consistent a pattern that a single example can be quoted as representative. The data obtained from blood samples during a 96 hour perfusion are shown in Table I, and those qualities which vary consistently are marked with a footnote. The most obvious changes were a fall in the packed cell volume and in levels of plasma cholesterol and alkaline phosphatase (Figs . 3 to 5) . A shift in the proportion of plasma proteins was also apparent although not so obvious. While total proteins remained relatively unchanged , there was an increase in fibrinogen and globulin with a concomitant slight fall in albumin. No such trends were apparent in the remainder of the values recorded. It is particularly noteworthy that the level of cir-
Volume 67
Prolonged circulatory assistance
Number 4
587
April, 1974
Table t. Analysis of a 96 hour perfusion in a 20-day-old lamb Before perju-
sion Assay
WBC (per c.mm.) Platelets [x 103 / c.mm.)
Hours of perfusion
I
12
I
I
Days after perfusion
I
I
I
96
1
8,500
6,550
16,200
6,050
406
323
377
381
1,064
6.4 22
8.1 24
6.8 20
6.2 18.5
1.3 5.29 3.6
1.5
5.37 3.1 2.2 339 483
5.00 2.7 2.3 333 393
2.3 5.4 3.0 2.4 351 360
5.86 3.0 2.9 608 460
6.15 3.3 2.9 655 460
40.4 31.6 36.1 27 29.4 74 83 67.5 83 75 No bilirubin detected in any specimen 3.8 4.0 4.4 4.7 4.5 5.0 5.5 6.0 5.3 1.2 1.5 1.3 1.3 1.3 9.1 7.35 8.9 9.65 7.5 15 34 29 21
23.4 68
17.9 70
13.8 63
18.3 76
5.3 5.6
5.3 5.6 1.0 8.2
5.3 1.3 7.6
6.6
24
48
0
1
5,000
5,000
10,800
6,250
6,450
226
609
378
453
8.0 25.5
8.0 23
8.3 24.5
1.8 6.25 4.3 2.0 401 480
4.1 5.77 4.0 1.8 311 433
42.8 5.03 3.6 1.4 410 547
72
3
I~
Hemoglobin * (Gm. %)
PCV* (%) Plasma hemoglobin (mg. %) Total protein (Gm. %) Albumin* (Gm. %) Globulin* (Gm. %) Fibrinogen* (mg. %) LDH (units/ml.) Alk. Phos. * (KA units %) Cholesterol* (mg. %) Bilirubin (mg. %) K+ (mEq./L.) Ca H (mEq./L.) Mg" (mEq./L.) PO, (mg. %) Urea (mg. %)
1.7
269 493
1.1
9.3
7.7 24
8.0
5.6 383
23.3 70
10.9 38
Legend: WBC, White blood cells. PCY, Packed ceIl volume. LDH, Lactic dehydrogenase. 'These values showed a consistent pattern of change.
culating platelets did not fall significantly, nor was measurable hemolysis a feature. Also striking was the stable level of lactic dehydrogenase. All the lambs survived, appeared normal during perfusion, and showed no apparent change in condition on return to their pens. All gained weight at the expected rate while on perfusion. Although it has not been possible to exclude tissue edema as a factor in this weight gain, we believe that the subsequent sustained gain noted in all 6 lambs indicates a normal growth pattern. Management in the restraining cage was without important incident even though the animals were lively and normally active. The cannulation sites remained dry, but an occasional change of dressing was necessary in 3 lambs after periods of particular exuberance. No transfusion was needed to make up for hemorrhage in any of them. Histologic examination of the internal surface of tubes selected at random from
the oxygenators failed to demonstrate adherent material either of amorphous fibrin or of cellular deposits. At the end of I experiment a small thrombus was found in the entry port to one tube; and at the end of another, a delicate fibrin thrombus, originating in the sample port of the reservoir, extended along many centimeters of the circuit tubing. Otherwise the circuits appeared entirely clean after being rinsed. Discussion
Previous reports of such perfusions have underlined the difficulty of ensuring adequate anticoagulation without coincident hemorrhage. 4 . " It is true that thrombocytopenia in association with high heparin levels has been a cause of death. We noticed a striking absence of such problems in spite of a heparin dosage similar to that used in conventional open-heart surgery. Maintenance of a satisfactory platelet level probably was helpful. As closer control of anti-
The Journal af
588
Melrose and Singh
Thoracic and Cardiovascular Surgery
30 ~
25
\
\
\
, \
20 15
12
24
48
72
% Days Post Perfusion
Hours of Perfusion
Control
Fig. 3. Average fall in packed cell volume (per cent) in 6 lambs. 55 45
,
,
35 25 15
12 Control
24
48
Hours of Perfusion
72
96
Days Post Perfusion
Fig. 4. Average fall in plasma alkaline phosphatase (KA units per cent) in 6 lambs.
