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J Thorac Cardiovasc Surg 1994;107:822-828
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Interactions between preischemic hypothermia and cardioplegic solutions in the neonatal lamb heart

Boston, Mass.

From the Department of Cardiovascular Surgery, Children's Hospital and Harvard Medical School, Boston, Mass.

Received for publication Dec. 8, 1992. Accepted for publication Aug. 17, 1993. Address for reprints: John E. Mayer, Jr., MD, Department of Cardiovascular Surgery, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.

Abstract

Hypothermia is believed to improve the tolerance to both ischemia and cardiopulmonary bypass and is commonly used during heart operations, particularly in the neonate. However, hypothermia also causes calcium to accumulate in the myocyte experimentally, and an increase in intracellular calcium during ischemia may worsen the effect of ischemia and impair the postischemic recovery of function. This effect of hypothermia on intracellular calcium has generally not been considered in experiments that attempt to optimize the composition of cardioplegic solutions. We have evaluated the impact of hypothermia before cardioplegic ischemia on the efficacy of two common cardioplegic solutions, one with calcium (St. Thomas' Hospital cardioplegia) and the other without calcium (glucose-potassium cardioplegia), in 37 isolated blood-perfused neonatal lamb hearts. Left ventricular maximal developed pressure, positive maximum of the first derivative of left ventricular pressure, left ventricular stiffness constant at 10 mm Hg end-diastolic pressure, coronary blood flow, and myocardial oxygen consumption were measured before and 30 minutes after 2 hours of cold ischemia. After baseline measurements were made, two groups of hearts (ST-C and GK-C) had perfusion-cooling for 10 minutes to 17° C myocardial temperature, and two other groups (ST-NC and GK-NC) had the same period of normothermic perfusion. Then the hearts were arrested with 4° C St. Thomas' cardioplegia in groups ST-C and ST-NC and with glucose-potassium cardioplegia in groups GK-C and GK-NC. In the groups without preischemic cooling, both St. Thomas' (group ST-NC) and glucose-potassium (group GK-NC) cardioplegia resulted in a similar recovery of function compared with baseline levels (group ST-NC: developed pressure = 91.3% ± 9.2%, dP/dt = 88.1% ± 8.9%, left ventricular stiffness constant = 96.1% ± 3.3%; group GK-NC: developed pressure = 89.3% ± 6.9%, dP/dt = 82.6% ± 8.8%, left ventricular stiffness constant = 99.4% ± 2.0%; data are mean plus or minus the standard deviation). However, with preischemic cooling, St. Thomas' cardioplegia (group ST-C) resulted in a significantly reduced recovery of both systolic and diastolic function (developed pressure = 81.6% ± 6.2%, dP/dt = 75.1% ± 8.4%, left ventricular stiffness constant = 103.7% ± 2.7%) compared with that for both glucose-potassium cardioplegia (group GK-C: developed pressure = 92.4% ± 8.7%, dP/dt = 83.7% ± 6.0%, left ventricular stiffness constant = 100.5% ± 2.1%) and St. Thomas' cardioplegia without preischemic cooling (group ST-NC) (p < 0.05). The results suggest that hypothermia before cardioplegia has a significant impact on postischemic recovery, but that this effect is dependent on the composition of the cardioplegic solution. These effects may be related to the effects of hypothermia and ischemia on intracellular calcium homeostasis although the precise mechanisms remain unclear. However, these results emphasize the importance of considering the interactions between myocardial hypothermia before ischemia and the ischemic episode itself when the optimal composition of cardioplegic solutions for the neonatal heart is being investigated. (J THORAC CARDIOVASC SURG 1994;107:822-8)

The widespread use of cardioplegia has contributed to the improved results of cardiac operations, ^1,2 and the evolution of the composition of these solutions has been based on a large body of experimental work. ³ Most neonatal cardiac operations are done at deep hypothermia, which necessitates whole-body perfusion cooling, but most of the experimental studies on cardioplegic solutions have been done either at normothermia or without myocardial cooling before hypothermic cardioplegic ischemia. It has been documented that hypothermia causes increased levels of intracellular calcium in isolated myocytes and in isolated muscle preparations, ^4-6 and, when hypothermia is combined with ischemia, the induced intracellular accumulation of calcium may exacerbate the injury resulting from both ischemia and reperfusion. ⁷ Immature hearts may be more susceptible to the damage related to intracellular calcium overload. ^7,8 In some studies, the optimal composition of one cardioplegic solution is different for hypothermic ischemia from that for normothermic ischemia, ⁹ but the interactions between hypothermia before ischemia and cardioplegia composition remain unclear. In the present study, the impact of preischemic perfusion cooling on the efficacy of two different cardioplegic solutions was evaluated.

