| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Thorac Cardiovasc Surg 1994;107:527-0535
© 1994 Mosby, Inc.
Cardiopulmonary Bypass, Myocardial Management, and Support Techniques |
Minneapolis, Minn.
Supported by the 20th American College of Surgeons Scholarship (J.W.B.); National Research Service Awards HL 07259-02 and HL 06964-02 (J.W.B and T.P.B) from the National Institutes of Health; American Heart Association, Minnesota Affiliate Research Fellowship (T.J.L.); and grants from the Minnesota Medical Foundation; the American Heart Association, Minnesota Affiliate; and the National Institutes of Health (HL 22152-05).
Presented at the C. Walton Lillehei Surgical Symposium, Minneapolis, Minn., Oct. 21-22, 1988.
Received for publication Nov. 10, 1989. Accepted for publication July 20, 1993. Address for reprints: J. W. Blatchford III, MD, Division of Thoracic and Cardiovascular Surgery, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-8879.
Abstract
The effects of cardiopulmonary bypass and cardioplegic arrest on left ventricular systolic and diastolic function were studied in 20 intact neonatal lambs instrumented with ultrasonic dimension transducers and micromanometers for collection of left ventricular pressure-dimension data. Group I lambs underwent 2 hours of hypothermic cardiopulmonary bypass (25° C) alone; group II lambs underwent 2 hours of hypothermic cardiopulmonary bypass (25° C) with 1 hour of multidose, cold, crystalloid cardioplegic arrest (St. Thomas' Hospital No. 2 solution). The control neonatal lamb left ventricle was found to be relatively stiff, with the limit of diastolic filling reached at physiologic left ventricular filling pressures, resulting in apparent descending limbs of left ventricular function. After cardiopulmonary bypass, identical results were obtained in groups I and II. A significant loss of left ventricular compliance limited left ventricular performance via two mechanisms. First, left ventricular preload was significantly decreased, with a concomitant diminution in left ventricular stroke work; afterload (pressure work) was maintained at the expense of volume work (flow), which declined significantly. Second, preload behaved as though fixed, resulting in a loss of impedance matching (afterload mismatch). Although contractility as assessed by the end-systolic pressure-dimension relationship was significantly increased (because of increased levels of circulating catecholamines), global systolic performance as quantified by the stroke work/end-diastolic length relationship remained unchanged, reflecting the afterload sensitivity of the latter parameter in the face of fixed preload. We conclude that cardiopulmonary bypass in the intact neonate results in a loss of compliance and impedance matching rather than a loss of contractility; however, the addition of 1 hour of cold, crystalloid cardioplegic arrest results in no dysfunction beyond that attributable to cardiopulmonary bypass alone. (J THORAC CARDIOVASC SURG 1994;107:527-35)
Despite tremendous progress since the first successful direct-vision intracardiac procedure was done in 1952,
1 the mortality of cardiac surgery in the first weeks of life remains comparatively high. This observation, along with a growing body of evidence suggesting that the immature heart may differ significantly from that of the adult, has led to many recent investigations concerning the optimal method of myocardial preservation in the neonate. The majority of these studies, however, either have lacked the sophistication necessary to discriminate between systolic and diastolic dysfunction or have relied on isolated heart preparations, which fail to model noncoronary collateral flow and the effects of cardiopulmonary bypass (CPB). Using a clinically relevant model, we characterized the effects of CPB alone, and in combination with cardioplegic arrest, on the left ventricular (LV) systolic and diastolic function of the intact neonatal heart.
METHODS
Experimental preparation
Twenty neonatal lambs less than 7 days old (3.6 to 6.5 kg; 4.3 kg mean) were instrumented for collection of LV pressure and dimension data according to a modification of the technique described by Rankin and associates 2 (Fig. 1). Anesthesia was induced with 1% halothane and 99% oxygen by mask and was then maintained with the same mixture endotracheally throughout the experiment by volume-controlled ventilation. A fluid-filled polyvinylchloride catheter was inserted into the right femoral artery for measurement of systemic arterial blood pressure and determination of serial blood gases. Through a median sternotomy, pairs of ultrasonic dimension transducers (2 mm in diameter) were implanted to measure LV minor-axis diameter and equatorial lateral wall thickness. A 3F catheter-tipped micromanometer (Millar PC-330, Millar Instruments, Inc., Houston, Tex.) was passed through an LV apical stab incision to record intracavitary pressure. The right and left azygos systems were ligated at their respective junctions with the cranial (superior) vena cava and the coronary sinus. Rumel tourniquets were placed around the venae cavae for the production of transient vena caval occlusions.
