The influence of prearrest factors on the preservation of left ventricular function during cardiopulmonary bypass

J

THoRAc CARDIOV ASC SURG

79:812-821, 1980

The influence of prearrest factors on the preservation of left ventricular function during cardiopulmonary bypass Uniformly excellent myocardial protection during global ischemia in cardiac procedures requiring cessation of aortic root perfusion remains an elusive goal. This study establishes the importance of the preischemic inotropic state of the left ventricle and the arterial blood glucose concentration ([glucose]) immediately prior to an elective period of myocardial ischemia. Thirty-one experiments were performed on dogs subjected to 90 minutes of global ischemia on cardiopulmonary bypass at 28° C with perfusion pressure constantly maintained at 90 mm Hg. The maximum rate of development of left ventricular pressure (LVdp/dtma.r) at constant arterial and left atrial (LAP) pressures was used as a measure of contractility prior 10 ischemia. In a group of 18 of these dogs undergoing anoxic cardiac arrest, arterial blood [glucose], in conjunction with the preischemic LVdp/dtma.r and the cross-clamp to asystole time interval (metabolic supply/demand index), significantly predicted (p < 0.01) the functional result following the standard ischemic insult. In 13 other dogs with [glucose] >120 mg/100 ml and treated with potassium cardioplegia, "normal" preischemic LVdp/dtma.r (N = 7) was associated with a good functional result, but an elevated preischemic LVdp/dtma.r (N = 6) produced severe functional impairment following ischemia. Optimum myocardial protection thus involves minimizing metabolic demands and maximizing metabolic supply immediately prior to and during the period of aortic cross-clamping.

Eric G. Butchart, M.D., M. Terry McEnany, M.D., Gideon Strich, M.D., Costas Sbokos, M.D., and W. Gerald Austen, M.D., Boston, Mass.

In

the voluminous literature on myocardial protection, preischemic myocardial metabolism has received little attention. Although many techniques are currently used to reduce the metabolic demands of the heart during a period of ischemia, by means of hypothermia':" or cardioplegia':" or a combination of both ,9, 10 little account has been taken of any pre-manipulation factors which may modify the result of a measured period of ischemia in terms of return of ventricular function. Furthermore, unless the preischemic status of the heart is taken into consideration and standardized, it is impossible to adequately compare different methods of myocardial protection. From the Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Mass. This work was supported by National Institutes of Health Ischemic SCaR Grant, U.S. Public Health Service 5P50HL 176653. Received for publication Aug. 9, 1978. Accepted for publication Oct. 17, 1979. Address for reprints: M. Terry McEnany, M.D., Department of Surgery, The Miriam Hospital, Providence, R. I. 02906.

812

Because of the complex interplay of physiological, pharmacologic, and pathological factors, a meaningful comparison of methods of myocardial protection in man is difficult to obtain. A study allowing rigid control of experimental conditions was therefore undertaken in dogs. We sought to identify those factors which modified the effects of a standard period of global myocardial ischemia on left ventricular function. An experimental model was designed to (1) reproduce the degree of moderate hypothermia commonly used clinically; (2) maintain an adequate coronary perfusion pressure prior to and following global ischemia to avoid damage resulting from inadequate subendocardial blood flow; and (3) use an ischemic period long enough to delineate any effects of preischemic factors and to have clinical relevance.

Materials and methods Experiments were performed on 31 mongrel dogs subjected to 90 minutes of global myocardial ischemia on cardiopulmonary bypass at 28° C. A whole-blood prime was used and flow rates were adjusted to main-

0022-5223/80/060812+10$01.00/0 © 1980 The C. V. Mosby Co.