MATERIALS AND METHODS

Experimental preparation
An isolated blood-perfused heart preparation previously described was used to study 37 neonatal lambs (2.6 to 6.1 kg, 1 to 7 days old). ¹⁰ Coronary perfusion was established with a rollerpump–oxygenator system before isolation and removal of the heart to prevent any myocardial ischemia or hypothermia. Heparinized fresh blood derived from a donor sheep was used as the perfusate, and this was oxygenated with a mixture of 20% oxygen, 5% carbon dioxide, and 75% nitrogen by a bubble oxygenator (Bio-2; Bentley Laboratories, Inc., Santa, Ana, Calif.). Both the serum potassium and ionized calcium levels were controlled within normal ranges (4 to 5 mEq/L and 1.0 mEq/L, respectively) before a baseline equilibration period. The perfusate and the water bath were maintained at 37° C by a heater-circulator except during hypothermic phases of the experiment when ice water was circulated through the heat exchanger and the water bath. Temperatures of the perfusate, water bath, and myocardium were monitored with thermal probes. Coronary perfusion pressure was maintained constant at 60 mm Hg, except during the cooling and reperfusion periods. A latex balloon containing a pressure transducer (SPC-350, Millar Instruments, Inc., Houston, Tex.) was placed in the left ventricle (LV) through an apical stab wound to measure LV function.

Measurements
LV function was evaluated during isovolumic contraction by stepwise inflation of the intraventricular balloon as described previously. ¹⁰ The recovery of systolic function was evaluated by measuring the maximum developed pressure (DP) and positive maximum of the first derivative of LV pressure (dP/dt). The balloon volume to produce an end-diastolic pressure (EDP) of 10 mm Hg was measured to calculate the LV stiffness constant according to an equation reported by Mirsky and Parmely ¹¹ and to evaluate LV developed pressure (LVDP) and dP/dt at that constant balloon volume. Coronary blood flow was measured by an electromagnetic flowmeter (MFV-3100, Nihon Kohden Corp., Tokyo, Japan), which was connected to the venous cannula draining the coronary return. Myocardial oxygen consumption was measured before ischemia, 5 minutes into perfusion cooling, and at 15 and 30 minutes of reperfusion. Arterial and venous blood samples were collected in the beating, nonworking state. The oxygen consumption was calculated from the hemoglobin concentration and the oxygen tension and saturation measured with a blood gas analyzer (Corning model 280; Ciba-Corning, Medfield, Mass.) as previously described. ¹⁰ The need for electrical defibrillation after reperfusion was recorded in each experiment.

Experimental protocol
Baseline measurements were made after an initial 20-minute perfusion equilibration period. Both perfusate and water bath were cooled over a 10-minute period to 15° C in groups ST-C and GK-C (St = St. Thomas Hospital; GK = glucose-potassium). Groups ST-NC and GK-NC were not cooled before ischemia, but had an additional 10 minutes of normothermic perfusion instead of cooling (n = 8 for each group). Then the hearts were arrested with 20 ml/kg body weight of 4° C ST cardioplegic solution (Plegisol, Abbott Laboratories, North Chicago, Ill.) in groups ST-C and ST-NC and with GK cardioplegic solution in groups GK-C and GK-NC over 2 minutes followed by topical cold saline. A second dose of 10 ml/kg of cardioplegic solution was given after 60 minutes. The composition of the ST cardioplegic solution was 110 mmol/L NaCl, 16 mmol/L KCl, 16 mmol/L MgCl₂, and 1.2 mmol/L CaCl₂. Sodium bicarbonate 10 mmol/L was added just before use (pH 7.4 at 37° C, osmolarity 324 mOsm/L). The composition of the GK cardioplegic solution was 0.45% sodium chloride and 2.5% dextrose solution (Abbott Laboratories, North Chicago, Ill.) with 20 mmol/L potassium chloride and 6 mmol/L sodium bicarbonate (pH 7.4 at 37° C, osmolarity 360 mOsm/L). The possibility of a trace calcium contamination in the GK solution was not excluded.

