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COMPARATIVE MERITS AND RESULTS OF PRIMES OF BLOOD AND FIVE PER CENT DEXTROSE IN WATER FOR HEART-LUNG MACHINES: ANALYSIS OF 250 PATIENTS
COMPARATIVE MERITS A N D RESULTS OF PRIMES OF BLOOD A N D FIVE PER CENT DEXTROSE I N W A T E R FOR HEART-LUNG MACHINES: ANALYSIS OF 250 PATIENTS Nazih
Zuhdi, M.D.*
William Oklahoma
(by invitation),
Sheldon, M.D. City,
John Carey, M.D.*
(by invitation),
and Allen Gréer,
(by
invitation),
M.D.*
Okla.
T
o pretend, to drift, and then to assert are overt manifestations of our anxiety due to the incompleteness and fallibility of human knowledge. It is absurd to transpqse into a harmonic denominator the multiplicity of premises, the pro fusion of techniques, and the myriad of data published since the historic achieve ment of John Gibbon, Jr. De Bakey pointed out that many of the physiologic studies related to eardiopulmonary bypass probably will require re-evaluation in view of newer advances. Yet there is available to every man, through past and immediate experience, affirmations that are true only with certain perim eters. The clinical data presented are to be interpreted within this narrow frame of specific definitions, and the elimination of experimental data from this dis cussion is for this purpose of clarity. THE HEART-LUNG MACHINE
The oxygenator is a scaled down DeWall-Lillehei oxygenator and the pump a finger Sigmamotor pump. 1 One pump head is needed for total body perfusion; the venous blood and cardiotomy suction blood flows, by gravity, into the verti cal oxygenating tube. When coronary perfusion is contemplated, a second pump head is used on the negative side of the total body perfusion pump. The heat exchanger is a stainless steel coil introduced inside the plastic helix. Water at 4° C. and 45° C. is countercurrently pumped into it to cool or warm blood (Fig. I ) . 2 This was the basic unit used in this entire series. In the first 21 patients, a blanket and/or stainless steel tubes in a venous reservoir were used as heat exchangers, in addition. 3 In a patient weighing 4.3 kilograms, changes were made to render safe the perfusion of such a small infant, and consisted of a venous reservoir and a cross connection between the arterial and venous limbs. Its volume predicated heparinized blood as a prime. Read at the Forty-third Annual Meeting of The American Association for Thoracic Sur gery a t Houston, Texas, April 8-10, 1963. •Address: 430 N. "W. 12th, Oklahoma City, Okla. 66
Vol. 47, No. 1 January, 1964
P E I M E S FOR HEART-LUNG MACHINES
67
THE PRIMING VOLUME
At the present time, a ratio of flow rate per minute to priming volume of 1 is optimal from the standpoint of blood turnover per minute and from the standpoint of the operator of the heart-lung machine. We have usually adhered to a ratio of about 1.25 in blood primes and blood substitute primes. The amount of blood used for a blood prime is less than the amount of blood used to prime most commonly used systems. This may be important in the interpreta tion of our results. The priming volume is calculated by the formula, weight in kilograms times 16 ml., which is equivalent to about one third of the daily fluid requirements at the rate of 2 ml. per hour per kilogram of body weight. The actual range of
iTo Heat Source Vacuum Source 7 Cardiotomy Suction ** = ^
Stainless Steel Tube in Mayon Helix
Patient Arterial, Pump "Oxygen Fig. 1.—Schematic drawing oi the double helical reservoir system used in this study.
the priming volume with a blood substitute in our patients varied from 150 ml. to 1,500 ml., the latter being used for all patients who weighed more than 75 kilograms. Significantly larger priming volumes with a blood substitute should not be used because of the severe degree of hemodilution one incurs. The low flow rates are not necessitated by the hemodilution principle, and this priming volume which is advocated may be adequate for substantially higher flow rates. Fresh heparinized blood drawn within 24 hours is used as a blood prime, and 5 per cent dextrose in water as a blood substitute prime. MODERATE INTERNAL HYPOTHERMIA
Moderate internal hypothermia from 28° C. to 30° C. as measured in the mid-esophagus is a useful, but not essential, modality. It has no known harmful effects. Oxygen utilization by the tissues is not impaired and the physiologic parameters are not severely upset. It does slow down the " t e m p o " and permits the safe usage of relatively low flow rates. The warming up process is stopped at around 33° C.
Z U H D I E T AL.
68
J. Thoracic and Cardiovas. Surg.
TABLE I . ENUMERATION OF 36 D E A T H S I N TIME OF DEATH AFTER OPERATION
NATURE OF DEFECT
1 M.C.*
37 hr., 30 min.
T. O . F
Disruption of V. S. D.
Technical
2 V.A.*
4 da.
T. O. F .
Complete A-V block
Technical
3 H.A.*
At operation
Single ventricle
Complete A-V block
Technical, inherent
4 M. G.*
At operation
V. S. D.
Severe pulmonary hyper tension
Inherent
INITIALS
CAUSE OF DEATH
CLASSIFICATION
GROUP 1
GBOUP
SA
5 F.B.*
At operation
6 H. F . *
18 hr.
V. S. D.
7 T.U.*
26 hr.
A-V Communie
8 S.U.*
4 mo.
M.I. M.S.
9 B.A.*
13 hr., 45 min.
I. A. D.-V. S. D. Marked hypertrophy of right Inherent P . D. ventricle Pulmonary hypertension with arteriolar sclerosis
A. S. (acquired)
Unrecognized cardiae arrest during induction of anesthesia
Technical
Fresh anteroseptal myocardial Cardiac infarction complication Massive infection with sternal disruption
Technical
Bleeding from aortotomy
Technical
Atrioventrieular block
Technical
10 T. E .
At operation
11 G.I.*
19 hr.
M. S.
Calcification of entire left Perfusion atrium and auricle with aortie stenosis, mitral stenosis, and insufficiency; did not regain consciousness
12 E. S.t
3 hr., 50 min.
M. S.
Class V—Left intra-atrial clot, 207 grams
13 H . E . *
4 da.
14 C. H.i
3 hr., 45 min.
T. 0 . F .
15 C. 0 4
At operation
16 S. T.*
23 hr., 43 min.
17 H. 0.*
4 da. after operation
18 M. A.}
A t operation
V. S. D.
Transposition Chylothorax of great Iatrogenic hyperpotassemia vessels
Inherent Technical
Bleeding from previous aorto-pulmonary shunt
Technical
A. S. (acquired)
Aortic valvular replacement
Technical, inherent
Myocardial disease
Exploratory cardiotomy
Inherent
Bight ventricular hypoplasia
Inherent
Aortie valve replacement
Technical
V. S. D. A.I.
hegend: Group 1.—Blood primed heart-lung machine. Group 2A.—5% dextrose in water primed heart-lung machine. Group 2B.—5% dextrose in water primed heart-lung machine. A.I.—Aortic insufficiency. A.S.—Aortic stenosis. T.O.F.—Tetralogy of Pallot. V.S.D.—Ven tricular septal defect M.I.—Mitral insufficiency. M.S.—Mitral stenosis. P.D.—Patent ductus arteriosus. (I.A.D.—Interatrial defect. P.S.—Pulmonary stenosis. •Autopsy. tCause of death established without autopsy. îDied at operation.
69
P R I M E S FOR HEART-LUNG MACHINES
Vol. 47, No. 1 January, 1964
THIS SERIES OF 250 CONSECUTIVE P A T I E N T S
19 S. T.*
71 hr.
T. O. F .
20 A. XL*
71 hr.
P.S.
21 S. T.*
2 hr., 30 min.
22 W . A . *
8 da.
P.S.
Unrelieved stenosis of base of pulmonary valve
Technical
23 L. A.*
5 da.
M.S.
Anteroseptal myocardial infarction
Cardiac complication
24 R. L.t
At operation
A. S. (acquired)
Aortic valve replacement
Technical
25 W . A .
13 hr., 45 min.
T. O. F .
Inherent Hypoplasia of pulmonary artery; small left ventricle
26 M. A.
44 hr., 45 min.
M.S. (recurrent)
Class V—poor cardiac output Inherent
27 B. B.*
28 hr., 30 min.
V. S. D.
28 M. C *
18 hr., 50 min.
V. S. D.
Bleeding from previous aorto- Technical pulmonary shunt Marked hypertrophy of right Inherent, technical ventricle Infundibular stenosis not relieved Massive pulmonary atelectasis Pulmonary complication
Atresia of right ventricle
Inherent
P.S.
Unrelieved infundibular stenosis
Technical
GBOUP SB 29 T. H.
At operation
M.S.
Class V
Technical
30 H. U.
63 hr., 43 min.
M.S.
Class V ; died suddenly; no postmortem examination
Unknown
31 P . O.t
At operation
M.S.
Class V—mitral valve replacement
Inherent
32 H . E .
At operation
M.S. (recurrent)
Mitral valve replacement; sutures taken deep in myocardium
Technical
33 S. T.*
24 hr.
P.S.
Cardiac tamponade
Technical
34 S. T.î
At operation
M.I.
Class V—mitral valve re placement
Inherent, technical
35 S.L.*
50 hr., 55 min.
36 G. 0 .
4 da.