Volume 79

Preservation of LV function during CPR

Number 6

8 13

June, 1980

Arterial Pressure

Arterial Return

LA Pressure

LA Return (Function Curves) LV Drill Biopsies Heart Water

Coronary Sinus Samples LV PresSure LV DP/DT Venous DrainaQe Coronary Blood Flow SA Node Crushed Atrial Pacing 160/Min

Fig. 1. Bypass circuitry. If blood is returned through the left atrial (LA) return line at a measured rate, a standard left ventricular (LV) function curve can be obtained. SA, Sinoatrial.

tain a constant mean arterial pressure (MAP) of 90 mm Hg. In addition, so that a constant heart rate could be maintained, the sinoatrial node was crushed and atrial pacing instituted at 160 beats/min. Blood gases and electrolytes were maintained within a physiological range with close monitoring. A method of cardiopulmonary bypass previously described from this laboratory, II which offers the option of total bypass or right heart bypass (Fig. 1), was used to measure left ventricular function by forcing the left ventricle to perform graduated levels of work with incremental increases in blood flow to the left atrium. Flow through the left ventricle was increased in increments of 400 mllmin up to 4,000 mllmin, and thereby left atrial pressure (LAP) was gradually increased. A 1 to 2 minute stabilizing period was allowed after each increment before recording. The MAP was maintained at 90 mm Hg by adjusting systemic flow through the arterial cannula. If the MAP began to rise above 90 mm Hg with the main arterial pump already off (which happened frequently with left atrial flows over 2,800 mil min), a Y-connection on the arterial line allowed "bleeding off" into the cardiotomy reservoir, the rate of "bleeding off" being controlled to maintain the MAP at 90 mm Hg. Varying the preload (LAP) with a constant MAP

made it possible to plot left ventricular stroke work (LVSW) against LAP to produce a Sarnoff ventricular function curve and to plot the maximum rate of development of left ventricular pressure (L Vdp/dtm ax ) against LAP. The stroke work (Sarnoff) curve was used to measure cardiac performance, and LVdp/dtm ax (at MAP 90 mm Hg and LAP 7 mm Hg) was used as an index of contractility. Cardiac performance 60 minutes following reperfusion was compared with control values. Third and fourth order orthogonal polynomials were used to construct a least square "best fit" curvilinear regression curve (regressing LAP on L VSW), with at least eight points for each curve. Mathematical center of mass (COM) of each curve was then determined for both the x (LAP) and y (LVSW) axes. A change in COM (loss of function) could be computed by subtracting the COM after ischemia from the control COM. This change described any "shift to the right" of the function curve.P Postischemic cardiac performance was then graded according to the percentage loss of function as follows (Fig. 2): Class I <20% loss of function, Class II 20% to 50% loss of function, and Class III >50% loss of function. Myocardial water content, expressed as a wet

8 14

The Journal of Thoracic and Cardiovascular Surgery

Butchart et al.

I

r:~

Good Function «20% Loss)

f

LVSW

~oderately

Depressed

,\"OOtiOO (20-50%L",)

lated from measurements of coronary blood flow, myocardial oxygen extraction, and heart weight. Fiberoptic oximetry with a probe mounted in the right ventricular vent cannula (Fig. 1) allowed continuous monitoring of coronary venous oxygen saturation.

Experimental design

!

\severelY Depressed

/

•

(>50% Loss)

-

:

LAP Fig. 2. Grading of postischemic function by comparison with function curve before ischemic intervention. Class I, <20% loss. Class II, 20% to 50% loss. Class III, >50% loss of postischemicleft ventricularfunction. LVSW, Left ventricular stroke work. LAP, Left atrial pressure.

Table I. Composition of potassium cardioplegic solution Glucose

(grn/L) NaHCOa (grn/L) KCI (gm/L) NaCI (gm/L)

Analyzed values: Na+ (mEqlL) K+ (mEqlL) Osmolality (mOsm/kg) pH (at 3T C)

2 I 1.865 6.32 120

25 270 7.70

weight/dry weight ratio, was obtained from serial biopsies of the free wall of the left ventricle, taken with a pneumatic high-speed drill. 13 Total and regional coronary blood flows were measured. The right ventricle was drained with a large catheter into a graduated cylinder, and this blood was considered total coronary blood flow. Dogs which demonstrated coronary blood flow during the period of aortic cross-clamping were rejected from this study. Regional myocardial blood flow was measured by the radioactive microsphere technique.r"?" and the ratio between subendocardial (inner third) flow and subepicardial (outer third) flow (L VIIL Va) was used to quantitate relative subendocardial ischemia. Arterial-blood glucose concentration ([glucose]) was determined by the potassium ferricyanide technique. In some dogs, myocardial oxygen consumption (MV0 2 ) , in ml/min/IOO gm myocardium, was calcu-

