Metabolic enhancement of myocardial preservation during cardioplegic arrest

An experimental study was undertaken to evaluate the relative efficacy of oxygenated versus unoxygenated cardioplegic solutions and to determine if the addition of certain metabolically active substrates to cardioplegic solutions had any effect on myocardial preservation. Sixty-one pigs were divided into seven groups of animals (5 to 15 animals per group). The impact of different cardioplegic vehicles, i.e., crystalloid versus the oxygen-carrying vehicles, blood and Fluosol-DA, on preservation of high-energy phosphates (adenosine triphosphate and creatine phosphate) was examined in the first three animal groups. The influence of Krebs cycle intermediates, i.e., glutamate, malate, succinate and fumarate, on adenosine triphosphate and creatine phosphate preservation was evaluated in the other four animal groups. All hearts underwent 120 minutes of hypothermic cardioplegic arrest at 15 degrees C followed by 60 minutes of normothermic reperfusion. Higher adenosine triphosphate and creatine phosphate levels were maintained during arrest when oxygenated solutions were used as the cardioplegic vehicle and when any of the four intermediates were added to the crystalloid cardioplegic solution, especially succinate and fumarate. During reperfusion, however, adenosine triphosphate levels were uniformly lower than control whereas creatine phosphate levels rose to either control levels or higher in all groups. No significant intergroup difference could be identified during reperfusion. These findings lead to the conclusion that the presence of either oxygen or certain Krebs cycle intermediates enhances the protective effect of hyperkalemic hypothermic cardioplegia on high-energy phosphates during the arrest period only. This enhancement is not maintained during the reperfusion period.     

Oxygen requirements of the isolated rat heart during hypothermic cardioplegia. Effect of oxygenation on metabolic and functional recovery after five hours of arrest

Previous studies from this laboratory demonstrated that the use of an oxygenated cardioplegic solution in the hypothermic arrested rat heart resulted in improved preservation of high-energy phosphate stores (adenosine triphosphate and creatine phosphate), mechanical recovery during reperfusion, and preservation of myocardial ultrastructure. In the current study the effect of cardioplegic solutions oxygenated with 30%, 60%, and 95% oxygen was evaluated in the isolated rat heart with reference to the maintenance of adenosine triphosphate, creatine phosphate, oxygen consumption, functional recovery, and mitochondrial oxidative phosphorylation in vitro. Results indicate that the hearts receiving cardioplegic solutions supplemented with 95% oxygen and 5% carbon dioxide maintained adenosine triphosphate and creatine phosphate at control values for at least 5 hours. The oxygen consumption during elective cardiac arrest, mechanical performance during reperfusion, and in vitro mitochondrial oxygen uptake and phosphorylation rate were highest in the hearts receiving cardioplegic solutions supplemented with 95% oxygen when compared to solutions with 30% and 60% oxygen. Addition of glucose and insulin to the cardioplegic solution (95% oxygen) increased the adenosine triphosphate levels but failed to improve function after reperfusion. Although myocardial adenosine triphosphate and creatine phosphate were well preserved by the oxygenated cardioplegic solution, there was a discrepancy between the adenosine triphosphate levels at the end of the arrest period, which represents the potential for mechanical function, and the actual function of the hearts after 5 hours.     

Optimal myocardial preservation with an acalcemic crystalloid cardioplegic solution

The effect of the calcium and oxygen contents of a hyperkalemic glucose-containing cardioplegic solution on myocardial preservation was examined in the isolated working rat heart. The cardioplegic solution was delivered at 4 degrees C every 15 minutes during 2 hours of arrest, maintaining a myocardial temperature of 8 degrees +/- 2 degrees C. Hearts were reperfused in the Langendorff mode for 15 minutes and then resumed the working mode for a further 30 minutes. Groups of hearts were given the oxygenated cardioplegic solution containing an ionized calcium concentration of 0, 0.25, 0.75, or 1.25 mmol/L or the same solution nitrogenated to reduce the oxygen content and containing 0 or 0.75 mmol ionized calcium per liter. The myocardial adenosine triphosphate concentrations at the end of arrest in these six groups of hearts were 15.6 +/- 1.2, 9.5 +/- 0.5, 8.2 +/- 1.1, 4.9 +/- 1.8, 10.1 +/- 2.0, and 1.6 +/- 0.4 nmol/mg dry weight, respectively. At 5 minutes of working reperfusion, the percentages of prearrest aortic flow were 80 +/- 2, 62 +/- 4, 33 +/- 6, 37 +/- 5, 48 +/- 7 and 46 +/- 8, respectively. The differences among the groups in adenosine triphosphate concentrations and in functional recovery diminished during reperfusion. In hearts given the hypoxic calcium-containing solution, there was a marked increase in coronary vascular resistance during the administration of successive doses of cardioplegic solution, which was rapidly reversible upon reperfusion. These data indicate that hearts given the acalcemic oxygenated solution had better adenosine triphosphate preservation during arrest and better functional recovery than hearts in any other group. Addition of calcium to the oxygenated cardioplegic solution decreased adenosine triphosphate preservation and functional recovery. Oxygenation of the acalcemic solution increased adenosine triphosphate preservation and functional recovery. The lowest adenosine triphosphate levels at end arrest were observed in hearts given the hypoxic calcium-containing solution. In the setting of hypothermia and multidose administration, the addition of calcium to a cardioplegic solution resulted in increased energy depletion during arrest and depressed recovery.     