A. S. (acquired) M.S.
Did not regain consciousness Perfusion Probably Doing relatively well, then perfusion lost consciousness on third day
LOW F L O W RATES
The low flow rates are not used because of the hemodilution principle. They are safe within the scope of our time limits and our experience. It is absurd to recommend an over-all figure for flow rates per minute for all types of heartlung machines and all forms of perfusions. We have 214 long-term survivors in this series of 250 consecutive patients
70
ZTJHDI E T A L .
J- Thoracic and Cardiovas. Surg.
with the use of flow rates of 20 ml. per kilogram of body weight per minute. This maximal flow rate was used with blood primes and with water primes. All the survivors have no apparent neurological symptoms and have no notice able changes in their behavioral pattern; some have won scientific achievement awards and others are leading members of their community. These flow rates were adequate to maintain satisfactory body perfusion for open mitral valvuloplasty (March 31, 1960) in a patient in her early second trimester of pregnancy, with subsequent uneventful delivery of a full-term normal infant. At present, 3.years later, both are doing well.2 A mortality figure does not project a true perspective of all the different aspects of extracorporeal circulation. It does reflect the over-all sagacity of the surgeon. A painful death due to the learning period or a technical error does not echo the efficiency of a perfusion system or the validity of a flow rate. Table I enumerates the 36 deaths in this series of 250 consecutive patients, a combined mortality rate of 14.4 per cent. Table I I is an attempt at a compre hensive grouping of these deaths. Postmortem examination was permitted in 22 patients, and the cause of death was satisfactorily established in 11 more patients. TABLE
II*
Not Due to Perfusion Technical (Cases 1, 2, 3, 6, 8, 9, 10, 13, 14, 15, 18, 19, 20, 22, 24, 28, 29, 32, 33, 34) Inherent cardiac disease (Cases 3, 4, 5, 12, 15, 16, 17, 20, 25, 26, 27, 31, 34) Myocardial infarction (Cases 7, 23) Sudden death, cause undetermined (Case 29) Pulmonary atelectasis (Case 21) Possibly Due to Perfusion TJnresponsiveness fourth day after surgery (Case 36)
20 13 2 1 1 1
Due to Perfusion Brain edema (Cases 11, 35) 2 •Comprehensive grouping of causes of death in 36 patients in this series of 250 patients who were perfused at a maximum flow of 20 ml. per kilogram of body weight per minute. The figures between parentheses refer to the specific numerical order of patients in Table I. MATERIAL
Two hundred and fifty patients who had open-heart surgery with the use of the double helical reservoir heart-lung machine formed three evolutionary groups : Group 1.—Forty-five patients were connected to a blood primed heart-lung machine, 43 of them between May 29, 1959, and Feb. 25, 1960. Blood loss was replaced with citrated banked blood. An average of 1.5 mg. of aqueous heparin per kilogram of body weight was given intravenously prior to cannulation and an equivalent amount of Polybrene at the termination of the perfusion. Group 2.—Subgroup A: One hundred and seventy-one patients had openheart operation with a heart-lung machine primed with 5 per cent dextrose in water between Feb. 25, 1960, and July 18, 1962. Blood loss was replaced as in Group 1. An average of 3 mg. per kilogram of body weight of heparin was used and counteracted with an equivalent amount of Polybrene.
Vol. 47, No. 1 January, 1964
PRIMES FOR HEART-LUNG
71
MACHINES
Subgroup B: Thirty-four patients had open-heart operation with the heartlung machine primed with 5 per cent dextrose in water starting on Aug. 7, 1962. Blood loss was not replaced until deemed essential by the surgeon. This is usually delayed until the end of the perfusion, if feasible. In some selected cases, there was no blood replacement at all, before, during, or after operation. The three series do not contain an equal number of patients and lack random selectivity. This is somewhat balanced by the absence of selective ad mission to either group. COMPARATIVE RESULTS
It is apparent that an attempt at such an analysis will deal with one of the many facets of such a complex problem because of the medley and multitude of factors involved. The limitations of this endeavor are deliberately stressed. Neurological Manifestations, Electroencephalography, Immediate and Late Sequelae.-—The electroencephalogram remains active in both groups. Awakening is usually immediate at the end of operation and patients respond to verbal commands. Table I I I compares the various neurological manifestations in rela tion to perfusion time in both groups. The lengths of perfusions, partial and complete, were comparable in those who had the neurological complications and those who did not have any. These changes were completely reversible without any residual manifestations (Table I V ) . In Group 1 there was one patient (2.4 per cent) with reversible changes, in Group 2A there were 12 patients (8.78 per cent), and in Group 2B there was one patient (8.69 per cent).
TABLE III.
GROUP
1
N E U R O L O G I C A L C O M P L I C A T I O N S A N D D E A T H S I N R E L A T I O N TO P E R F U S I O N
NO. OP COMPLICA TIONS WITH COMPLETE RECOVERY
1 (2.4%)
PERFUSION TIME OF P A T I E N T S W I T H COMPLICATIONS (MIN.)
P E R F U S I O N T I M E OF PATIENTS WITHOUT COMPLICATIONS (MIN.)
TOTAL BODY B Y P A S S OF P A T I E N T S W I T H COMPLICATIONS (MIN.)
TOTAL BODY B Y P A S S OF P A T I E N T S W I T H O U T COMPLICATIONS (MIN.)
41 . 13
2A
12 (8.7%)
23 - 137
55TB" 12 - 69
2B
2 (8.6%)
72! 42Λ
PERFUSION TIME OF P A T I E N T S W I T H NEUROLOGICAL DEATH ( M I N . )
"PER FUSION DEATH"
TOTAL BODY B Y P A S S OF P A T I E N T S W I T H NEUROLOGICAL DEATH ( M I N . )
0
22 - 189 6Ï77 11 - 118
TIME
170 1 (0.6%)
25
3θ
121
43 - 83
14 - 92
46 - 75
62^5 5-58
14 - 70
6ÖT5 20 - 45
35.5
31.6
32.5
BXë
2 (2.5%)
ZUHDI E T AL.
72 TABLE IV.
GROUP
1
NEUROLOGICAL
COMPLICATIONS
J. Thoracic and Cardiovas. Surg. (EXCLUDING
MINOR* TIME OF APPEARANCE POST-SURGERY (DAYS)
MAJOR t TIME OP APPEARANCE POST-SURGERY (DAYS)
0 | 1 | 2 | 3 | 4 0 1 0 0 0
0 | 1 | 2 | 3 14 0 0 0 0 0
3
DEATHS) TOTAL NUMBER
or
OUTCOME
Complete recovery 2A 0 3 1 3 0 0 3 0 2 0 Complete recovery 0 1 0 0 1 2B 0 0 0 0 0 Complete recovery •Minor : Confusion, hallucination, restlessness, photophobia. fMajor : Convulsion, paresis, +Babinski.
NEUROLOGICAL COMPLICATIONS
1 (2.4%) 12 (8.78%) 2 (8.69%)
There were three deaths characterized by loss of consciousness. It is con ceivable that higher flow rates may have prevented the death of 2 patients and possibly of one more, or 1.2 per cent of this series. All three deaths were in adult patients who had operation on the mitral valve (2 patients) or aortic valve (one patient) for an acquired lesion. Cardiopulmonary Complications.—The myocardial response was excellent in both groups, ventricular fibrillation during operation was of no significance and either converted on its own to a regular rhythm or after the application of electroshock. There were two instances of myocardial infarction leading to death, both with anteroseptal location. Fresh myocardial necrosis and softening were not found at the postmortem examination of the remaining 20 patients. The postoperative pulmonary complications were collected from the x-ray films and are listed in Table V. There was one death from massive pulmonary atelectasis, an incidence of 0.4 per cent. Findings necessitating tracheotomy and intermittent positive pressure occurred in 2 patients. One of them had had mitral valve replacement, and the other had had mitral valvuloplasty ; both survived.
TABLE V. PULMONARY COMPLICATIONS AS T H E Y APPEARED IN THE POSTOPERATIVE X-RAY C H E S T FILMS
GROUP
CLEAR
ATELECTASIS, INFILTRATE, PNEUMONITIS
1 2A 2B
32 (68%) 88 (59.8%) 9 (50%)
11 ( 2 3 % ) 47 (31.9%) 7 (38.8%)
PNEUMOTHORAX
CONGESTION, PULMONARY EDEMA
3 (6.3%) 11 (7.5%) 1 (5.5%)
1 (5.5%) 3 (2.04%) 1 (2.12%)
PLEURAL FLUID
1 (0.68%)
Renal Findings.—Urine output in the first 24 hours following operation was 23.58 ml. per kilogram of body weight per 24 hours in Group 1, 31.92 ml. in Group 2A, and 41.73 ml. in Group 2B. The urine output increased in each group during the next 24 hours. Albumin in varying amounts was present in 85 per cent of the patients in Group 1 and in 83.5 per cent in Group 2, and in 100 per cent in Group 2B. Hematuria was present in 85 per cent in Group 1,
73
P R I M E S F O B HEART-LUNG MAC H I N E S
Vol. 47, No. ! January, 1964
TABLE VI. URINARY FINDINGS URINE OUTPUT ( M L . / K G . / 2 4 HR.)
|
MICROSCOPIC
HEMATURIA ALBUMINURIA GLYCOSURIA 24 HR Group 1 85% 23.58 85% 33.43 40% Group 2A 67.3% 31.92 31.3% 39.39 35.2% Group 2B 100% 41.73 61.5% 30.7% 54.96 •Only one patient had sufficient renal depression to be considered a case of renal shut down and recovery occurred without dialysis. 1ST 24 HR.