The following protocol was common to all experiments. Following a short period for stabilization on cardiopulmonary bypass, control measurements of arterial [glucose], left ventricular performance, contractility, water content, and regional coronary blood flow distribution were obtained. The left atrium was then vented, and systemic cooling using a heat exchanger in the bypass circuit was carried out to a ventricular septal temperature of 28° C over a period of 15 to 20 minutes. The ascending aorta was then cross-clamped for 90 minutes. Fifteen minutes before the end of this ischemic period, systemic rewarming to 37° C was begun so that, upon release of the cross-clamp, the heart was immediately reperfused with warm blood. If spontaneous defibrillation did not occur, the heart was electrically defibrillated within 1 minute of the beginning of reperfusion. Atrial pacing at 160 beats/min was then resumed. After 45 minutes of reperfusion, left ventricular water content and regional blood flow distribution were again measured. After 60 minutes of reperfusion, left ventricular performance and contractility were measured. In experiments in which cardioplegia was used (Groups B and C), an isosmotic solution buffered to pH 7.70, containing as its principal constituents K + (25 mEq/L) and glucose (200 mgllOO ml), was administered at 28° C in order not to alter myocardial temperature. A complete analysis of the solution is given in Table I. Immediately following aortic cross-clamping, the solution was injected into the aortic root in a quantity varied from 150 to 300 mi. In the 13 dogs in which cardioplegia was employed, no return of electrical or mechanical activity was observed during the 90 minute ischemic period. Dogs were divided into three groups: Group A (18 dogs): Anoxic arrest. In this group, no attempt was made to manipulate possible preischemic factors. During the cooling period prior to the institution of global ischemia, atrial pacing was discontinued and the heart was allowed to slow naturally as the temperature fell. At 28° C, the aortic cross-clamp was applied and the time for complete mechanical asystole noted for each ventricle.

Volume 79

Preservation of LV function during CPR

Number 6 June, 1980

8 15

~

~

GROUP A

!

Standard Error of Mean

GROUP A

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Fig. 3. Group A: Anoxic arrest. Myocardial weight wet/dry weight (W /D) ratios of the three functional classes of dog hearts following 90 minutes of global ischemia. There is a significantly greater amount of water in the poorly functioning ventricular wall (Class III).

Group B (seven dogs): Potassium cardioplegia with normal contractility. In this group, atrial pacing was again discontinued during the cooling period. All control arterial [glucose] levels were> 120 mg/100 ml. No attempt was made to manipulate contractility. Immediately following aortic cross-clamping, the potassium cardioplegic solution was injected into the aortic root, and the heart had arrested completely within 1 to 2 minutes.

Group C (six dogs): Potassium cardioplegia with increased contractility. As in Group B, control arterial [glucose] levels were > 120 mg/100 ml. Control measurements of MV0 2 were made on the beating, nonworking heart. Prior to cross-clamping of the aorta, however, a deliberate attempt was made to increase contractility by a combination of continued atrial pacing and the intra-aortic infusion of isoproterenol in a dose of 1 to 3 JLg/min, and the resulting increase in MV02 was recorded. As in Group B, asystole was then induced rapidly after aortic cross-clamping by means of the same potassium cardioplegic solution.

Results Group A: Anoxic arrest. The time taken for the two ventricles to reach asystole following clamping of the aorta was invariably different, the right ventricle always continuing to beat long after the left had arrested.

~ Q:::

p
P
!

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I

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Fig. 4. Group A: Anoxic arrest. The relative amount of subendocardial blood flow (LVI/LVO), Ratioof blood flow in the left ventricular subendocardium [I] and subepicardium [0] in the left ventricle following 90 minutes of global ischemia. The subendocardium is hypoperfused in the poorly functioning ventricles (Class III). Considerable variation also occurred in the time taken for the left ventricle to become asystolic (range 5 to 25 minutes). According to the functional classification of postischemic cardiac performance described earlier and illustrated in Fig. 2, three dogs were found to have <20% loss of function (Class I), 10 dogs had 20 to 50% loss of functional ability (Class II), and five demonstrated >50% loss of function (Class III). Class III included two dogs with "stone hearts. "17 This functional differentiation was corroborated by the ability to categorize all of the dogs in Group A into identical classes on the basis of two physiological parameters: (1) postreperfusion myocardial water content (an index of ischemic damage) and (2) subendocardial blood flow. The studies of postischemic left ventricular myocardial water content showed no increase in wet weight/ dry weight ratio from control in Class I dogs, but significant increases in myocardial water in Class II and III dogs (Fig. 3). Similarly, the left ventricular subendocardium after cross-clamping was found relatively ischemic (compared to control) only in Class III dogs; there was no diminution in myocardial blood flow in the dogs with <20% loss of function (Fig. 4). In examining the preischemic and postischemic

8 16

The Journal of Thoracic and Cardiovascular Surgery

Butchart et al.