|
After acquisition of control data, lambs were systemically heparinized (300 units/kg) and were cannulated for CPB. Venous cannulation in group I lambs (hypothermic CPB alone, n = 10) was established with a single cannula via the right atrial appendage; group II lambs (hypothermic CPB plus cardioplegic arrest, n = 10) underwent individual caval cannulation via the right atrial appendage and free wall, which permitted exclusion of systemic venous return to the heart during cardioplegic arrest. Arterial return in both groups was accomplished through the right carotid artery. A pediatric bubble oxygenator (Shiley S-070, Shiley, Inc., Irvine, Calif.) was used with a prime consisting of acid-citrate-dextrose whole sheep blood 800 ml; heparin 5000 units; mannitol (25%) 2 ml/kg; CaCl2 400 mg; methylprednisolone 125 mg; and NaHCO3 (8.4%) 15 to 20 ml (to correct pH to 7.4).
CPB was initiated at a flow rate of 100 to 125 ml/kg per minute and endotracheal ventilation was discontinued. The oxygenator was ventilated with 1% halothane and 99% oxygen during CPB. Group I and II lambs were rapidly cooled to a systemic temperature of 25° C with spontaneous ventricular fibrillation, and the pump flow was reduced to 60 to 80 ml/kg per minute (to limit noncoronary collateral flow), maintaining mixed venous oxygen tensions at a minimum of 30 mm Hg; systemic arterial pressure ranged between 30 to 40 mm Hg without pharmacologic manipulation. Arterial and mixed venous blood gas determinations were made every 15 minutes to assure adequate oxygenation and perfusion. An 
-stat strategy was followed for pH control. 3 Group I lambs underwent 2 hours of hypothermic CPB alone (including cooling and rewarming), with the left ventricle fibrillating and vented; the hearts were defibrillated when a myocardial temperature of 30° C was reached during rewarming. Group II lambs underwent an identical protocol with the addition of 1 hour of cold, crystalloid cardioplegic arrest. The caval tourniquets were tightened and the aorta was crossclamped. St. Thomas' Hospital No. 2 cardioplegic solution (4° C), 20 ml/kg, was infused into the proximal aortic root through a 21-gauge needle, achieving an initial myocardial temperature less than 10° C. The cardioplegic solution was vented through a loosened right atrial cannula pursestring suture and discarded; the left ventricle was vented. Cardioplegic solution (10 ml/kg) was readministered every 20 minutes during the 1 hour of ischemic arrest, reducing the myocardial temperature to less than 10° C. (The myocardium rewarmed to an average temperature of 18° C between infusions.) A total of 40 ml/kg of cardioplegic solution was administered to each lamb. After 1 hour of cardioplegic arrest, the aortic crossclamp was released, the caval tourniquets were loosened, and the animal was rewarmed to 37° C; the heart was defibrillated when a myocardial temperature of 30° C was reached. Lambs in both groups were separated from CPB without the use of inotropic agents and were transfused from the pump-oxygenator to an LVEDP of 10 to 15 mm Hg. Heparinization was not reversed. The condition of the lambs was allowed to stabilize, and they were then restudied at 20 minutes after CPB.
At the conclusion of each experiment, the lambs were killed and the positions of the ultrasonic dimension transducers were verified. LV mass was determined after excision of the atria, the right ventricular free wall, and the mitral and aortic valves.
Data acquisition and instrumentation
Analog measurements of pressures and dimensions were recorded on magnetic tape with a Hewlett-Packard 3968A FM recorder (Hewlett-Packard Co., Andover, Mass.) for subsequent analysis. Data were collected with the animals disconnected from the ventilator during a steady-state period and during the course of vena caval occlusion (20 seconds duration), resulting in the gradual reduction of the LVEDP to approximately 0 mg Hg.
The sonomicrometer used in these experiments (Triton Model 120, Triton Technology, San Diego, Calif.) has a sampling rate of 1.5 kHz and a minimum resolution of approximately 0.05 mm. The micromanometer was driven with a Hewlett-Packard 8805C pressure preamplifier and was zeroed to atmospheric pressure at 37° C. Systemic arterial pressure was measured with a Statham P23Db external transducer (Gould, Inc., Los Angeles, Calif.) connected to the femoral artery catheter. The transducer was driven with a Hewlett-Packard 8805C pressure preamplifier and zeroed to atmospheric pressure at the atrial level.