2ND
in 67.3 per cent in Group 2A, and in 100 per cent in Group 2B (Table V I ) . All of these changes are reversible in 1 to 4 days. More elaborate renal function tests were not performed and there is no reason in our close follow-up of these patients to suspect any residual kidney disease. More elaborate tests are being performed and will be reported later. There was one patient with renal shutdown who had a total perfusion time of 93 minutes, with total body bypass of 72 minutes. Recovery occurred without dialysis. The consecutive 24-hour urine outputs were 105 ml., 68 ml., 61 ml., 65 ml., 135 ml., 215 ml., 440 ml., and 670 ml. The mean arterial pressure during perfusion varied from 20 mm. Hg to 70 mm. Hg, with an average of 36.3 mm. Hg, and in Group 2 from 25 to 55 mm. Hg, with an average of 48 mm. Hg. The mean arterial pressure seems to be more predictable and stable in Group 2. Postoperative Chest Drainage and Postoperative Anemia.—Total drainage of the chest averaged 11.4 ml. per kilogram body weight for Group 1, 8.57 ml. for Group 2A, and 20.87 for Group 2B. This was usually replaced with banked citrated blood. The additional blood given (+4.27 ml. per kilogram in Group 2A and +7.23 ml. per kilogram in Group 2B) may roughly reflect what may clini cally represent post-perfusion anemia (Table V I I ) . TABLE V I I . POSTOPERATIVE C H E S T DRAINAGE AND BLOOD REPLACEMENT
1 2A 2B
CHEST DRAINAGE (ML./KG. BW)
BLOOD REPLACEMENT (ML./KG. BW)
BALANCE (ML./KG. BW)
11.4 8.57 20.87
7.64 12.7 28.1
-3.76 +4.27 +7.23
Tabulation of Patients.—Table V I I I contains a summary of the congenital heart defects which were corrected in each group. The mortality rate in Group 1 and Group 2A is 10 per cent and 11.3 per cent, respectively. Table IX indicates the increase in the number of acquired lesions in Group 2A when compared to Group 1. I t is apparent that direct comparison of mortality figures in these two groups is misleading. There are 2 cases in Group 2A of mitral valve replacement with the Starr-Edwards prosthesis. Both patients are doing well. Five similar attempts were made in Group 2B with one patient surviving. The series of acquired aortic valvular lesions is small.
74
J. Thoracic and Cardiovas. Surg.
ZUHDI E T AL.
TABLE V I I I . TOTAL NUMBER
OF P A T I E N T S
WITH
CONGENITAL
GROUP 1 CONGENITAL Interatrial defect Ventricular septal defect Pulmonary stenosis, valvular and infundibular Tetralogy of Fallot Aortic stenosis Supravalvular aortic stenosis A-V Communis Transposition of great vessels Totals
TABLE I X .
DEFECTS
IN E A C H
GROUP 2B
GROUP 2A
NO. 10 13
DEATHS 0 2
32 39
0 3
4 3
0
8 7 1 1 0 0 40
0 2 0 0 0 0 4
17 6 6 3 2 1 106
3 3 0 0 2 1 12
5 2 1 0 2 1 18
0 1 0 0 0 1 3
t
TOTAL NUMBER OF P A T I E N T S W I T H ACQUIRED DEFECTS IN E A C H
Mitral stenosis and mitral in sufficiency (M.S., M.I.) Mitral valve replacement Aortic stenosis A.S.) Exploratory cardiotomy (Expl. Card.) Totals
NO.
5 0 0
|
DEATHS
NO.
0 0 0
|
GROUP
GROUP 2 B
GROUP 2A
GROUP 1 ACQUIRED
GROUP
DEATHS
NO.
57 2 5
6 0 4
9 5 2
65
11
16
|
DEATHS
1 4 1
DISCUSSION
Landsteiner and Levine elaborated on the concept of individuality of human blood, including red blood cells, proteins, and other elements. The body re sponses to genetically different blood pooled in a pump oxygenator are multiple. However, the apparent and theoretical advantages of hemodilution and of the elimination of blood as a prime have not been substantiated in this comparative study. Larger series may have demonstrated that there is a reduction in anaphylactoid responses, sludging, acidosis, major and minor blood incompatibili ties, hepatitis, renal complications, and other manifestations. The cerebral manifestations in this series of patients do not seem related to length of perfusion time and total body bypass time, and cerebral changes have not been described during moderate internal hypothermia. All three cerebral deaths and most of the neurological complications occurred in patients who had had corrective surgery on either the mitral or aortic valves and they could have been due to calcific emboli or to air trapped in the left atrium or left ventricle. Two cerebral deaths occurred in Group 2B. This suggests that hemodilution, with a further decrease in red blood cell count due to blood loss which is not being replaced, may lead to tissue anoxia. The higher urine out puts in Group 2 as compared to Group 1 did not influence the postoperative course or the final outcome in either series. Albuminuria and hematuria are reversible. The ideal priming fluid to be used as a blood substitute is not determined. Five per cent dextrose in water is easily available, of simple composition, and
Vol. 47, No. I January, 1964
P R I M E S F O E HEART-LUNG MACHINES
75
extensively studied. Five per cent dextrose in water is slightly hypotonie with regard to the red blood cells. The volume of red cells that contain one gram of hemoglobin increases as the percentage of whole blood to 5 per cent dextrose in water decreases. However, it is apparent that the increase is small in the range of the degree of hemodilution we induce. The average rise in plasma hemoglobin following the mechanical fragility test in 5 patients was 22.1 mg. per cent, and, following an average perfusion of 60 minutes in 33 patients, was 13.9 mg. per cent. The feasibility of definitive priming of the extracorporeal system with a blood substitute inducing hemodilution is demonstrated. This should apply as well to systems for regional perfusion and dialysis. It is axiomatic that varia tions of this basic principle of hemodilution are bound to appear. CONCLUSIONS
1. The use of hemodilution without replacement of blood lost from the surgical field should be used only in selected patients. There is no apparent advantage in delaying blood replacement until the end of perfusion. Actually, this practice seems to have some detrimental effects, as evidenced in the statistics of Group 2B. 2. Group 1 and Group 2A yielded similar findings and statistics. The su periority of either is not established when used within our specific definitions. This clinical appraisal demonstrates that primes of 5 per cent dextrose in water, inducing intentional hemodilution, are safe, simple, efficient, physiological, and compare well with the conventional blood primes. SUMMARY
A clinical appraisal is presented of primes of blood and 5 per cent dextrose in water. The superiority of either is not demonstrated in this series of patients. REFERENCES 1. DeWall, R. A., Warden, H., Varco, E., and Lillehei, C. W. : The Helix Eeservoir Pump Oxygenator, Surg. Gynec. & Obst. 104: 699-710, 1957. 2. Zuhdi, N., Carey, J., and Greer, A.: Hemodilution for Body Perfusion, J . State Oklahoma M. A. 55: 88-107, 1963. DISCUSSION DR. ROBERT S. L I T W A K , New York, N. Y.—I would like to congratulate the authors on a very thoughtful contribution. We have used hemodilution techniques not primarily because of the logistics of blood procurement but to reduce what'we believe to be the significant clinical disadvantages of homologous blood infusion. [Slide] The diluent we have used has largely been 5 per cent dextrose in Ringer's solu tion. From a practical standpoint we use a 50© c e . bottle of dextrose in Ringer's solution and add 100 c e . of Albumisol, which is a 5 per cent solution of human serum albumin. Thus, for every 100 c.c. of dextrose in Ringer's solution one adds 1 gram of albumin. [Slide] We have used a ratio of 1 to 2 of diluent to blood. The heart-lung machine we have been using is the Gibbon-Mayo unit which has a pédiatrie priming volume of 2,200 ml. Thus, the diluent used has averaged 700 ml. and the average blood requirement has been 1,500 ml.
76
ZUHDI E T AL.
J. Thoracic and
Cardiovas. Surg.
I n the adult unit the priming volume is 3,400 ml. The diluent has averaged a little over one liter and approximately 2,300 ml. of whole blood has been used. Thus, in all cases the approximate ratio of diluent to whole blood has been 1 to 2, and one third of the entire priming volume has been diluent. [Slide] The conduct of perfusion has been fairly standard. We have carefully flushed out the pericardium and pleural cavities before putting the patient on perfusion, and then have returned all blood that has spilled over to the machine. At the end of the perfusion we have moderately overinfused as required, as many people have done. After the perfusion, we have collected the residual pump blood in ACD bags for use in the operating and recovery rooms. Despite the fact that there are about 75 ml. of ACD solution in each bag and that hemodilution has been employed, the average hematocrit has been 31. This blood has been traumatized, one can argue, and, indeed, this is so; but we would accept the traumatized blood in the pump oxygenator a large amount of which is the p a t i e n t ' s own blood, rather than infuse additional homologous blood with its attendant problems. Sixty-three cases of high-flow hemodilution perfusion have been performed. The patients appear to have fewer clinical manifestations of the homologous blood syndrome. The patients' blood clots well, and we fortunately have not experienced any of the problems Dr. Carter described yesterday. Using this technique, the average amount of blood required has been a portion of one bag of blood before the patient goes on perfusion, plus the amount of blood that we have got from the pump oxygenator. This has been a happy circumstance for the blood bank and certainly most salutary for the patients, who appear to do far better than the patients who have been infused with larger amounts of homologous blood.