GROUP A

I

Standard Errar of Mean

GROUP A

1

Standard Error of Mean

O~--~~-=--=~_-----J

Functional Closs I II ill L-p
Fig. 5. Group A: Anoxic arrest. The preischemic arterial [glucose] is predictive of the postischemic ventricular function folIowing 90 minutes of aortic cross-clamping at 28° C.

Fig. 6. Group A: Anoxic arrest. The combination of preischemic contractility (LVdp/dtLA P7J and arterial [glucose] can predict postischemic left ventricular function.

characteristics of the ventricular performance and the multiple variables recorded in the para-manipulation period, we found three factors operating on the ventricle prior to asystole which were significant in predicting the level of preservation of ventricular function as measured 60 minutes following the ischemic period (Figs. 5 to 9): (l) control (preischemic) arterial [glucose]; (2) the level of control contractility (L Vdp/ dtmaxLAP7); and (3) the interval between application of the aortic cross-clamp and left ventricular arrest (minutes). Each of these values is easily determined and monitored in the clinical setting and, thereby, potentially provides a real-time guide in the protection of the ischemic heart during cardiac operations. Only one of these factors was found to be significant in isolation-the control (preischemic) arterial [glucose] (Fig. 5). Preischemic contractility was significant when combined either with arterial [glucose] (Fig. 6) or with the cross clamp-left ventricular asystole interval (Fig. 7). Most significant (p < 0.005) was the index derived by dividing the arterial [glucose] by the crossclamp-left ventricular asystole interval (Fig. 8). Since glucose is the only important substrate which myocardium can metabolize anaerobically, the index combining all three factors, arterial [glucose] » (cross-clamp-left ventricular asystole interval x L Vdp/dt), may be regarded as a metabolic supply/

demand index, relating a measure of the availability of substrate to two features of substrate utilization-force of contraction and duration of ischemic mechanical activity. Values of this index below 1.5 were associated with serious functional impairment (Class III), whereas values above 4.5 were associated with little or no functional impairment (Class I, Fig. 9). Attempts were then made to abolish the adverse effects of two factors (low arterial [glucose] and the longischemic time of the anoxic contracting left ventricle) and to study the third (contractility) in more detail (Groups B and C). By ensuring that preischemic [glucose] was > 120 mg/ 100 ml and by inducing rapid asystole immediately after the onset of global ischemia with a hyperkalemic cardioplegic solution containing 200 mg/100 ml glucose, we were able to study preischemic contractility (L Vdp/dt max) as the only variable factor. Group B (seven dogs). In this group, no attempt was made to manipulate preischemic contractility, L Vdp/dtmax, which varied spontaneously from 2,800 mm Hg/sec to 3,600 mm Hg/sec during the control function run. Five dogs had <20% loss of function and two dogs, 20% to 35% loss of function (Fig. 10). It thus appeared that, if arterial [glucose] was high and asystole rapid, these levels of contractility were relatively safe.

Volume 79

Preservation of LV function during CPR

Number 6

8 17

June, 1900

GROUP A

I

Standard Error of Mean

,

... ....

t}

0'----------'

III

FunctionolCloss I

II

ill

L - p< 0,05----.J

Fig. 7. Group A: Anoxic arrest. The product of preischemic contractility (LVdp/dtLAP7) and arrest time (cross-c1amp-L V asystole interval in minutes) can predict deterioration of postischemic left ventricular function (Class III).