The myocardial temperature between infusions of cardioplegic solution was maintained at 10° C by control of the temperature of the water bath. Reperfusion was begun with the perfusate at room temperature (25° C) and then rewarming was done over a 25-minute period. Mean coronary perfusion pressure was maintained at 20 mm Hg during the first 5 minutes, raised to 40 mm Hg during the second 5 minutes, and then kept at 60 mm Hg until the end of experiment. ¹² Another group of five hearts underwent perfusion-cooling under the same conditions except that the LV balloon was kept inflated to create an EDP of 0 mm Hg. The changes in LVDP and dP/dt during cooling were recorded. All animals received humane 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 (NIH Publication No. 86-23, revised in 1985).

All results were reported as mean plus or minus the standard deviation and analyzed by a statistical analysis system (SPSS, SPSS Inc., Berkeley, Calif.). Differences within a group were assessed by repeated one-way measures analysis of variance or paired t test, or both tests. Differences between groups were assessed by one-way analysis of variance or two-way repeated measures analysis of variance. Data were further compared by use of a Student-Newman-Keuls test if the analysis of variance was significant. A p value less than 0.05 was considered statistically significant.

RESULTS

Baseline values (Table I).
There were no statistically significant differences (analysis of variance p value >0.05) in the baseline data among the four groups. All the remaining data are reported as percentage of the baseline values.

Heart rate (Table II).

LV function (Table III).

Coronary blood flow (Table IV).

Oxygen consumption (Table V).

Need for defibrillation
The proportion of the hearts that needed defibrillation for persistent ventricular fibrillation after reperfusion (beyond 5 minutes of reperfusion) in each group was 75% in group ST-C, 12.5% in group ST-NC, 25% in group GK-C, and 37.5% in GK-NC (p = 0.08 by ² test).

DISCUSSION

Rebeyka and colleagues ^7,13 have reported that prearrest hypothermia has an adverse effect on recovery of myocardial function after ST cardioplegic ischemia and have implicated hypothermia-induced calcium accumulation as the mechanism for this effect. However, prior investigators have not addressed the relation between the effects of preischemic hypothermia and the composition of the cardioplegic solution. In the present study we found that the efficacy of ST cardioplegia was reduced significantly by myocardial perfusion-cooling before cardioplegic ischemia, but also found that, in contrast, the efficacy of the GK cardioplegia was not affected by preischemic hypothermia. These results point out the critical importance of experimental conditions (in this case, whether there is preischemic hypothermia) when the protective effects of a cardioplegic solution are being evaluated. They also imply that many cardioplegic solutions that have been developed to achieve maximum protection under experimental conditions may not have the optimal composition for clinical use, inasmuch as many research models have not included the period of preischemic myocardial cooling that is commonly used in clinical cardiac operations.