DE. LEO CTJELLO, Minneapolis, Minn.—First, I would like to congratulate Dr. Zuhdi for his excellent results and for his contribution in the field of hemodilution. At our University Hospital, different hemodiluting solutions have been used to prime the pump oxygenator. These solutions were 5 per cent dextrose in water, equal amounts of blood and 10 per cent low molecular weight dextran in normal saline (10 per cent L M W D ) , and 10 per cent LMWD alone. [Slide] Patients with similar body weight, similar heart lesions, and similar duration of perfusion were selected. There were 98 patients. [Slide] We have studied the postoperative urine output in these three groups of patients and found no significant difference in the total amount of urine at the end of the first 24 hours (5 per cent D / W = 24.54 plus 11.77 c.e./Kg.; blood and LMWD = 26.30 ± 11.81 c.c./Kg.; and LMWD = 19.45 ± 11.87 c.c./Kg.). Those patients hemodiluted with 5 per cent D / W had a faster diuresis during the first 3 hours. [Slide] We measured their plasma hemoglobin at the end of the bypass in milligrams per minute of perfusion. I n those patients in whom LMWD or equal parts of LMWD and blood were used, the lowest plasma hemoglobin level was observed. [Slide] These findings are in agreement with an in vitro study which proves the wellknown fact that 5 per cent D / W is a hypotonie solution (the isotonic is 5.7 per cent) and in creases the fragility of the red blood cell. Under sterile conditions we mixed equal parts of heparinized fresh human blood and 5 per cent D / W and equal parts of LMWD and heparinized fresh human blood. At the end of one hour the plasma hemoglobin levels were 230 mg. in the 5 per cent D / W group and practically none in the group that received dextran. [Slide] With an electromagnetic flowmeter we measured the renal blood flow of dogs during a one hour period of cardiopulmonary bypass with the use of different hemodiluting agents. When 5 per cent D / W was used to prime the pump oxygenator, there was a progressive fall in the renal blood flow, more marked during the last 30 minutes of perfusion. In those dogs in which the pump oxygenator was primed with LMWD, there was an increase in the renal blood flow or it remained constant during the whole period of bypass. When homologous
Vol. 47, No. 1 January, 1964
P R I M E S FOB HEART-LUNG MACHINES
77
blood was used, a more or less constant renal blood flow was recorded. These changes in renal blood flow are mainly due to the faster diffusion of dextrose in water and to the plasma expander properties of LMWD. This clinical and experimental study demonstrates some of the advantages of low molecular weight dextran over 5 per cent dextrose in water as a prim ing solution during cardiopulmonary bypass. DR. F L E T C H E R A. MILLER, Minneapolis, Minn.—I personally am indebted to Dr. Zuhdi for acquainting us with this technique of perfusion. However, we thought that the flow rates he was using might be a little low, and accordingly we took this problem to the experi mental laboratory for evaluation. A series of 20 animals was used, using random selection. [Slide] Ten animals were primed with 5 per cent glucose; a 20 c.c./min./Kg. flow was used a t a temperature of 25° to 30° C , as Dr. Zuhdi has advocated. Of these, 7 animals lived longer than 48 hours, but 2 were less than satisfactory in their final outcome. One of tliese, the one living the longest, showed definite central nervous system damage, more of a cerebellar type of reaction. Three died in less than 24 hours, which gave good results of 50 per cent. [Slide] The other 10 dogs were submitted to higher flow rates; a flow of 60 to 80 c.c./min./Kg. and normothermia were used. Of these, 9 were long-term survivors. One died, which gave acceptably good results of 90 per cent. DR. WILFORD B. N E P T U N E , Boston, Mass.—Perhaps some of ycu may recall that before this Association in Los Angeles in 1959, I presented the cases of 10 patients who had had open-heart surgery without the use of donor blood prime. At that time we were using a hand-made piece of equipment whereby we could layer the saline prime on top of the inflow blood. After obtaining our commercial equipment this was no longer possible, and, since that time, we have been using what amounts to hemodilution. We have used various types of donor solutions, including saline, glucose in water, but, at the present time, prefer low molecular weight dextran because we believe it improves the perfusion of the microcirculation, and we also like its osmotic diuretic effect. We have never used heparinized blood. We do replace blood loss with bank blood, and for safety we usually set up about 5 pints of ACD bank blood per open-heart operation. We think this technique is not only safe and practical but in actuality is superior. We have never had a bleeding syndrome. We have never seen what has been described as homologous blood problems, and, in fact, we have been fortunate in not even seeing a case of homologous serum jaundice. I have certainly appreciated hearing this presentation and am delighted with the results that have been shown today. DR. L E W I S H. BOSHER, Richmond, Va.—I have enjoyed Dr. Zuhdi's presentation, although I do not agree with his low flow rates. We do not have the advantages of a low prime oxygenator, such as he has described, and in utilizing hemodilution it is necessary or desirable to use larger amounts of diluting fluid. We use an appropriate amount of albumin to obtain the proper oncotic pressure. The hematocrit is lowered by dilution to a level of about 30 per cent when the blood prime is mixed with the patient's blood volume. We have obtained good clots in the test tube at the termination of our perfusion, but feel that there is a definite problem with oozing in the wound. This we believe to be due not only to platelet destruction but also to platelet dilution. For this reason, we have utilized platelet transfusions after neutralization of heparin with protamine. This has helped us and has been beneficial in restoring the coagulation mechanism more rapidly to normal. I t has been difficult to obtain truly convincing evidence for this by platelet counts, and we are in the process of instituting some studies with tagged platelets. More recently, by means of a rapid centrifuge, we have removed the platelets from the blood prime which we are to use in the pump oxygenator, and have returned these platelets
78
Z U H D I E T AL.
J. Thoracic and Cardiovas. Surg.
after termination of the perfusion. This has had one additional advantage In that we have seen less evidence of vasoconstriction after the operation, presumably due to a reduction in platelet destruction. The platelet counts have been markedly reduced during the perfusion and we have restored these partially after perfusion. DR. H E N R Y T. BAHNSON, Pittsburgh, P a . — I would like to raise one point of caution, Mr. President. Recently, during a stay in Vienna, while working with a pump oxygenator which we were filling with a mixture of glucose, saline, and blood, when I asked for the tubing to connect to the patient, the person operating the pump alarmingly stated, " T h e whole thing is c l o t t e d . " I t became evident on further study by the group in Vienna that this was due to several things. First, we were diluting the blood and with this were diluting the heparin, but, more important, we were using an ethylene oxide sterilizer in which ethylene oxide was mixed with C0 2 , and the chamber was subjected to a three atmospheres pressure. The additional C0 2 was slow to come out of an object that is sterilized in this apparatus, and hence the p H of the blood and glucose mixture was lowered. This could be corrected by heparin. I t could be corrected also by filling with pure blood in which the heparin was not diluted and where there was a greater buffer system, or preven tion of clotting was possible simply by washing out the sterilizer with saline. This is perhaps not pertinent to many of the machines in this country, but I mention it because many of the really bad bleeding problems are due to depletion of fibrinogen, not due to inadequate neutralization of heparin. The fact that the blood grossly clotted in the machine before connecting it to the patient in these cases was fortunate rather than causing partial activation of the clotting mechanism and continued clotting in the patient during the bypass, which is the event that in most instances leads to depletion of fibrinogen. DR. Z U H D I (Closing).—This clinical comparative study demonstrates that the " h o mologous blood syndrome ' ' did not occur in our series of blood primes. If it escaped our scrutiny, it certainly was of no apparent significance for the conduct of the perfusion, the postoperative course, or the final outcome. Analysis of Group 2B in which blood replacement was delayed reveals that cerebral complications, including the 2 patients who failed to regain consciousness, the findings in urinary microscopic studies, pulmonary complications, and postoperative chest drainage were higher than in Group 1 and Group 2A. We should be very careful in appraising hemodilution in the proper perspective of over-all body hemodynamics. The studies of Dr. Cuello on the persistence in circulation of the dextrose solution and dextran solution are very informative. Using repeated doses of radioactive iodinated albumin, we found that 5 per cent dextrose solution will remain in circulation for about an hour. Studies beyond that period of time were not performed. The studies of Dr. Miller concerning brain damage and low flow rates point out what we have repeatedly maintained, that the flow rates we advocate are safe within the scope of our time limits and our experience. We do not advocate low flow rates for all types of perfusions and systems. I t is true that 5 per cent dextrose in water is slightly hypotonie with regard to the red cells. The volume of red cells containing 1 Gm. of hemoglobin increases as the percentage of whole blood to 5 per cent dextrose in water decreases. However, the increase is small in the range of the degree of induced hemodilution. The average rise in plasma hemoglobin following mechanical fragility tests was 22.1 mg. per cent. Following an average perfusion of 60 minutes, the average rise in plasma hemoglobin in 33 patients was 13.9 mg. per cent. I n addition, exposed to one hour perfusion with this system, the life of a red blood cell of a dog is de creased from 24 days to 20 days, as measured by the apparent chromium« half-life. These are comparable results to similar studies with blood primes. The ideal solution for priming is as yet undetermined. At the present time, 5 per cent dextrose in water is very satisfactory. I t is easily available, of simple composition, extensively studied, has no ' ' holding characteristic, ' ' and may have some protective action on the myocardium. I n summary, blood primes are good primes; 5 per cent dextrose in water primes are as good. I thank all the discussers.