Group C (six dogs). In another six dogs, following the completion of the control function studies, left atrial flow was adjusted to maintain an LAP of 7 mm Hg, and isoproterenol was infused into the aortic root at a rate sufficient to raise the LVdp/dt to >5,000 mm Hg/sec (this dose varied from 1 to 3 /-Lg/min). Total cardiopulmonary bypass was then resumed with the left heart vented, and cooling was commenced while the isoproterenol infusion was maintained. Since isoproterenol can cause subendocardial ischemia when its inotropic and chronotropic actions result in myocardial oxygen requirements exceeding oxygen supply, 18 it was necessary to measure the distribution of left ventricular blood flow immediately prior to aortic cross-clamping to ensure that any postischemic functional impairment was not due to the additive effect of a period of pre-existing subendocardial ischemia. The mean value of L VIIL VO in these six dogs was 1.14 (range 0.91 to 1.38), indicating no relative subendocardial ischemia. Myocardial oxygen consumption (MV0 2 ) was calculated immediately prior to aortic cross-clamping and expressed as a percentage increase over the control value for the nonworking heart. Of the six dogs in this

NS---.J

~p<0,005.....J

o'----------""c:=...------""""'---.:.:.:u"----------'

Functional Closs I

m

II

L p<0 ,0 5J L

Fig. 8. Group A: Anoxic arrest. The most significant predictors of postischemic function can be attained by dividing arterial [glucose] by arrest time (min.).

GROUP A

~~

i::::"G .~

L;:]

h..~

V)

Cr)

-.....J s;

of Mean

§

~ ~~~ E: :::s ~ ~" "<~ ~ ~

t:::: ~

~

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7,5

6,0

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<:)

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3.0

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Fig. 9. Group A: Anoxic arrest. A metabolic supply/demand index can be obtained by dividing arterial [glucose] by the product of a contractility measurement (L Vdp/dt LAP 7 ) and arrest time (min.). Values of this index greater than 4.5 were associated with excellent functional preservation and values below 1.5 consistently predicted poor ventricular performance.

8 18

The Journal of Thoracic and Cardiovascular Surgery

Butchart et al.

GROUP C

.Control

(~"t"

20-35% Loss of Function,n=2

LVSW

LVSW

i i GROUP B

50-60% Loss of Function / ( M V 0 2 +<90%), n=2

I~

100% Loss of Function (MV0 2 • >90%), n= 4

LAP LAP Fig. 10. Group B: Cardioplegia and normal contractility. Excellent postischemic ventricular function can be expected in dogs with arterial [glucose] > 120 mg/ I00 ml if the heart is quickly arrested, so long as the preischemic L Vdp/dt is not excessively elevated. group, the two that showed preischemic increases in MV02 of <90% (39% and 84%) developed 50% to 60% loss of function following ischemia, whereas the four dogs that showed preischemic increases in MV0 2 of >90% (90%, 114%, 124%, and 130%) all exhibited a total loss of function (Fig. 11).

Discussion In determining the magnitude of an ischemic insult to the myocardium, the myocardial status during three intervals is important: i.e., the preischemic, ischemic, and postischemic periods. This study established the importance of the preischemic and early ischemic periods, and the results demonstrate that the balance between energy supply and demand immediately prior to the onset of global ischemia is critical in determining the outcome of a given anoxic insult. Under normal aerobic conditions, many different nutrients can be used by the heart for oxidation to create high-energy phosphate bonds. Free fatty acids form the principal substrate, but lactate, acetate, acetoacetate, glucose, pyruvate, and amino acids may all be used, according to their concentration in arterial blood.!" However, under anaerobic conditions, glucose is the only important substrate, but is used very inefficiently, its ability to produce adenosine triphosphate (ATP) dropping to 5.5% of its aerobic capability." Under anaerobic conditions, especially with any electromechanical activity, ATP utilization quickly outstrips production, and a fall in the concentration of

Fig. 11. Cardioplegia in hearts with increased preischemic contractility. Quick cardioplegic arrest cannot protect the heart which has been stimulated to a high preischemic L Vdp/dt. All hearts had severe depression of postischemic function.