The precise mechanisms to explain our findings are unclear, but they seem likely to involve interactions among several factors including calcium homeostasis, hypothermia, and ischemia. The level of cytosolic Ca²⁺ in a normal myocyte is strictly controlled in a relatively low range (50 to 400 nmol/L) compared with the extracellular concentration (1.0 mmol/L) by the coordinated operation of several mechanisms. ¹⁴ These include (1) the Na⁺ Ca²⁺ exchange system, which moves Na⁺ and Ca²⁺ in either direction across the plasma membrane by Na⁺-Ca²⁺ exchange; (2) an adenosine triphosphate–driven Ca²⁺ pump that extrudes Ca²⁺ across the plasma membrane; (3) voltage-gated and receptor-operated Ca²⁺ channels that mediate Ca²⁺ entry from the extracellular fluid; (4) the sarcoplasmic reticulum, which sequesters Ca²⁺ by an adenosine triphosphate–driven transport mechanism and can also release Ca²⁺ back into the cytosol during cell activation; (5) mitochondria, which can also sequester Ca²⁺ by an adenosine triphosphate–dependent or oxidative metabolism-fueled transport mechanism and can release Ca²⁺ by an Na⁺-dependent (mitochondrial Na⁺/Ca²⁺exchange) or Na⁺-independent mechanism; and (6) cytosolic binding proteins, such as calmodulin, which can rapidly buffer Ca²⁺. The net direction of Ca²⁺ movement is largely determined by the Na⁺/Ca²⁺ exchange system, which is dependent on (1) the Na⁺ electrochemical gradient created by the Na⁺/ K⁺ pump and (2) the Ca²⁺ electrochemical gradient. Low extracellular sodium concentration with normal extracellular calcium concentration promotes Ca²⁺ influx via Na⁺/Ca²⁺ exchanger. ¹⁵ Potassium ion concentration also can interact with Ca²⁺ influx via the Na⁺/K⁺ pump and Na⁺/Ca²⁺ exchanger and via activation of voltage-dependent ion channels by depolarization. Magnesium ion reduces Ca²⁺ influx by inhibition of Na⁺/Ca²⁺ exchange. ¹⁶ Low pH also can inhibit Ca²⁺ influx by inhibition of Na⁺/Ca²⁺ exchange. ¹⁷ During hypothermic cardioplegic ischemia, any or all of these mechanisms for control of the cytosolic Ca²⁺ level may be affected by temperature, ischemia, and the composition of the cardioplegic solution. Passive diffusion may also contribute to ion shifts during ischemia.

The effects of hypothermia on the cell are complex. The rate of all chemical reactions is temperature dependent, but the temperature dependency of various biochemical reactions is more complex and variable than that of biophysical reactions, and thus hypothermia can change the balance of biochemical reactions in a cell, including those regulating intracellular ion concentration. ¹⁸ Hypothermic perfusion has been shown to induce elevation of cytosolic free ionized calcium ([Ca²⁺]i) in myocardium presumably because of differing sensitivities of various intracellular ion regulatory systems, such as the Na⁺/ Ca²⁺ exchanger and the Na⁺/K⁺ pump, to low temperatures. ^4-6 The positive inotropic effect and increased myocardial oxygen consumption per beat observed with hypothermia in the present study were likely a reflection of increased [Ca²⁺]i. Elevation of the [Ca²⁺]i may worsen the injury that results from ischemia and reperfusion by increasing muscle tone, and thus oxygen consumption, during ischemia and by activation of Ca²⁺-dependent degradative enzyme systems, particularly during reperfusion. ^19,20 Ischemia also contributes to intracellular Ca²⁺ accumulation by loss of energy stores that maintain the electrochemical gradients across the cell membrane.

The optimal composition of cardioplegic solutions for the neonate remains a topic of controversy. ^21-28 The composition of the ST cardioplegic solution was initially determined on the basis of numerous experiments that attempted to optimize the concentrations of various factors including pH, Ca²⁺, Mg²⁺, Na⁺, and K⁺. However, most of the experiments were done in normothermic ischemia models or in hypothermic ischemia models without perfusion cooling before cardioplegia. ²¹ Relatively poor functional recovery has been demonstrated in some experiments in neonatal compared with adult hearts with the use of the ST cardioplegic solution. ^22,29 The neonatal heart seems more susceptible to intracellular accumulation of Ca²⁺, perhaps because of a reduced capacity to sequester intracellular Ca²⁺. ^8,30,31

Our observation that the use of calcium-containing ST cardioplegic solution resulted in reduced recovery with preischemic hypothermia, whereas the non-calcium-containing GK cardioplegic solution did not, implies that the reduced recovery with preischemic hypothermia may be related to the Ca²⁺ concentration in the cardioplegic solutions. In support of this inference, Baker, Olinger, and Baker ²⁷ have reported that a reduced calcium concentration (0.3 mmol/L) in ST cardioplegic solution provided better postischemic recovery in the immature rabbit heart, although Zweng and coworkers ²⁸ reported that 1.2 mmol/L calcium concentration was optimal. We speculate that hypothermia before ischemia leads to elevated [Ca²⁺]i, and that the absence of Ca²⁺ in the GK solution prevented further Ca²⁺ accumulation. The higher level of [Ca²⁺] in ST solution may allow continued influx of Ca²⁺ during ischemia, despite the antagonistic effects of Na⁺ and Mg²⁺ in the solution.