/ Days Post Perfusion
Fig. 5. Average fall in plasma cholesterol (milligrams per 100 m\.) in 6 lambs.
coagulation can easily be achieved, we are confident that the system is adequately safe in this regard. While hemoglobin values fell in all of the animals, there was no evidence that this fall was primarily due to hemolysis; the
plasma hemoglobin level exceeded 6 mg. per cent in only four of the thirty samples analyzed, and these four high values were undoubtedly due to sampling technique as they occurred as isolated instances. The low initial value for hemoglobin is a normal
Volume 67
Prolonged circulatory assistance
Number 4
589
April,1974
finding in sheep and is not significant. Account must be taken of primary dilution, of periodic extraction of blood for sampling, and of minimal but demonstrable loss into the tissues around the entrance and exit incisions. Without recourse to labeling techniques it is not possible to ascribe proportional responsibility, but it is evident that the measured fall is no barrier to the use of this perfusion system. The fall in plasma cholesterol and alkaline phosphatase is of unknown significance as yet. We are particularly encouraged by the absence of any deposits in the oscillating tubes, as this supports the concept that active mixing in this part of the system prevents local stagnation and cellular debris. n The presence of a small clot in the entry port on one occasion could be explained by the fact that donor blood was introduced into the circuit without prior filtration, but the second thrombus indicates a need for more careful sampling arrangements. These preliminary results have been very encouraging. We now propose to magnify the effects of this perfusion system by substantially increasing the proportion of the cardiac output passing through it, by substituting arterial in place of venous return, and by running the oxygenator at its maximum efficiency. If comparable results are obtained, the device can be considered ready for clinical evaluation. Meanwhile, a much more determined analysis of those qualities that varied is being undertaken.
We would like to acknowledge the members of our team: J. Fleming, F. E. Williams, Jennifer Becket, R. L. Elliott, 1. S. Adams, R. Read, M. P. Lamb, D. Wilson, and D. Martin. REFERENCES
2
3
4
5
6
Hill, J. D., de Leval, M. R., Fallat, R. J., Bramson, M. L., Eberhart, R. C., Schulte, H. D., Osborn, J. J., Barber, R., and Gerbode, F.: Acute Respiratory Insufficiency: Treatment With Prolonged Extracorporeal Oxygenation, J. THoRAc. CARDIOVASC. SURG. 64: 551, 1972. Melrose, D. G., Burns, N., Singh, M. P., Elliott, R. L., Read, R., Williams, F. E., Becket, J., Lamb, M. P., and Adams, J. S.: Oscillating Silicone Membrane Tubes: A New Principle of Extracorporeal Respiration, Biomed. Eng. 7: 60, 1972. Lande, A. J., Edwards, M. L., Blach, J. H., Carlson, R. G., Subramanian, V. A., Ascheim, R. S., Scheidt, S. S., Fillmore, S., KilIip, T., III, and Lillehei, C. W.: Clinical Experience With Emergency Use of Prolonged Cardiopulmonary Bypass With a Membrane Oxygenator, Ann. Thorac. Surg. 10: 409, 1970. Kolobow, Y., Spragg, R. C., Pierce, J. F., and Zapol, W. M.: Extended Term (to 16 Days) Partial Extracorporeal Blood Gas Exchange With the Spiral Membrane Lung in Unanesthetized Lambs, Trans. Am. Soc. Artif. Intern. Organs 17: 350, 1971. Hill, J. D., de Leval, M. R., Mielke, C. H., Jr., Bramson, M. L., and Gerbode, F.: Clinical Prolonged Extracorporeal Circulation for Respiratory Insufficiency: Hematological Effects, Trans. Am. Soc. Artif. Intern. Organs 18: 546, 1972. Friedman, L. I., Richardson, P. D., and Galetti, P. M.: Observations of Acute Thrombogenesis in Membrane Oxygenators, Trans. Am. Soc. Artif. Intern. Organs 17: 369, 1971.