high-energy phosphates results. The level of creatine phosphate is the first to deteriorate, since resynthesis of ATP continues until the pool of creatine phosphate is almost exhausted. Thereafter, the level of intracellular ATP decreases continuously at a rate governed by the intensity of glycolysis. Once it falls to a critical level of 4 ILmole/gm wet tissue, the ischemic tolerance of the myocardium has been exceeded." Levels below 4 ILmole/gm are associated with severe functional impairment and ultrastructural changes on reperfusion. 22 Intracellular glycogen also becomes rapidly depleted under anaerobic conditions owing to increased glycogenolysis, and there is evidence that enhanced glycogen stores prior to ischemia may transiently facilitate anaerobic ATP production. 23 Energy utilization. It is thus clearly important to maintain glycogen and high-energy phosphate stores at optimum levels, prior to any temporary myocardial ischemia, by minimizing utilization. The result of Group C (cardioplegia with increased contractility) demonstrate the adverse effect of raising contractility immediately prior to ischemia, even though the heart was arrested rapidly and completely following the placement of the arotic cross-clamp. This suggests that energy stores already may have been considerably depleted before the onset of ischemia, since it known that a rise in contractility increases the utilization of highenergy phosphates. 24 The alternative explanation, that isoproterenol may increase basal metabolism so that increased utilization of energy stores continues after

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Preservation of LV function during CPR

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June. 1980

asystole has been induced, is refuted by the work of Klocke and co-workers;" They showed that, in the potassium-arrested heart, isoproterenol caused only a minimal increase in basal MV02. The results of Group B (cardioplegia with normal contractility) show that contractility within a "normal" range is not a significant factor in determining the outcome of a period of ischemia in this study provided that arterial glucose levels are maintained in the high range of normal and the heart is arrested immediately after the onset of ischemia. However, the results of Group A (anoxic arrest) show that the level of contractility, even though it may be within the "normal" range, may be a significant factor when combined with either a low arterial [glucose] or with a prolonged period of anoxic left ventricular contraction. Hypoglycemia itself may tend to enhance contractility, since it is associated with increased catecholamine secretion, but catecholamine levels were not studied. The utilization of myocardial energy stores parallels MV02, the determinants of which have been enumerated by Braunwald.P" The most important are basal metabolism (which accounts for 20% of the MV02 of the beating heart), intracardiac systolic pressure and myocardial wall tension, cardiac work, contractility, and heart rate. That portion of MV02 related to intracardiac pressure, wall tension, and cardiac work is largely abolished by total cardiopulmonary bypass with the left heart vented. If the need to lower energy utilization and MV0 2 prior to the onset of global ischemia is accepted, the determinants of MV02 which must be modified are (l) basal metabolism, (2) contractility, and (3) heart rate. Reduction in energy utilization and MV02 may be achieved by hypothermia and/or pharmacologic measures. During aerobic conditions, the fall in MV02 seen with hypothermia is brought about principally by a fall in heart rate, since comtractility increases during mild hypothermia.V: 28 reaching a maximum at 28° C29 and declining thereafter, ultimately becoming subnormal at 22° to 25° C.30 In addition, left ventricular compliance progressively decreases with hypothermia.": 32 and MV02 tends to increase owing to a rise in wall tension. This may explain why, despite an overall fall in MV02, left ventricular oxygen consumption per beat in the perfused nonworking heart continues to rise as the temperature is lowered to 22° C. 28 Graham and co-workers'" studied the effects of negative inotropic drugs on MV02 and demonstrated reductions with procaine and ,a-adrenergic blocking agents. If short-acting ,a-adrenergic blockers can be used in the preischemic period, they would seem to