We have not yet done experiments that use varying levels of calcium in ST cardioplegic solution in combination with preischemic hypothermia. Also, it is unclear why the results in group ST-NC (nearly complete recovery of LVDP) were different from those observed by Baker, Olinger, and Baker. ²⁷ Both species differences (lamb versus rabbit) and model differences (blood versus Krebs-Henseleit perfusate) seem likely to be involved although the precise mechanisms underlying the observed differences are speculative. These differences in outcome reemphasize the importance of the model used in assessing the efficacy of cardioplegic solutions.

We did not observe calcium paradox with the GK cardioplegic solution ³²; however, both trace amounts of calcium (0.025 mmol/L) in a cardioplegic solution ^33,34 and hypothermia ³⁵ have been reported to effectively prevent calcium paradox. The duration and volume of the calcium-free perfusate are also important factors, ¹⁶ and there is some evidence that the immature heart may be less susceptible to the phenomenon. ³⁶

Other factors besides the composition of the cardioplegic solution can interact with the effects of preischemic hypothermia. We have recently shown that the Ca²⁺ concentration in the perfusate during perfusion cooling will modify the effect of perfusion cooling. ³⁷ This finding may be clinically relevant because citrate-phosphate-dextrose blood (which has a low [Ca²⁺]) is often used as a part of pump-oxygenator priming in the clinical situation, especially in neonates. ³⁷ The acid-base strategy during cooling and systemic response to hypothermia may further modify these effects. These additional factors may limit the application of the present findings to the more complex clinical situation. Finally, it should be recalled that the vascular smooth muscle in the coronary vasculature is sensitive to extracellular [Ca²⁺]. ¹⁴ We have noted increased coronary vascular resistance during preischemic cooling with normal plasma [Ca²⁺] levels and reduced resistance when the [Ca²⁺] level was lowered in our previous study. ³⁷ In the current study, all hearts were perfused with blood having a normal plasma [Ca²⁺] level during the preischemic and reperfusion periods. Postischemic coronary blood flow tended to be higher in the GK without preischemic cooling group, although the difference was not statistically significant. The effects of various cardioplegic solutions on the coronary vasculature have not been well studied, and the role of vascular events in the current experiments is unclear.

The intent of this study was not to propose the superiority of the GK solution for neonatal myocardial protection. However, one possible inference from this study is that calcium concentration in the present ST solution may be higher than is optimal in the presence of hypothermia before and during ischemia. Robinson and Harwood ⁹ reached similar conclusions in a study of hypothermic ischemia in adult rats and Baker, Olinger, and Baker ²⁷ reported similar results in immature rabbits. These findings contrast with those of Zweng and colleagues, ²⁸ although their experiments were conducted in crystalloid-perfused hearts subjected to normothermic ischemia. There are likely to be other mechanisms besides control of intracellular calcium that affect the efficacy of cardioplegia, and there may be species differences that limit the applicability of data in the neonatal lamb to the human neonate. Further dose-response studies with a more clinically relevant model are needed to determine the optimal composition of the cardioplegic solution for the neonatal heart.

CONCLUSIONS

The results of the present study reinforce the concept that myocardial perfusion cooling before cardioplegic ischemia may have a significant impact on the protective effects of cardioplegic solution in the neonatal lamb heart. The optimal composition of cardioplegic solution for the neonatal heart may need to be reevaluated considering this effect. Most important, however, this study demonstrates the potential for unanticipated interactions between variables such as hypothermia, cardioplegia, calcium, and ischemia and reemphasizes the importance of carefully considering the differences between the experimental model and clinical model before extrapolating experimental results to clinical practice.

Acknowledgments

We thank Mark A. Cioffi, MAT, for his technical assistance and Ms. Susan Purkis for preparing the manuscript.

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