Zuhdi, M.D.*
William Oklahoma
(by invitation),
Sheldon, M.D. City,
John Carey, M.D.*
(by invitation),
and Allen Gréer,
(by
invitation),
M.D.*
Okla.
T
o pretend, to drift, and then to assert are overt manifestations of our anxiety due to the incompleteness and fallibility of human knowledge. It is absurd to transpqse into a harmonic denominator the multiplicity of premises, the pro fusion of techniques, and the myriad of data published since the historic achieve ment of John Gibbon, Jr. De Bakey pointed out that many of the physiologic studies related to eardiopulmonary bypass probably will require re-evaluation in view of newer advances. Yet there is available to every man, through past and immediate experience, affirmations that are true only with certain perim eters. The clinical data presented are to be interpreted within this narrow frame of specific definitions, and the elimination of experimental data from this dis cussion is for this purpose of clarity. THE HEART-LUNG MACHINE
The oxygenator is a scaled down DeWall-Lillehei oxygenator and the pump a finger Sigmamotor pump. 1 One pump head is needed for total body perfusion; the venous blood and cardiotomy suction blood flows, by gravity, into the verti cal oxygenating tube. When coronary perfusion is contemplated, a second pump head is used on the negative side of the total body perfusion pump. The heat exchanger is a stainless steel coil introduced inside the plastic helix. Water at 4° C. and 45° C. is countercurrently pumped into it to cool or warm blood (Fig. I ) . 2 This was the basic unit used in this entire series. In the first 21 patients, a blanket and/or stainless steel tubes in a venous reservoir were used as heat exchangers, in addition. 3 In a patient weighing 4.3 kilograms, changes were made to render safe the perfusion of such a small infant, and consisted of a venous reservoir and a cross connection between the arterial and venous limbs. Its volume predicated heparinized blood as a prime. Read at the Forty-third Annual Meeting of The American Association for Thoracic Sur gery a t Houston, Texas, April 8-10, 1963. •Address: 430 N. "W. 12th, Oklahoma City, Okla. 66
Vol. 47, No. 1 January, 1964
P E I M E S FOR HEART-LUNG MACHINES
67
THE PRIMING VOLUME
At the present time, a ratio of flow rate per minute to priming volume of 1 is optimal from the standpoint of blood turnover per minute and from the standpoint of the operator of the heart-lung machine. We have usually adhered to a ratio of about 1.25 in blood primes and blood substitute primes. The amount of blood used for a blood prime is less than the amount of blood used to prime most commonly used systems. This may be important in the interpreta tion of our results. The priming volume is calculated by the formula, weight in kilograms times 16 ml., which is equivalent to about one third of the daily fluid requirements at the rate of 2 ml. per hour per kilogram of body weight. The actual range of
iTo Heat Source Vacuum Source 7 Cardiotomy Suction ** = ^
Stainless Steel Tube in Mayon Helix
Patient Arterial, Pump "Oxygen Fig. 1.—Schematic drawing oi the double helical reservoir system used in this study.
the priming volume with a blood substitute in our patients varied from 150 ml. to 1,500 ml., the latter being used for all patients who weighed more than 75 kilograms. Significantly larger priming volumes with a blood substitute should not be used because of the severe degree of hemodilution one incurs. The low flow rates are not necessitated by the hemodilution principle, and this priming volume which is advocated may be adequate for substantially higher flow rates. Fresh heparinized blood drawn within 24 hours is used as a blood prime, and 5 per cent dextrose in water as a blood substitute prime. MODERATE INTERNAL HYPOTHERMIA
Moderate internal hypothermia from 28° C. to 30° C. as measured in the mid-esophagus is a useful, but not essential, modality. It has no known harmful effects. Oxygen utilization by the tissues is not impaired and the physiologic parameters are not severely upset. It does slow down the " t e m p o " and permits the safe usage of relatively low flow rates. The warming up process is stopped at around 33° C.
Z U H D I E T AL.
68
J. Thoracic and Cardiovas. Surg.
TABLE I . ENUMERATION OF 36 D E A T H S I N TIME OF DEATH AFTER OPERATION
NATURE OF DEFECT
1 M.C.*
37 hr., 30 min.
T. O . F
Disruption of V. S. D.
Technical
2 V.A.*
4 da.
T. O. F .
Complete A-V block
Technical
3 H.A.*
At operation
Single ventricle
Complete A-V block
Technical, inherent
4 M. G.*
At operation
V. S. D.
Severe pulmonary hyper tension
Inherent
INITIALS
CAUSE OF DEATH
CLASSIFICATION
GROUP 1
GBOUP
SA
5 F.B.*
At operation
6 H. F . *
18 hr.
V. S. D.
7 T.U.*
26 hr.
A-V Communie
8 S.U.*
4 mo.
M.I. M.S.
9 B.A.*
13 hr., 45 min.
I. A. D.-V. S. D. Marked hypertrophy of right Inherent P . D. ventricle Pulmonary hypertension with arteriolar sclerosis
A. S. (acquired)
Unrecognized cardiae arrest during induction of anesthesia
Technical
Fresh anteroseptal myocardial Cardiac infarction complication Massive infection with sternal disruption
Technical
Bleeding from aortotomy
Technical
Atrioventrieular block
Technical
10 T. E .
At operation
11 G.I.*
19 hr.
M. S.
Calcification of entire left Perfusion atrium and auricle with aortie stenosis, mitral stenosis, and insufficiency; did not regain consciousness
12 E. S.t
3 hr., 50 min.
M. S.
Class V—Left intra-atrial clot, 207 grams
13 H . E . *
4 da.
14 C. H.i
3 hr., 45 min.
T. 0 . F .
15 C. 0 4
At operation
16 S. T.*
23 hr., 43 min.
17 H. 0.*
4 da. after operation
18 M. A.}
A t operation
V. S. D.
Transposition Chylothorax of great Iatrogenic hyperpotassemia vessels
Inherent Technical
Bleeding from previous aorto-pulmonary shunt
Technical
A. S. (acquired)
Aortic valvular replacement
Technical, inherent
Myocardial disease
Exploratory cardiotomy
Inherent
Bight ventricular hypoplasia
Inherent
Aortie valve replacement
Technical
V. S. D. A.I.
hegend: Group 1.—Blood primed heart-lung machine. Group 2A.—5% dextrose in water primed heart-lung machine. Group 2B.—5% dextrose in water primed heart-lung machine. A.I.—Aortic insufficiency. A.S.—Aortic stenosis. T.O.F.—Tetralogy of Pallot. V.S.D.—Ven tricular septal defect M.I.—Mitral insufficiency. M.S.—Mitral stenosis. P.D.—Patent ductus arteriosus. (I.A.D.—Interatrial defect. P.S.—Pulmonary stenosis. •Autopsy. tCause of death established without autopsy. îDied at operation.
69
P R I M E S FOR HEART-LUNG MACHINES
Vol. 47, No. 1 January, 1964
THIS SERIES OF 250 CONSECUTIVE P A T I E N T S
19 S. T.*
71 hr.
T. O. F .
20 A. XL*
71 hr.
P.S.
21 S. T.*
2 hr., 30 min.
22 W . A . *
8 da.
P.S.
Unrelieved stenosis of base of pulmonary valve
Technical
23 L. A.*
5 da.
M.S.
Anteroseptal myocardial infarction
Cardiac complication
24 R. L.t
At operation
A. S. (acquired)
Aortic valve replacement
Technical
25 W . A .
13 hr., 45 min.
T. O. F .
Inherent Hypoplasia of pulmonary artery; small left ventricle
26 M. A.
44 hr., 45 min.
M.S. (recurrent)
Class V—poor cardiac output Inherent
27 B. B.*
28 hr., 30 min.
V. S. D.
28 M. C *
18 hr., 50 min.
V. S. D.
Bleeding from previous aorto- Technical pulmonary shunt Marked hypertrophy of right Inherent, technical ventricle Infundibular stenosis not relieved Massive pulmonary atelectasis Pulmonary complication
Atresia of right ventricle
Inherent
P.S.
Unrelieved infundibular stenosis
Technical
GBOUP SB 29 T. H.
At operation
M.S.
Class V
Technical
30 H. U.
63 hr., 43 min.
M.S.
Class V ; died suddenly; no postmortem examination
Unknown
31 P . O.t
At operation
M.S.
Class V—mitral valve replacement
Inherent
32 H . E .
At operation
M.S. (recurrent)
Mitral valve replacement; sutures taken deep in myocardium
Technical
33 S. T.*
24 hr.
P.S.
Cardiac tamponade
Technical
34 S. T.î
At operation
M.I.
Class V—mitral valve re placement
Inherent, technical
35 S.L.*
50 hr., 55 min.
36 G. 0 .
4 da.