offer an advantage, in combination with hypothermia, to bring about a reduction in contractility beyond that which hypothermia alone is able to achieve. Energy supplies. The present study has demonstrated, for the first time, that spontaneously varying (unmanipulated) arterial glucose levels have a very pronounced effect on the postischemic functional result following a standard ischemic insult and that an arterial [glucose] of > 150 mg/lOO ml alone appears to have a marked protective effect in anoxic arrest (Group A). Since ATP production during global ischemia can take place only as the result of anaerobic glycolysis, a sufficient supply of glucose must be provided. This may be achieved in the form of increased glycogen stores or high-normal or elevated arterial glucose levels, which may be used in the period between cross-clamping the aorta and ventricular systole. Scheuer and Stezoski'" showed that enhanced glycogen stores in catecholamine-depleted rat hearts facilitated ATP production during ischemia, and Hewitt and colleagues" were able to increase cardiac glycogen levels in dogs by feeding an all-fat diet for 3 days and subsequently demonstrate improved postischemic left ventricular function in comparison with control animals. However, dogs with normal glycogen levels whose hearts were perfused with 5% dextrose during the ischemic period did only slightly better than those with elevated glycogen levels. Austen and co-workers;" studying anoxic arrest in dogs, demonstrated improved postischemic ventricular performance after injecting 200 ml of a solution containing one-third 20% glucose and two-thirds oxygenated blood into the aorta immediately following cross-clamping, giving a perfusate glucose level of 2,000 to 3,000 mg/lOO m!. Further evidence of the beneficial effects of glucose is provided by studies of the isolated perfused rat heart," in which perfusion with glucose during anoxia preserved myocardial concentrations of high-energy phosphates, and by studies of the isolated rabbit papillary muscle, 37 in which glucose was found to retard damage to myocardial protein synthetic mechanisms. Translating the experimental results of this study into clinical practice, five observations emerge which are essential in planning optimum myocardial protection during periods of ischemia on cardiopulmonary bypass: I. Conditions during the period immediately prior to ischemia are of great importance in determining the available energy reserves during the ischemic period. 2. The functional result following a period of global ischemia is determined partly by the available energy reserves and the demands made upon them. 3. Contractility is an important determinant of

The Journal of

820 Butchart et al.

MV0 2 , and increased energy utilization in the preischemic period resulting from excessively high levels of contractility may deplete myocardial energy reserves. Under these circumstances, even hypothermia and potassium cardioplegia may not prevent severe functional impairment, unless the ischemic period is very short. 4. Hypothermia can reduce overall MV0 2 but does not reduce contractility. l3-adrenergic blockade may be required if further reduction in preischemic MV0 2 is to be achieved by reducing contractility. 5. Asystole should be induced as rapidly as possible following the onset of ischemia, by means of a cardioplegic solution. The use of the metabolic supply/demand index described in this study may aid, therefore, in the clinical management of patients operated upon with the surgical adjunct of ischemic arrest with or without chemical cardioplegia. REFERENCES Shumway NE, Lower RR: Topical cardiac hypothermia for extended periods of anoxic arrest. Surg Forum 10:563, 1959 2 Urschel HC, Greenberg 11: Differential cardiac hypothermia for elective cardioplegia. Ann Surg 152:845, 1960 3 Tyers GFO, Hughes HC, Todd Gl, Williams DR, Andrews El, Prophet GA, Waldhausen lA: Protection from ischemic cardiac arrest by coronary perfusion with cold Ringer's lactate solution. 1 THoRAc CARDIOVASC SURG 67:411, 1974 4 Meyer 1, Reul Gl, Sandiford FM, Wukasch DC, Norman lC, Hallman GL, Cooley DA: The value of moderate hypothermia during anoxic cardiac arrest for coronary artery surgery. 1 Cardiovasc Surg 16:465, 1975 5 Sealy WC, Young WG, Brown IW, Harris lS, Merritt DH: Potassium, magnesium, and neostigmine for controlled cardioplegia. 1 THORAC SURG 37:655, 1959 6 Reidemeister lC, Heberer G, Bretschneider Hl: Induced cardiac arrest by sodium and calcium depletion and application of procaine. Int Surg 47:535, 1967 7 Kirsch U, Rodewald G, Kalmar P: Induced ischemic arrest. 1 THoRAc CARDIOVASC SURG 63: 121, 1972 8 Gay WA, Ebert PA, Kass RM: The protective effects of induced hyperkalemia during total circulatory arrest. Surgery 78:22, 1975 9 Hearse Dl, Stewart DA, Braimbridge MV: Hypothermic arrest and potassium arrest. Circ Res 36:481, 1975 IO Hearse Dl, Stewart DA, Braimbridge MV: Cellular protection during myocardial ischemia. Circulation 54: 193, 1976 II Mundth ED, Wanibuchi Y, Wright 1, Austen WG: Right heart-pulmonary circulatory bypass. I. Study of left ventricular function. 1 Surg Res 15:404, 1973 12 Kay HR, Rao S, Butchart EG, Sbokos C, Eldridge R,