D. G. Melrose, M.A., M.RC.P., F.RC.S., * and M. P. Singh, M.B.B.S., F.RC.S.(E.),** London, England
E xtracorporeal circulation of blood is a routine matter both for renal dialysis and for open-heart surgery. Man can survive for a lifetime without kidneys provided intermittent dialysis is carried out, and it is possible to circulate the entire cardiac output through a heart-lung machine for short periods. In chronic dialysis it is common practice to pass the blood volume of the patient through the machine approximately once in 30 minutes, perhaps 24 times in all. In total body perfusion this volume is exchanged in about 2 minutes, perhaps 100 times in all. To date the latter system has proved too destructive to allow its use for more than 4 or 5 hours at a time. The advent of membrane oxygenators now offers the prospect of greatly lengthening this time scale. Several people owe their lives to devices that can be used to assist the circulation for up to a week.':" This study describes the continuous in vivo circulation of blood through an ef-
•
From the Department of Surgery, Royal Postgraduate Medical School, Ducane Road, London W12 OHS, England. This study is supported by a project grant from the Medical Research Council. Received for publication Nov. 8, 1973. • Professor of Surgical Science. • ·Consultant Paediatric Surgeon.
584
ficient membrane oxygenator system" for between 48 and 96 hours. During this time the blood volume has been circulated between 1,000 and 4,000 times. Young Iambs remained conscious, free to feed and to move about during this time, and suffered no obvious change in health. Our object was primarily to define those areas in which biological change occurs as a preliminary to an attempt to maintain the total circulation for protracted periods. Method
Six lambs between 7 and 21 days of age were used. Each was initially premedicated with acetylpromazine (0.1 mg. per kilogram) and anesthetized with halothane through a face mask. The jugular veins were then exposed at operation under sterile conditions, and into each was passed a silicone rubber T tube. One tube drained blood from the right atrium and from the head and the other returned it to the other jugular vein. T tubes were used to diminish any interference of the normal cerebral circulation. Anticoagulation was ensured by an injection of 3 mg. per kilogram into the animal followed by intermittent doses of 1 to 1.5 mg. per kilogram per hour into the circuit. After cannulation the animals were
Volume 67 Number 4
Prolonged circulatory assistance
585
April, 1974
OUT
Fig. 1. Polydimethyl siloxane circuit tubing, reservoir, heat exchanger, and membrane oxygenator.