Data analysis
The recorded physiologic data were digitized at 5 msec intervals on a PDP 11/34 computer (Digital Equipment Corp., Maynard, Mass.). The geometry of the left ventricle was modeled as an ellipsoidal shell with a circular equator. Dynamic midwall minor axis circumference (c) was determined by the equation
c = 
(b - h) (1)
where b is the external minor axis diameter and h is the equatorial lateral wall thickness. To provide data in clinically familiar terms, dynamic internal LV volume, VI, was calculated from the two measured LV axes (b and h) and the mass, M, of the left ventricle:
VI = /6 (b - 2h)2(a - 1.1h) (2)
where a is the external major axis diameter. Since
M = 1.07 (VE - VI) (3)
and
VE = /6 (b2a) (4)
where 1.07 is the specific gravity (grams per cubic centimeter) of the myocardium and VE is the external volume of the left ventricle, a could be calculated from equations 3 and 4 on the basis of a knowledge of M, which was determined at autopsy. The slope and intercept of the linear relationship between LV volume and midwall circumference 4 were then determined for each animal to allow calculation of LV volumes from the circumferential data for the control study period, because LV mass could vary during the course of the study.
A computerized algorithm was used to identify the diastolic and ejection phases of the cardiac cycle as previously described by Visner and associates. 5
LV transmural pressure (TMP) was equal to LV intracavitary pressure, as pleural pressure was equal to atmospheric pressure.
For the purpose of demonstrating the relationship between TMP and unnormalized LV midwall circumference (diastolic chamber compliance), diastolic pressure-circumference data selected from multiple cardiac cycles (20 to 30) during vena caval occlusion were fitted to the equation
TMP = 
(eßc - eßco), (5)
a modification of the Kelvin viscoelastic equation (equation 7), 6 where and ß are constants determined bynonlinear least-squares regression analysis and co is the unstressed midwall minor axis circumference (TMP = 0 mm Hg). To allow for comparison between ventricles with different co values, LV midwall circumference was normalized according to a Lagrangian strain definition:
c = (c - co)/co (6)
where c is te Lagrangian strain of c. The unstressed dimensions were determined by linear regression analysis from the stroke work/end-diastolic length (SW/EDL) relationship (equation 9). Pressure-strain data (normalized diastolic chamber compliance) of low strain velocity (less than 0.03/sec) were then fitted to the Kelvin viscoelastic equation by nonlinear least-squares regression analysis:
TMP = (eße - 1). (7)
Midwall circumferences and circumferential strains at TMPs of 5, 10, and 15 mm Hg were compared for the control and post-CPB periods in each lamb.
Net equatorial circumferential stroke work, SWc, was calculated as the integral of LV pressure, P, with respect to midwall circumference, c, over each cardiac cycle by the formula
SWc = 
P 
dc. (8)
By linear regression analysis, data obtained during the steady state and during vena caval occlusion were fitted to the formula
SWc = Mw(EDc - cw) (9)
relating circumferential stroke work to LV end diastolic circumference (EDc) with slope Mw and x-intercept cw (identical to co). 7 This relationship has been shown to be a highly linear, inotropically sensitive descriptor of LV performance.
LV contractility was evaluated with the load-independent index, Emax, defined as the slope of the linear relationship between end systolic pressure and dimension. An iterative computer program was used to define end systole. 8 By linear regression analysis, pressure and dimension data obtained during vena caval occlusion were fitted to the equation
PES = Emax (cES - Vd) (10)
where PES is end-systolic pressure, cES is end-systolic midwall circumference, Vd is the intercept of the line with the dimension axis, and Emax is the slope of the line.
LV afterload was calculated as mean ejection phase midwall circumferential Laplace stress 9 by the equation
c = 1.36 TMP(b - h)/h (11)
where c is midwall circumferential Laplace stress at the equator.
Statistical methods
An analysis of variance was done with the unpaired t test to compare group I and group II control data; the paired t test was used to compare control data and post-CPB data.
Animal care
All animals received care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1978).
RESULTS
LV diastolic mechanics
LV diastolic data are presented in Table I and Fig. 2. LV diastolic chamber compliance for a representative control lamb is illustrated in Fig. 2, A. Note that the neonatal lamb left ventricle was found to be relatively stiff (noncompliant), with the limit of diastolic filling reached at physiologic LV filling pressures (10 to 15 mm Hg): Starling (or preload) reserves were therefore limited.
|
|
Hemodynamics
Hemodynamic data are presented in Table II. Control data for groups I and II were not significantly different for any parameter. Heart rate, peak systolic LV pressure, and afterload did not change significantly after CPB in either group. Although statistically identical LVEDPs and circumferences were achieved after CPB in both groups I and II, true preload (c - co) was significantly diminished after CPB, because of the increase in co (and consequent loss of chamber compliance).