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Austen WG, McEnany MT: Correlation between ischemic metabolism and post ischemic cardiac function. 1 Surg Res 24:193, 1978 Erdmann Al, Barrett LV: The measurement of myocardial water. Circ Res (in press) Rudolph AM, Heymann MS: The circulation of the fetus in utero. Circ Res 21:163, 1967 Domenech Rl, Hoffman JIE, Nobel MIM, Saunders KG, Henson lR, Subijanto S: Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res 25:581, 1969 Buckberg GD, Luck JC, Payne DB, Hoffman JIE, Archie lP, Fixler DE: Some sources of error in measuring regional blood flow with radioactive microspheres. 1 Appl Physiol 31:598, 1971 Cooley DA, Reul Gl, Wukasch DC: Ischemic contracture of the heart: "Stone Heart. " Am 1 Cardiol 29:575, 1972 Buckberg GD, Ross G: Effects of isoprenaline on coronary blood flow. Its distribution and myocardial performance. Cardiovasc Res 7:429, 1973 Bing Rl: Cardiac metabolism. Physiol Rev 45:171,1965 Kones Rl: Metabolism of the acutely ischemic and hypoxic heart. Crit Care Med 1:321, 1973 Bretschneider Hl, Hubner G, Knoll D, Hohr B, Nordbeck H, Spieckermann PG: Myocardial resistance and tolerance to ischemia. Physiological and biochemical basis. 1 Cardiovasc Surg 16:241, 1975 Spieckermann PG: Uberlebens und Wiederbelebungszeit des Herzens. Anaesthesiol Wiederbelebung 66: I, 1973 Scheuer 1, Stezoski SW: Enhanced glycogenolysis: A protective mechanism in catecholamine-depleted rat hearts. Circulation 40:Suppl 3: 1969 Chandler BM, Sonnenblick EH, Pool PE: Mechanochemistry of cardiac muscle. III. Effects of norepinephrine on the utilization of high-energy phosphates. Circ Res 22:729, 1968 Klocke Fl, Kaiser GA, Ross 1 Jr, Braunwald E: Mechanism of increase of myocardial oxygen uptake produced by catecholamines. Am 1 Physiol 209:913, 1965 Braunwald E: The determinants of myocardial oxygen consumption. Physiologist 12:65, 1969 Monroe RG, Strang RH, LaFarge CG, Levy 1: Ventricular performance, pressure-volume relationships, and O 2 consumption during hypothermia. Am 1 Physiol 206:67, 1964 Buckberg GD, Brazier lR, Nelson RL, Goldstein SM, McConnell DH, Cooper N: Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating and arrested heart. J THORAC CARDIOVASC SURG 73:87, 1977 Badeer HS: Effect of hypothermia on the contractile capacity of the myocardium. 1 THORAC CARDIOVASC SURG 53:651, 1967 Austen WG: Studies of contractile force in man. The effect of myocardial hypothermia on coronary perfusion during aortic occlusion. Circulation 32:372, 1965

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Preservation of LV function during CPR

Number 6 June, 1980

31 Remensnyder JP, Austen WG: Diastolic pressure-volume relationships of the left ventricle during hypothermia. J THoRAc CARDIOVASC SURG 49:339, 1965 32 Templeton GH, Wildenthal K, Willerson IT, Reardon WC: Influence of temperature on the mechanical properties of cardiac muscle. Circ Res 34:624, 1974 33 Graham TP, Ross J Jr, Covell JW, Sonnenblick EH, Clancy RL: Myocardial oxygen consumption in acute experimental cardiac depression. Circ Res 21: 123, 1967 34 Hewitt RL, Lolley DM, Adrouny GA, Drapanas T: Protective effect of glycogen and glucose on the anoxic arrested heart. Surgery 75:1,1974

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35 Austen WG, Greenberg JJ, Piccinini JC: Myocardial function and contractile force affected by glucose loading of the heart during anoxia. Surgery 57:839, 1965 36 Hearse DJ, Chain EB: The role of glucose in the survival and "recovery" of the anoxic isolated perfused rat heart. Biochem J 128:1125, 1972 37 Peterson MB, Lesch M: Studies on the reversibility of anoxic damage to the myocardial protein synthetic mechanism. Effects of glucose. J Mol Cell Cardiol 7: 175, 1975

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