placed in a restraining cage and connected to the extracorporeal circuit. Perfusion was adjusted to approximate half the cardiac output (calculated from the body weight) and was maintained for predetermined periods of 48 hours in 2 lambs, 72 hours in 2, and 96 hours in 2. As soon as the animal was normally awake, bottle feeding with milk was commenced. Every effort made to ensure that as normal a life as possible was allowed. Restraint was limited to preventing the lamb from rotating in its cage in order to avoid kinking of the tubes, and the animal was under observation at all times. On no occasion, nor for any reason, was it necessary to modify the protocol or to cut short
the chosen perfusion time. Blood samples from entry and exit points of the oxygenator were taken at intervals, and all urine was collected; otherwise the animals were not disturbed by additional monitoring. The extracorporeal circuit consisted of a Sarns roller pump, normally used in renal dialysis, and an oxygenator composed of twenty-four silicone tubes (2 mm. in diameter, 1.65 M. in length, and 65 p. in wall thickness) (Fig. 1). The tubes were first formed into a plait and then secured at each end into a silicone rubber manifold. Plaiting produces a self-supporting and stable configuration which has proved easy to assemble and remarkably reliable in use (Fig. 2). The internal surface area of the
The Journal of
586
Melrose and Singh
Thorac ic and Card iovascular Surgery
Fig. 2. Section of oxygenator showing twenty-four tube plait.
oxygenator was 0.22 sq. M. All circuit tubing was of silicone rubber (7 mm. internal diameter). The return tubing passed through a heat exchanger to maintain normal blood temperature. * The machine was primed with crossmatched sheep blood; in all, approximately 250 ml. of donor blood was used to prime the oxygenator and to make up losses due to sampling over the 48 to 96 hour period . No transfusion as such was given, either of blood or of electrolytes. Venous blood entered the oxygenator at a gravity head of 100 cm. of water and was pumped from there by the roller pump at a rate of between 150 and 300 ml. per minute. The roller pump speed was controlled by a microswitch, which sensed the volume of a silicone rubber reservoir and adjusted to compensate automatically for changes in venous return. A comparison of the flow rates measured with the animals standing and lying down showed a variance of approximately 20 per cent. Very little manual supervision was required. The oxygenator was oscillated at approximately 75 strokes per minute through a 30 degree angle to provide normal arterial tensions for oxygen and carbon dioxide. The gas mixture contained 90 per cent oxygen and 7 per cent carbon dioxide and entered the oxygenator humidified at a flow rate of I to 1.5 L. per minute. "Both oxygen ator and circu it tubing was made to our specific ation by Mr . John Belgian of J. G. Franklin and Sons ( Searle Gr oup), Lane End Road, High Wycombe, Bucks, En gland .
At the appropriate time the Iambs were re-anesthetized with halothane and oxygen, the tubes were removed, the veins were resutured with 6-0 Ethiflex, and continuity of flow was re-established. Ampicillin (500 mg.) was administered daily during perfusion and for 3 days postoperatively. Samples of the silicone material used in the oxygenator were taken at the end of each perfusion for histology. This necessitated a change of oxygenator after 3 experiments, and thus two were used for the series. Cleaning between perfusions was carried out by circulating for 1 hour a five per cent sodium hydroxide solution followed by rinsing with 5 per cent hydrochloric acid and then distilled water . For convenience, sterilization was effected by the circulation of a 2 per cent solution of formaldehyde followed by rinsing with sterile distilled water and sterile saline prior to priming. Each oxygenator was run for an aggregate of approximately 300 hours without any evidence of leaks or of deterioration in efficiency. Results Considerable difficulty attends presentation of the available data: Statistics on so small a sample are inadmissible, and even averaging is inadequate. However, the results from each experiment form so consistent a pattern that a single example can be quoted as representative. The data obtained from blood samples during a 96 hour perfusion are shown in Table I, and those qualities which vary consistently are marked with a footnote. The most obvious changes were a fall in the packed cell volume and in levels of plasma cholesterol and alkaline phosphatase (Figs . 3 to 5) . A shift in the proportion of plasma proteins was also apparent although not so obvious. While total proteins remained relatively unchanged , there was an increase in fibrinogen and globulin with a concomitant slight fall in albumin. No such trends were apparent in the remainder of the values recorded. It is particularly noteworthy that the level of cir-
Volume 67
Prolonged circulatory assistance
Number 4
587
April, 1974
Table t. Analysis of a 96 hour perfusion in a 20-day-old lamb Before perju-
sion Assay
WBC (per c.mm.) Platelets [x 103 / c.mm.)