|
Contractility and systolic performance
LV contractility as assessed by Emax increased significantly after CPB in both groups I and II (Table III). This was associated with increased levels of circulating catecholamines after CPB. 10
|
Table III. In both groups, the slope, Mw, increased, but this increase did not reach statistical significance. The x-intercept, cw (co), increased significantly in both groups to a comparable extent. The functional consequence of this rightward, parallel shift in the SW/EDL relationship was that at identical end-diastolic circumferences (as denoted by the broken vertical line in Fig. 3, B and C), less actual stroke work was recruited after CPB, although the rate (or slope of the relationship) of work production remained unchanged.
|
The neonatal lamb left ventricle was found to be relatively noncompliant, with the limit of diastolic filling reached at a TMP of approximately 10 to 15 mm Hg. Because Starling reserves were consequently exhausted at physiologic LV filling pressures, the neonatal lamb was severely limited in its ability to adapt by means of the Starling mechanism. Although previous studies that compared the relative stiffness of immature and adult myocardium have produced conflicting results, 11 the data obtained in this study suggest that the chamber compliance of the intact neonatal left ventricle is significantly less than that of the mature heart. This limited compliance did not reflect pericardial influences, inasmuch as the pericardium was opened, and was unlikely to be the result of halothane anesthesia, because the latter has been shown to decrease contractility but not to affect LV compliance. 12 Descending limbs of the SW/EDL relationship were observed even in control lambs at TMPs of 10 to 15 mm Hg as a direct consequence of exhaustion of LV preload at these filling pressures. Fig. 4 illustrates the SW/EDL relationship superimposed on a simultaneous plot of LV chamber compliance in a representative example. Stroke work increased linearly with end-diastolic circumference (preload) until the steep portion of the LV compliance curve was reached: here an increase in TMP no longer obtained a significant increase in end-diastolic dimension, and stroke work dropped off. This should be regarded as an apparent descending limb of function resulting from fixation of preload, rather than a true descending limb of the sarcomere length-tension relationship. 13 Such apparent descending limbs of function have been observed previously to occur only at supraphysiologic LV filling pressures, 13, 14 presumably because of the more compliant nature of the adult canine hearts studied. Clinically, these findings suggest that although the Starling mechanism is operative, volume loading to TMPs greater than 10 to 15 mm Hg will be of limited utility in the neonate and may, in fact, result in operation on a descending limb of function. This is in remarkably close agreement with the clinical findings of Burrows and associates, 15 who studied volume loading in infants after CPB and found that LVEDPs in excess of 12 to 14 mm Hg resulted in an 8% to 31% decrease in cardiac output.
|
10; this finding is consistent with previous studies in both isolated and intact adult hearts in which a loss of compliance associated with CPB was related to edema formation and an increase in LV mass. 16-18 Significantly, cardioplegic arrest resulted in no loss of compliance (or resultant limitation of systolic performance) beyond that attributable to CPB alone, which is consonant with other studies that document adequate myocardial protection in the normal neonatal heart with crystalloid cardioplegia. 19, 20 Extrapolating to the clinical situation, much of the LV dysfunction associated with cardiac surgery in the neonate appears to be caused by the effects of CPB itself, rather than ischemic arrest protected with cardioplegia. This contention is further supported both by a retrospective clinical study in which the use of circulatory arrest or low-flow CPB was shown by logistic regression analysis to confer a decreased risk of hospital death 21 and by an experimental study from our laboratory that demonstrated superior myocardial protection with profoundly hypothermic total circulatory arrest (and limited CPB) compared with cardioplegic arrest with conventional CPB. 22 As suggestedby Kirklin, 23 an increased understanding of (and development of methods for attenuating or blocking) the damaging effects of CPB, to which the neonate appears to be particularly susceptible, may be a useful avenue for further investigation.
It is clear from an examination of Fig. 2 that detection of the loss of chamber compliance in the lambs was dependent on an accurate determination of the increase in co, inasmuch as the steep, right-hand portion of the compliance curve was unchanged. A corollary is that end-diastolic dimension was no more an adequate descriptor of preload than TMP, because both were unchanged after CPB, despite a significant loss of LV compliance. The quantity (EDc - co) accurately described LV preload, as Figs. 2 and 3 demonstrate and as is apparent from an examination of equation 9. The quantity (EDc - co) may be termed pressure-recruitable preload in a fashion analogous to that suggested by Glower and associates 7 in defining preload-recruitable stroke work.