A. S. (acquired) M.S.
Did not regain consciousness Perfusion Probably Doing relatively well, then perfusion lost consciousness on third day
LOW F L O W RATES
The low flow rates are not used because of the hemodilution principle. They are safe within the scope of our time limits and our experience. It is absurd to recommend an over-all figure for flow rates per minute for all types of heartlung machines and all forms of perfusions. We have 214 long-term survivors in this series of 250 consecutive patients
70
ZTJHDI E T A L .
J- Thoracic and Cardiovas. Surg.
with the use of flow rates of 20 ml. per kilogram of body weight per minute. This maximal flow rate was used with blood primes and with water primes. All the survivors have no apparent neurological symptoms and have no notice able changes in their behavioral pattern; some have won scientific achievement awards and others are leading members of their community. These flow rates were adequate to maintain satisfactory body perfusion for open mitral valvuloplasty (March 31, 1960) in a patient in her early second trimester of pregnancy, with subsequent uneventful delivery of a full-term normal infant. At present, 3.years later, both are doing well.2 A mortality figure does not project a true perspective of all the different aspects of extracorporeal circulation. It does reflect the over-all sagacity of the surgeon. A painful death due to the learning period or a technical error does not echo the efficiency of a perfusion system or the validity of a flow rate. Table I enumerates the 36 deaths in this series of 250 consecutive patients, a combined mortality rate of 14.4 per cent. Table I I is an attempt at a compre hensive grouping of these deaths. Postmortem examination was permitted in 22 patients, and the cause of death was satisfactorily established in 11 more patients. TABLE
II*
Not Due to Perfusion Technical (Cases 1, 2, 3, 6, 8, 9, 10, 13, 14, 15, 18, 19, 20, 22, 24, 28, 29, 32, 33, 34) Inherent cardiac disease (Cases 3, 4, 5, 12, 15, 16, 17, 20, 25, 26, 27, 31, 34) Myocardial infarction (Cases 7, 23) Sudden death, cause undetermined (Case 29) Pulmonary atelectasis (Case 21) Possibly Due to Perfusion TJnresponsiveness fourth day after surgery (Case 36)
20 13 2 1 1 1
Due to Perfusion Brain edema (Cases 11, 35) 2 •Comprehensive grouping of causes of death in 36 patients in this series of 250 patients who were perfused at a maximum flow of 20 ml. per kilogram of body weight per minute. The figures between parentheses refer to the specific numerical order of patients in Table I. MATERIAL
Two hundred and fifty patients who had open-heart surgery with the use of the double helical reservoir heart-lung machine formed three evolutionary groups : Group 1.—Forty-five patients were connected to a blood primed heart-lung machine, 43 of them between May 29, 1959, and Feb. 25, 1960. Blood loss was replaced with citrated banked blood. An average of 1.5 mg. of aqueous heparin per kilogram of body weight was given intravenously prior to cannulation and an equivalent amount of Polybrene at the termination of the perfusion. Group 2.—Subgroup A: One hundred and seventy-one patients had openheart operation with a heart-lung machine primed with 5 per cent dextrose in water between Feb. 25, 1960, and July 18, 1962. Blood loss was replaced as in Group 1. An average of 3 mg. per kilogram of body weight of heparin was used and counteracted with an equivalent amount of Polybrene.
Vol. 47, No. 1 January, 1964
PRIMES FOR HEART-LUNG
71
MACHINES
Subgroup B: Thirty-four patients had open-heart operation with the heartlung machine primed with 5 per cent dextrose in water starting on Aug. 7, 1962. Blood loss was not replaced until deemed essential by the surgeon. This is usually delayed until the end of the perfusion, if feasible. In some selected cases, there was no blood replacement at all, before, during, or after operation. The three series do not contain an equal number of patients and lack random selectivity. This is somewhat balanced by the absence of selective ad mission to either group. COMPARATIVE RESULTS
It is apparent that an attempt at such an analysis will deal with one of the many facets of such a complex problem because of the medley and multitude of factors involved. The limitations of this endeavor are deliberately stressed. Neurological Manifestations, Electroencephalography, Immediate and Late Sequelae.-—The electroencephalogram remains active in both groups. Awakening is usually immediate at the end of operation and patients respond to verbal commands. Table I I I compares the various neurological manifestations in rela tion to perfusion time in both groups. The lengths of perfusions, partial and complete, were comparable in those who had the neurological complications and those who did not have any. These changes were completely reversible without any residual manifestations (Table I V ) . In Group 1 there was one patient (2.4 per cent) with reversible changes, in Group 2A there were 12 patients (8.78 per cent), and in Group 2B there was one patient (8.69 per cent).
TABLE III.
GROUP
1
N E U R O L O G I C A L C O M P L I C A T I O N S A N D D E A T H S I N R E L A T I O N TO P E R F U S I O N
NO. OP COMPLICA TIONS WITH COMPLETE RECOVERY
1 (2.4%)
PERFUSION TIME OF P A T I E N T S W I T H COMPLICATIONS (MIN.)
P E R F U S I O N T I M E OF PATIENTS WITHOUT COMPLICATIONS (MIN.)
TOTAL BODY B Y P A S S OF P A T I E N T S W I T H COMPLICATIONS (MIN.)
TOTAL BODY B Y P A S S OF P A T I E N T S W I T H O U T COMPLICATIONS (MIN.)
41 . 13
2A
12 (8.7%)
23 - 137
55TB" 12 - 69
2B
2 (8.6%)
72! 42Λ
PERFUSION TIME OF P A T I E N T S W I T H NEUROLOGICAL DEATH ( M I N . )
"PER FUSION DEATH"
TOTAL BODY B Y P A S S OF P A T I E N T S W I T H NEUROLOGICAL DEATH ( M I N . )
0
22 - 189 6Ï77 11 - 118
TIME
170 1 (0.6%)
25
3θ
121
43 - 83
14 - 92
46 - 75
62^5 5-58
14 - 70
6ÖT5 20 - 45
35.5
31.6
32.5
BXë
2 (2.5%)
ZUHDI E T AL.
72 TABLE IV.
GROUP
1
NEUROLOGICAL
COMPLICATIONS
J. Thoracic and Cardiovas. Surg. (EXCLUDING
MINOR* TIME OF APPEARANCE POST-SURGERY (DAYS)
MAJOR t TIME OP APPEARANCE POST-SURGERY (DAYS)
0 | 1 | 2 | 3 | 4 0 1 0 0 0
0 | 1 | 2 | 3 14 0 0 0 0 0
3
DEATHS) TOTAL NUMBER
or
OUTCOME
Complete recovery 2A 0 3 1 3 0 0 3 0 2 0 Complete recovery 0 1 0 0 1 2B 0 0 0 0 0 Complete recovery •Minor : Confusion, hallucination, restlessness, photophobia. fMajor : Convulsion, paresis, +Babinski.
NEUROLOGICAL COMPLICATIONS
1 (2.4%) 12 (8.78%) 2 (8.69%)
There were three deaths characterized by loss of consciousness. It is con ceivable that higher flow rates may have prevented the death of 2 patients and possibly of one more, or 1.2 per cent of this series. All three deaths were in adult patients who had operation on the mitral valve (2 patients) or aortic valve (one patient) for an acquired lesion. Cardiopulmonary Complications.—The myocardial response was excellent in both groups, ventricular fibrillation during operation was of no significance and either converted on its own to a regular rhythm or after the application of electroshock. There were two instances of myocardial infarction leading to death, both with anteroseptal location. Fresh myocardial necrosis and softening were not found at the postmortem examination of the remaining 20 patients. The postoperative pulmonary complications were collected from the x-ray films and are listed in Table V. There was one death from massive pulmonary atelectasis, an incidence of 0.4 per cent. Findings necessitating tracheotomy and intermittent positive pressure occurred in 2 patients. One of them had had mitral valve replacement, and the other had had mitral valvuloplasty ; both survived.
TABLE V. PULMONARY COMPLICATIONS AS T H E Y APPEARED IN THE POSTOPERATIVE X-RAY C H E S T FILMS
GROUP
CLEAR
ATELECTASIS, INFILTRATE, PNEUMONITIS
1 2A 2B
32 (68%) 88 (59.8%) 9 (50%)
11 ( 2 3 % ) 47 (31.9%) 7 (38.8%)
PNEUMOTHORAX
CONGESTION, PULMONARY EDEMA
3 (6.3%) 11 (7.5%) 1 (5.5%)
1 (5.5%) 3 (2.04%) 1 (2.12%)
PLEURAL FLUID
1 (0.68%)
Renal Findings.—Urine output in the first 24 hours following operation was 23.58 ml. per kilogram of body weight per 24 hours in Group 1, 31.92 ml. in Group 2A, and 41.73 ml. in Group 2B. The urine output increased in each group during the next 24 hours. Albumin in varying amounts was present in 85 per cent of the patients in Group 1 and in 83.5 per cent in Group 2, and in 100 per cent in Group 2B. Hematuria was present in 85 per cent in Group 1,
73
P R I M E S F O B HEART-LUNG MAC H I N E S
Vol. 47, No. ! January, 1964
TABLE VI. URINARY FINDINGS URINE OUTPUT ( M L . / K G . / 2 4 HR.)
|
MICROSCOPIC
HEMATURIA ALBUMINURIA GLYCOSURIA 24 HR Group 1 85% 23.58 85% 33.43 40% Group 2A 67.3% 31.92 31.3% 39.39 35.2% Group 2B 100% 41.73 61.5% 30.7% 54.96 •Only one patient had sufficient renal depression to be considered a case of renal shut down and recovery occurred without dialysis. 1ST 24 HR.