Hours of perfusion
I
12
I
I
Days after perfusion
I
I
I
96
1
8,500
6,550
16,200
6,050
406
323
377
381
1,064
6.4 22
8.1 24
6.8 20
6.2 18.5
1.3 5.29 3.6
1.5
5.37 3.1 2.2 339 483
5.00 2.7 2.3 333 393
2.3 5.4 3.0 2.4 351 360
5.86 3.0 2.9 608 460
6.15 3.3 2.9 655 460
40.4 31.6 36.1 27 29.4 74 83 67.5 83 75 No bilirubin detected in any specimen 3.8 4.0 4.4 4.7 4.5 5.0 5.5 6.0 5.3 1.2 1.5 1.3 1.3 1.3 9.1 7.35 8.9 9.65 7.5 15 34 29 21
23.4 68
17.9 70
13.8 63
18.3 76
5.3 5.6
5.3 5.6 1.0 8.2
5.3 1.3 7.6
6.6
24
48
0
1
5,000
5,000
10,800
6,250
6,450
226
609
378
453
8.0 25.5
8.0 23
8.3 24.5
1.8 6.25 4.3 2.0 401 480
4.1 5.77 4.0 1.8 311 433
42.8 5.03 3.6 1.4 410 547
72
3
I~
Hemoglobin * (Gm. %)
PCV* (%) Plasma hemoglobin (mg. %) Total protein (Gm. %) Albumin* (Gm. %) Globulin* (Gm. %) Fibrinogen* (mg. %) LDH (units/ml.) Alk. Phos. * (KA units %) Cholesterol* (mg. %) Bilirubin (mg. %) K+ (mEq./L.) Ca H (mEq./L.) Mg" (mEq./L.) PO, (mg. %) Urea (mg. %)
1.7
269 493
1.1
9.3
7.7 24
8.0
5.6 383
23.3 70
10.9 38
Legend: WBC, White blood cells. PCY, Packed ceIl volume. LDH, Lactic dehydrogenase. 'These values showed a consistent pattern of change.
culating platelets did not fall significantly, nor was measurable hemolysis a feature. Also striking was the stable level of lactic dehydrogenase. All the lambs survived, appeared normal during perfusion, and showed no apparent change in condition on return to their pens. All gained weight at the expected rate while on perfusion. Although it has not been possible to exclude tissue edema as a factor in this weight gain, we believe that the subsequent sustained gain noted in all 6 lambs indicates a normal growth pattern. Management in the restraining cage was without important incident even though the animals were lively and normally active. The cannulation sites remained dry, but an occasional change of dressing was necessary in 3 lambs after periods of particular exuberance. No transfusion was needed to make up for hemorrhage in any of them. Histologic examination of the internal surface of tubes selected at random from
the oxygenators failed to demonstrate adherent material either of amorphous fibrin or of cellular deposits. At the end of I experiment a small thrombus was found in the entry port to one tube; and at the end of another, a delicate fibrin thrombus, originating in the sample port of the reservoir, extended along many centimeters of the circuit tubing. Otherwise the circuits appeared entirely clean after being rinsed. Discussion
Previous reports of such perfusions have underlined the difficulty of ensuring adequate anticoagulation without coincident hemorrhage. 4 . " It is true that thrombocytopenia in association with high heparin levels has been a cause of death. We noticed a striking absence of such problems in spite of a heparin dosage similar to that used in conventional open-heart surgery. Maintenance of a satisfactory platelet level probably was helpful. As closer control of anti-
The Journal af
588
Melrose and Singh
Thoracic and Cardiovascular Surgery
30 ~
25
\
\
\
, \
20 15
12
24
48
72
% Days Post Perfusion
Hours of Perfusion
Control
Fig. 3. Average fall in packed cell volume (per cent) in 6 lambs. 55 45
,
,
35 25 15
12 Control
24
48
Hours of Perfusion
72
96
Days Post Perfusion
Fig. 4. Average fall in plasma alkaline phosphatase (KA units per cent) in 6 lambs.