Table II demonstrates that in groups I and II there was a significant decrease in pressure-recruitable preload after CPB. Net stroke work decreased in both groups; pressure work (afterload) was maintained at the expense of circumferential shortening (and volume work), reflecting the strategy of the intact organism to maintain cerebral and coronary perfusion pressure at the expense of flow output. The significant increase in contractility as assessed by Emax was inadequate to compensate for the loss of LV preload. LV performance as described by the slope of the SW/EDL relationship remained unchanged after CPB. Because the SW/EDL relationship has been shown to be inotropically sensitive, the question can be raised as to why Emax increased but not Mw. The answer lies in an appreciation of the fact that the SW/EDL relationship is an index of LV performance and not purely of contractility (Emax): as such, Mw is sensitive to changes in afterload and impedance matching. Previous studies in which the SW/EDL relationship was shown to be relatively insensitive to changes in afterload used compliant adult canine heart models in which changes in afterload were compensated for by an increase in end-diastolic dimension (preload), thus maintaining stroke work. 7, 24 In the intact neonatal lamb, however, preload behaves as though fixed: this sets the stage for afterload mismatch (or loss of impedance matching), a concept originally qualitatively defined by Ross 25 and that now can be given quantitative expression according to the work of Myhre and associates. 26 In the present study, the post-CPB lamb heart was constrained to maintain afterload (pressure generation) despite a significantly reduced, fixed preload; a loss of impedance matching resulted, reflected in the discrepancy between Emax (contractility) and Mw (systolic performance). This is supported by previous studies from our laboratory in which afterload reduction with sodium nitroprusside after CPB was able to restore volume work and increase Mw. 10 Thus when preload behaves as though fixed, Mw becomes highly sensitive to changes in afterload, the left ventricle being no longer able to use the Starling mechanism to adapt to changes in afterload. In the clinical setting, careful attention should be given to systemic pressure and avoidance of hypertension to minimize afterload mismatch.
The technique of sonomicrometry and the indices of LV function used have been previously validated. Although physiologic conditions with the chest open may differ from those of the unanesthetized subject with the chest closed, the conditions of the present study rigorously reproduce those of the clinical situation. We measured only two of the three orthogonal axes of the left ventricle, but the interventions used should affect the left ventricle globally: it is therefore unlikely that a two-dimensional analysis of mechanics would result in any serious error. The estimation of control LV volumes by the technique described in the Methods section has not been rigorously validated. Volumetric data were calculated for purposes of clinical correlation, and the arguments presented do not rest on the results of these calculations. The theoretic and experimental proof of the assertions regarding the afterload sensitivity of the SW/EDL relationship are beyond the scope of the present communication and will be the subject of subsequent papers.
In conclusion, with the use of a clinically relevant model, we have studied the effects of CPB and cardioplegic arrest on the systolic and diastolic LV function of the intact neonatal heart. The neonatal left ventricle was found to be relatively stiff; although the Starling principle was operative, preload reserves became fully exhausted at physiologic LV filling pressures, resulting in descending limbs of LV function. CPB was associated with impaired systolic performance as a consequence of LV diastolic dysfunction characterized by a loss of LV compliance and impedance matching rather than a loss of contractility. Ischemic cardiac arrest protected by cold, crystalloid cardioplegia resulted in no dysfunction beyond that attributable to CPB alone. These findings help to clarify the mechanism of LV dysfunction associated with cardiac surgery in the neonate.
Acknowledgments
We express our appreciation to our perfusionist, John Borner, for his invaluable technical assistance. Peggy Thomas prepared the manuscript.
References
This article has been cited by other articles:
|
|
 |
|
  S. Nemoto, M. Aoki, C. Dehua, and Y. Imai Effects of carnitine on cardiac function after cardioplegic ischemia in neonatal rabbit hearts Ann. Thorac. Surg., January 1, 2001; 71(1): 254 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. DiBernardo, P. M. Kirshbom, L. A. Skaryak, R. L. Quarterman, R. L. Johnson, M. J. Davies, J. W. Gaynor, and R. M. Ungerleider Acute functional consequences of left ventriculotomy Ann. Thorac. Surg., July 1, 1998; 66(1): 159 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Young, I. O. Choy, N. K. Silva, D. Y. Obayashi, and H. E. Barkan ANTEGRADE COLD BLOOD CARDIOPLEGIA IS NOT DEMONSTRABLY ADVANTAGEOUS OVER COLD CRYSTALLOID CARDIOPLEGIA IN SURGERY FOR CONGENITAL HEART DISEASE J. Thorac. Cardiovasc. Surg., December 1, 1997; 114(6): 1002 - 1009. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