2ND
in 67.3 per cent in Group 2A, and in 100 per cent in Group 2B (Table V I ) . All of these changes are reversible in 1 to 4 days. More elaborate renal function tests were not performed and there is no reason in our close follow-up of these patients to suspect any residual kidney disease. More elaborate tests are being performed and will be reported later. There was one patient with renal shutdown who had a total perfusion time of 93 minutes, with total body bypass of 72 minutes. Recovery occurred without dialysis. The consecutive 24-hour urine outputs were 105 ml., 68 ml., 61 ml., 65 ml., 135 ml., 215 ml., 440 ml., and 670 ml. The mean arterial pressure during perfusion varied from 20 mm. Hg to 70 mm. Hg, with an average of 36.3 mm. Hg, and in Group 2 from 25 to 55 mm. Hg, with an average of 48 mm. Hg. The mean arterial pressure seems to be more predictable and stable in Group 2. Postoperative Chest Drainage and Postoperative Anemia.—Total drainage of the chest averaged 11.4 ml. per kilogram body weight for Group 1, 8.57 ml. for Group 2A, and 20.87 for Group 2B. This was usually replaced with banked citrated blood. The additional blood given (+4.27 ml. per kilogram in Group 2A and +7.23 ml. per kilogram in Group 2B) may roughly reflect what may clini cally represent post-perfusion anemia (Table V I I ) . TABLE V I I . POSTOPERATIVE C H E S T DRAINAGE AND BLOOD REPLACEMENT
1 2A 2B
CHEST DRAINAGE (ML./KG. BW)
BLOOD REPLACEMENT (ML./KG. BW)
BALANCE (ML./KG. BW)
11.4 8.57 20.87
7.64 12.7 28.1
-3.76 +4.27 +7.23
Tabulation of Patients.—Table V I I I contains a summary of the congenital heart defects which were corrected in each group. The mortality rate in Group 1 and Group 2A is 10 per cent and 11.3 per cent, respectively. Table IX indicates the increase in the number of acquired lesions in Group 2A when compared to Group 1. I t is apparent that direct comparison of mortality figures in these two groups is misleading. There are 2 cases in Group 2A of mitral valve replacement with the Starr-Edwards prosthesis. Both patients are doing well. Five similar attempts were made in Group 2B with one patient surviving. The series of acquired aortic valvular lesions is small.
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ZUHDI E T AL.
TABLE V I I I . TOTAL NUMBER
OF P A T I E N T S
WITH
CONGENITAL
GROUP 1 CONGENITAL Interatrial defect Ventricular septal defect Pulmonary stenosis, valvular and infundibular Tetralogy of Fallot Aortic stenosis Supravalvular aortic stenosis A-V Communis Transposition of great vessels Totals
TABLE I X .
DEFECTS
IN E A C H
GROUP 2B
GROUP 2A
NO. 10 13
DEATHS 0 2
32 39
0 3
4 3
0
8 7 1 1 0 0 40
0 2 0 0 0 0 4
17 6 6 3 2 1 106
3 3 0 0 2 1 12
5 2 1 0 2 1 18
0 1 0 0 0 1 3
t
TOTAL NUMBER OF P A T I E N T S W I T H ACQUIRED DEFECTS IN E A C H
Mitral stenosis and mitral in sufficiency (M.S., M.I.) Mitral valve replacement Aortic stenosis A.S.) Exploratory cardiotomy (Expl. Card.) Totals
NO.
5 0 0
|
DEATHS
NO.
0 0 0
|
GROUP
GROUP 2 B
GROUP 2A
GROUP 1 ACQUIRED
GROUP
DEATHS
NO.
57 2 5
6 0 4
9 5 2
65
11
16
|
DEATHS
1 4 1
DISCUSSION
Landsteiner and Levine elaborated on the concept of individuality of human blood, including red blood cells, proteins, and other elements. The body re sponses to genetically different blood pooled in a pump oxygenator are multiple. However, the apparent and theoretical advantages of hemodilution and of the elimination of blood as a prime have not been substantiated in this comparative study. Larger series may have demonstrated that there is a reduction in anaphylactoid responses, sludging, acidosis, major and minor blood incompatibili ties, hepatitis, renal complications, and other manifestations. The cerebral manifestations in this series of patients do not seem related to length of perfusion time and total body bypass time, and cerebral changes have not been described during moderate internal hypothermia. All three cerebral deaths and most of the neurological complications occurred in patients who had had corrective surgery on either the mitral or aortic valves and they could have been due to calcific emboli or to air trapped in the left atrium or left ventricle. Two cerebral deaths occurred in Group 2B. This suggests that hemodilution, with a further decrease in red blood cell count due to blood loss which is not being replaced, may lead to tissue anoxia. The higher urine out puts in Group 2 as compared to Group 1 did not influence the postoperative course or the final outcome in either series. Albuminuria and hematuria are reversible. The ideal priming fluid to be used as a blood substitute is not determined. Five per cent dextrose in water is easily available, of simple composition, and
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extensively studied. Five per cent dextrose in water is slightly hypotonie with regard to the red blood cells. The volume of red cells that contain one gram of hemoglobin increases as the percentage of whole blood to 5 per cent dextrose in water decreases. However, it is apparent that the increase is small in the range of the degree of hemodilution we induce. The average rise in plasma hemoglobin following the mechanical fragility test in 5 patients was 22.1 mg. per cent, and, following an average perfusion of 60 minutes in 33 patients, was 13.9 mg. per cent. The feasibility of definitive priming of the extracorporeal system with a blood substitute inducing hemodilution is demonstrated. This should apply as well to systems for regional perfusion and dialysis. It is axiomatic that varia tions of this basic principle of hemodilution are bound to appear. CONCLUSIONS
1. The use of hemodilution without replacement of blood lost from the surgical field should be used only in selected patients. There is no apparent advantage in delaying blood replacement until the end of perfusion. Actually, this practice seems to have some detrimental effects, as evidenced in the statistics of Group 2B. 2. Group 1 and Group 2A yielded similar findings and statistics. The su periority of either is not established when used within our specific definitions. This clinical appraisal demonstrates that primes of 5 per cent dextrose in water, inducing intentional hemodilution, are safe, simple, efficient, physiological, and compare well with the conventional blood primes. SUMMARY
A clinical appraisal is presented of primes of blood and 5 per cent dextrose in water. The superiority of either is not demonstrated in this series of patients. REFERENCES 1. DeWall, R. A., Warden, H., Varco, E., and Lillehei, C. W. : The Helix Eeservoir Pump Oxygenator, Surg. Gynec. & Obst. 104: 699-710, 1957. 2. Zuhdi, N., Carey, J., and Greer, A.: Hemodilution for Body Perfusion, J . State Oklahoma M. A. 55: 88-107, 1963. DISCUSSION DR. ROBERT S. L I T W A K , New York, N. Y.—I would like to congratulate the authors on a very thoughtful contribution. We have used hemodilution techniques not primarily because of the logistics of blood procurement but to reduce what'we believe to be the significant clinical disadvantages of homologous blood infusion. [Slide] The diluent we have used has largely been 5 per cent dextrose in Ringer's solu tion. From a practical standpoint we use a 50© c e . bottle of dextrose in Ringer's solution and add 100 c e . of Albumisol, which is a 5 per cent solution of human serum albumin. Thus, for every 100 c.c. of dextrose in Ringer's solution one adds 1 gram of albumin. [Slide] We have used a ratio of 1 to 2 of diluent to blood. The heart-lung machine we have been using is the Gibbon-Mayo unit which has a pédiatrie priming volume of 2,200 ml. Thus, the diluent used has averaged 700 ml. and the average blood requirement has been 1,500 ml.
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Cardiovas. Surg.
I n the adult unit the priming volume is 3,400 ml. The diluent has averaged a little over one liter and approximately 2,300 ml. of whole blood has been used. Thus, in all cases the approximate ratio of diluent to whole blood has been 1 to 2, and one third of the entire priming volume has been diluent. [Slide] The conduct of perfusion has been fairly standard. We have carefully flushed out the pericardium and pleural cavities before putting the patient on perfusion, and then have returned all blood that has spilled over to the machine. At the end of the perfusion we have moderately overinfused as required, as many people have done. After the perfusion, we have collected the residual pump blood in ACD bags for use in the operating and recovery rooms. Despite the fact that there are about 75 ml. of ACD solution in each bag and that hemodilution has been employed, the average hematocrit has been 31. This blood has been traumatized, one can argue, and, indeed, this is so; but we would accept the traumatized blood in the pump oxygenator a large amount of which is the p a t i e n t ' s own blood, rather than infuse additional homologous blood with its attendant problems. Sixty-three cases of high-flow hemodilution perfusion have been performed. The patients appear to have fewer clinical manifestations of the homologous blood syndrome. The patients' blood clots well, and we fortunately have not experienced any of the problems Dr. Carter described yesterday. Using this technique, the average amount of blood required has been a portion of one bag of blood before the patient goes on perfusion, plus the amount of blood that we have got from the pump oxygenator. This has been a happy circumstance for the blood bank and certainly most salutary for the patients, who appear to do far better than the patients who have been infused with larger amounts of homologous blood.