/ Days Post Perfusion
Fig. 5. Average fall in plasma cholesterol (milligrams per 100 m\.) in 6 lambs.
coagulation can easily be achieved, we are confident that the system is adequately safe in this regard. While hemoglobin values fell in all of the animals, there was no evidence that this fall was primarily due to hemolysis; the
plasma hemoglobin level exceeded 6 mg. per cent in only four of the thirty samples analyzed, and these four high values were undoubtedly due to sampling technique as they occurred as isolated instances. The low initial value for hemoglobin is a normal
Volume 67
Prolonged circulatory assistance
Number 4
589
April,1974
finding in sheep and is not significant. Account must be taken of primary dilution, of periodic extraction of blood for sampling, and of minimal but demonstrable loss into the tissues around the entrance and exit incisions. Without recourse to labeling techniques it is not possible to ascribe proportional responsibility, but it is evident that the measured fall is no barrier to the use of this perfusion system. The fall in plasma cholesterol and alkaline phosphatase is of unknown significance as yet. We are particularly encouraged by the absence of any deposits in the oscillating tubes, as this supports the concept that active mixing in this part of the system prevents local stagnation and cellular debris. n The presence of a small clot in the entry port on one occasion could be explained by the fact that donor blood was introduced into the circuit without prior filtration, but the second thrombus indicates a need for more careful sampling arrangements. These preliminary results have been very encouraging. We now propose to magnify the effects of this perfusion system by substantially increasing the proportion of the cardiac output passing through it, by substituting arterial in place of venous return, and by running the oxygenator at its maximum efficiency. If comparable results are obtained, the device can be considered ready for clinical evaluation. Meanwhile, a much more determined analysis of those qualities that varied is being undertaken.
We would like to acknowledge the members of our team: J. Fleming, F. E. Williams, Jennifer Becket, R. L. Elliott, 1. S. Adams, R. Read, M. P. Lamb, D. Wilson, and D. Martin. REFERENCES
2
3
4
5
6
Hill, J. D., de Leval, M. R., Fallat, R. J., Bramson, M. L., Eberhart, R. C., Schulte, H. D., Osborn, J. J., Barber, R., and Gerbode, F.: Acute Respiratory Insufficiency: Treatment With Prolonged Extracorporeal Oxygenation, J. THoRAc. CARDIOVASC. SURG. 64: 551, 1972. Melrose, D. G., Burns, N., Singh, M. P., Elliott, R. L., Read, R., Williams, F. E., Becket, J., Lamb, M. P., and Adams, J. S.: Oscillating Silicone Membrane Tubes: A New Principle of Extracorporeal Respiration, Biomed. Eng. 7: 60, 1972. Lande, A. J., Edwards, M. L., Blach, J. H., Carlson, R. G., Subramanian, V. A., Ascheim, R. S., Scheidt, S. S., Fillmore, S., KilIip, T., III, and Lillehei, C. W.: Clinical Experience With Emergency Use of Prolonged Cardiopulmonary Bypass With a Membrane Oxygenator, Ann. Thorac. Surg. 10: 409, 1970. Kolobow, Y., Spragg, R. C., Pierce, J. F., and Zapol, W. M.: Extended Term (to 16 Days) Partial Extracorporeal Blood Gas Exchange With the Spiral Membrane Lung in Unanesthetized Lambs, Trans. Am. Soc. Artif. Intern. Organs 17: 350, 1971. Hill, J. D., de Leval, M. R., Mielke, C. H., Jr., Bramson, M. L., and Gerbode, F.: Clinical Prolonged Extracorporeal Circulation for Respiratory Insufficiency: Hematological Effects, Trans. Am. Soc. Artif. Intern. Organs 18: 546, 1972. Friedman, L. I., Richardson, P. D., and Galetti, P. M.: Observations of Acute Thrombogenesis in Membrane Oxygenators, Trans. Am. Soc. Artif. Intern. Organs 17: 369, 1971.