DE. LEO CTJELLO, Minneapolis, Minn.—First, I would like to congratulate Dr. Zuhdi for his excellent results and for his contribution in the field of hemodilution. At our University Hospital, different hemodiluting solutions have been used to prime the pump oxygenator. These solutions were 5 per cent dextrose in water, equal amounts of blood and 10 per cent low molecular weight dextran in normal saline (10 per cent L M W D ) , and 10 per cent LMWD alone. [Slide] Patients with similar body weight, similar heart lesions, and similar duration of perfusion were selected. There were 98 patients. [Slide] We have studied the postoperative urine output in these three groups of patients and found no significant difference in the total amount of urine at the end of the first 24 hours (5 per cent D / W = 24.54 plus 11.77 c.e./Kg.; blood and LMWD = 26.30 ± 11.81 c.c./Kg.; and LMWD = 19.45 ± 11.87 c.c./Kg.). Those patients hemodiluted with 5 per cent D / W had a faster diuresis during the first 3 hours. [Slide] We measured their plasma hemoglobin at the end of the bypass in milligrams per minute of perfusion. I n those patients in whom LMWD or equal parts of LMWD and blood were used, the lowest plasma hemoglobin level was observed. [Slide] These findings are in agreement with an in vitro study which proves the wellknown fact that 5 per cent D / W is a hypotonie solution (the isotonic is 5.7 per cent) and in creases the fragility of the red blood cell. Under sterile conditions we mixed equal parts of heparinized fresh human blood and 5 per cent D / W and equal parts of LMWD and heparinized fresh human blood. At the end of one hour the plasma hemoglobin levels were 230 mg. in the 5 per cent D / W group and practically none in the group that received dextran. [Slide] With an electromagnetic flowmeter we measured the renal blood flow of dogs during a one hour period of cardiopulmonary bypass with the use of different hemodiluting agents. When 5 per cent D / W was used to prime the pump oxygenator, there was a progressive fall in the renal blood flow, more marked during the last 30 minutes of perfusion. In those dogs in which the pump oxygenator was primed with LMWD, there was an increase in the renal blood flow or it remained constant during the whole period of bypass. When homologous
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blood was used, a more or less constant renal blood flow was recorded. These changes in renal blood flow are mainly due to the faster diffusion of dextrose in water and to the plasma expander properties of LMWD. This clinical and experimental study demonstrates some of the advantages of low molecular weight dextran over 5 per cent dextrose in water as a prim ing solution during cardiopulmonary bypass. DR. F L E T C H E R A. MILLER, Minneapolis, Minn.—I personally am indebted to Dr. Zuhdi for acquainting us with this technique of perfusion. However, we thought that the flow rates he was using might be a little low, and accordingly we took this problem to the experi mental laboratory for evaluation. A series of 20 animals was used, using random selection. [Slide] Ten animals were primed with 5 per cent glucose; a 20 c.c./min./Kg. flow was used a t a temperature of 25° to 30° C , as Dr. Zuhdi has advocated. Of these, 7 animals lived longer than 48 hours, but 2 were less than satisfactory in their final outcome. One of tliese, the one living the longest, showed definite central nervous system damage, more of a cerebellar type of reaction. Three died in less than 24 hours, which gave good results of 50 per cent. [Slide] The other 10 dogs were submitted to higher flow rates; a flow of 60 to 80 c.c./min./Kg. and normothermia were used. Of these, 9 were long-term survivors. One died, which gave acceptably good results of 90 per cent. DR. WILFORD B. N E P T U N E , Boston, Mass.—Perhaps some of ycu may recall that before this Association in Los Angeles in 1959, I presented the cases of 10 patients who had had open-heart surgery without the use of donor blood prime. At that time we were using a hand-made piece of equipment whereby we could layer the saline prime on top of the inflow blood. After obtaining our commercial equipment this was no longer possible, and, since that time, we have been using what amounts to hemodilution. We have used various types of donor solutions, including saline, glucose in water, but, at the present time, prefer low molecular weight dextran because we believe it improves the perfusion of the microcirculation, and we also like its osmotic diuretic effect. We have never used heparinized blood. We do replace blood loss with bank blood, and for safety we usually set up about 5 pints of ACD bank blood per open-heart operation. We think this technique is not only safe and practical but in actuality is superior. We have never had a bleeding syndrome. We have never seen what has been described as homologous blood problems, and, in fact, we have been fortunate in not even seeing a case of homologous serum jaundice. I have certainly appreciated hearing this presentation and am delighted with the results that have been shown today. DR. L E W I S H. BOSHER, Richmond, Va.—I have enjoyed Dr. Zuhdi's presentation, although I do not agree with his low flow rates. We do not have the advantages of a low prime oxygenator, such as he has described, and in utilizing hemodilution it is necessary or desirable to use larger amounts of diluting fluid. We use an appropriate amount of albumin to obtain the proper oncotic pressure. The hematocrit is lowered by dilution to a level of about 30 per cent when the blood prime is mixed with the patient's blood volume. We have obtained good clots in the test tube at the termination of our perfusion, but feel that there is a definite problem with oozing in the wound. This we believe to be due not only to platelet destruction but also to platelet dilution. For this reason, we have utilized platelet transfusions after neutralization of heparin with protamine. This has helped us and has been beneficial in restoring the coagulation mechanism more rapidly to normal. I t has been difficult to obtain truly convincing evidence for this by platelet counts, and we are in the process of instituting some studies with tagged platelets. More recently, by means of a rapid centrifuge, we have removed the platelets from the blood prime which we are to use in the pump oxygenator, and have returned these platelets
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J. Thoracic and Cardiovas. Surg.
after termination of the perfusion. This has had one additional advantage In that we have seen less evidence of vasoconstriction after the operation, presumably due to a reduction in platelet destruction. The platelet counts have been markedly reduced during the perfusion and we have restored these partially after perfusion. DR. H E N R Y T. BAHNSON, Pittsburgh, P a . — I would like to raise one point of caution, Mr. President. Recently, during a stay in Vienna, while working with a pump oxygenator which we were filling with a mixture of glucose, saline, and blood, when I asked for the tubing to connect to the patient, the person operating the pump alarmingly stated, " T h e whole thing is c l o t t e d . " I t became evident on further study by the group in Vienna that this was due to several things. First, we were diluting the blood and with this were diluting the heparin, but, more important, we were using an ethylene oxide sterilizer in which ethylene oxide was mixed with C0 2 , and the chamber was subjected to a three atmospheres pressure. The additional C0 2 was slow to come out of an object that is sterilized in this apparatus, and hence the p H of the blood and glucose mixture was lowered. This could be corrected by heparin. I t could be corrected also by filling with pure blood in which the heparin was not diluted and where there was a greater buffer system, or preven tion of clotting was possible simply by washing out the sterilizer with saline. This is perhaps not pertinent to many of the machines in this country, but I mention it because many of the really bad bleeding problems are due to depletion of fibrinogen, not due to inadequate neutralization of heparin. The fact that the blood grossly clotted in the machine before connecting it to the patient in these cases was fortunate rather than causing partial activation of the clotting mechanism and continued clotting in the patient during the bypass, which is the event that in most instances leads to depletion of fibrinogen. DR. Z U H D I (Closing).—This clinical comparative study demonstrates that the " h o mologous blood syndrome ' ' did not occur in our series of blood primes. If it escaped our scrutiny, it certainly was of no apparent significance for the conduct of the perfusion, the postoperative course, or the final outcome. Analysis of Group 2B in which blood replacement was delayed reveals that cerebral complications, including the 2 patients who failed to regain consciousness, the findings in urinary microscopic studies, pulmonary complications, and postoperative chest drainage were higher than in Group 1 and Group 2A. We should be very careful in appraising hemodilution in the proper perspective of over-all body hemodynamics. The studies of Dr. Cuello on the persistence in circulation of the dextrose solution and dextran solution are very informative. Using repeated doses of radioactive iodinated albumin, we found that 5 per cent dextrose solution will remain in circulation for about an hour. Studies beyond that period of time were not performed. The studies of Dr. Miller concerning brain damage and low flow rates point out what we have repeatedly maintained, that the flow rates we advocate are safe within the scope of our time limits and our experience. We do not advocate low flow rates for all types of perfusions and systems. I t is true that 5 per cent dextrose in water is slightly hypotonie with regard to the red cells. The volume of red cells containing 1 Gm. of hemoglobin increases as the percentage of whole blood to 5 per cent dextrose in water decreases. However, the increase is small in the range of the degree of induced hemodilution. The average rise in plasma hemoglobin following mechanical fragility tests was 22.1 mg. per cent. Following an average perfusion of 60 minutes, the average rise in plasma hemoglobin in 33 patients was 13.9 mg. per cent. I n addition, exposed to one hour perfusion with this system, the life of a red blood cell of a dog is de creased from 24 days to 20 days, as measured by the apparent chromium« half-life. These are comparable results to similar studies with blood primes. The ideal solution for priming is as yet undetermined. At the present time, 5 per cent dextrose in water is very satisfactory. I t is easily available, of simple composition, extensively studied, has no ' ' holding characteristic, ' ' and may have some protective action on the myocardium. I n summary, blood primes are good primes; 5 per cent dextrose in water primes are as good. I thank all the discussers.