Effect of oxygenated crystalloid cardioplegia on the functional and metabolic recovery of the isolated perfused rat heart

The use of an oxygenated crystalloid cardioplegic solution to improve myocardial preservation during elective cardiac arrest was evaluated with the isolated perfused rat heart used as a model. Experiments were conducted at 4 degrees C and 20 degrees C. The oxygen tension of the nonoxygenated and oxygenated cardioplegic solutions averaged 117 and 440 mm Hg, respectively. At 4 degrees C, the adenosine triphosphate content of hearts subjected to 120 minutes of oxygenated cardioplegia was significantly higher than that of the nonoxygenated cardioplegia group. However, functional recovery during reperfusion was similar for both groups. At 20 degrees C, the myocardial adenosine triphosphate concentration decreased at a significantly faster rate during ischemia in the group receiving nonoxygenated cardioplegia compared with the oxygenated cardioplegia group. Hearts subjected to 180 minutes of ischemia with oxygenated cardioplegia had a normal ultrastructural appearance whereas hearts subjected to 120 minutes of nonoxygenated cardioplegia showed severe ischemic damage. Myocardial functional recovery in the group receiving oxygenated cardioplegia exceeded that of the group receiving nonoxygenated cardioplegia. The use of myocardial adenosine triphosphate concentration at the end of the ischemic period to predict subsequent cardiac output, peak systolic pressure, and total myocardial work showed significant positive correlations.     

Benefits of glucose and oxygen in multidose cold cardioplegia.

We tested the effects of glucose and oxygen in cardioplegic solutions on myocardial protection in the isolated perfused working rat heart. Recovery from 2 hours' hypothermic (8 degrees C) cardioplegic arrest was examined in 93 hearts. Cardioplegic solution, which was delivered every 15 minutes, was supplemented with glucose 28 mmol/L as a substrate or sucrose 28 mmol/L as a nonmetabolizable osmotic control; it was equilibrated with either 98% oxygen or 98% nitrogen, both with 2% carbon dioxide. Four combinations of hyperkalemic cardioplegic solution were studied: nitrogen-sucrose, nitrogen-glucose, oxygen-sucrose, and oxygen-glucose. During hypothermic arrest, oxygenation of cardioplegic solution greatly reduced myocardial lactate production and prevented ischemic contracture as indicated by coronary vascular resistance. Glucose increased lactate production modestly but significantly only when the cardioplegic solution was nitrogenated. Although end-arrest myocardial adenosine triphosphate and creatine phosphate were greatly increased by oxygenation of cardioplegic solution (p less than 0.005), we could not detect improved preservation of these high-energy phosphates by glucose. Averaged over reperfusion, percent recovery of cardiac output for the nitrogen-sucrose, nitrogen-glucose, oxygen-sucrose, and oxygen-glucose solutions was 32.3% +/- 6.1%, 45.9% +/- 4.6%, 44.5% +/- 4.6%, and 62.2% +/- 4.5%, respectively. Oxygenation of the glucose solution or addition of glucose to the oxygenated solution significantly improved recovery of cardiac output. The benefits of glucose and oxygen were additive, so that the oxygen-glucose cardioplegic solution provided the best functional recovery. We conclude that the addition of glucose to the fully oxygenated multidose cold cardioplegic solution improves functional recovery without increasing lactate production during arrest.     

Myocardial preservation related to magnesium content of hyperkalemic cardioplegic solutions at 8 degrees C

This study investigates whether the addition of magnesium to a hyperkalemic cardioplegic solution containing 0.1 mM ionized calcium improves myocardial preservation, and whether there is an optimal magnesium concentration in this solution. Isolated perfused rat hearts were arrested for two hours by this cardioplegic solution, which was fully oxygenated and infused at 8 degrees C every 15 minutes to simulate clinical conditions. The cardioplegic solution contained either 0, 2, 4, 8, 16, or 32 mM magnesium. At end-arrest, the myocardial creatine phosphate concentration (nanomoles per milligram of dry weight) was 20.7 +/- 2.1, 22.9 +/- 1.7, 24.8 +/- 2.0, 31.3 +/- 1.4, 33.1 +/- 1.8, and 31.6 +/- 0.8, respectively, in hearts given cardioplegic solution containing these magnesium concentrations. Thus, the concentration of creatine phosphate was significantly higher at end-arrest when the cardioplegic solution contained 8, 16, or 32 mM than 0 or 2 mM magnesium (p less than 0.002) or 4 mM magnesium (p less than 0.02), and highest with 16 mM magnesium. Also, creatine phosphate was more sensitive to the magnesium concentration of the cardioplegic solution than was end-arrest adenosine triphosphate levels, which did not differ among the experimental groups. Aortic flow, expressed as a percentage of prearrest aortic flow, was 60.3 +/- 5.0, 70.2 +/- 5.5, 71.6 +/- 4.4, 71.8 +/- 4.8, 81.0 +/- 5.0, and 71.8 +/- 5.3, respectively. The addition of magnesium to the cardioplegic solution improved recovery of aortic flow (p less than 0.05, 16 mM versus 0 mM magnesium). We conclude from these data that with deep myocardial hypothermia and at an ionized calcium concentration of 0.1 mM, the addition of magnesium, over a broad concentration range, improved preservation of myocardial creatine phosphate and, at a concentration of 16 mM, improved aortic flow. The optimal magnesium concentration in the cardioplegic solution was 16 mM.     

Enhanced myocardial protection with high-energy phosphates in St. Thomas' Hospital cardioplegic solution. Synergism of adenosine triphosphate and creatine phosphate

The potential for improving myocardial protection with the high-energy phosphates adenosine triphosphate and creatine phosphate was evaluated by adding them to the St. Thomas' Hospital cardioplegic solution in the isolated, working rat heart model of cardiopulmonary bypass and ischemic arrest. Dose-response studies with an adenosine triphosphate range of 0.05 to 10.0 mmol/L showed 0.1 mmol/L to be the optimal concentration for recovery of aortic flow and cardiac output after 40 minutes of normothermic (37 degrees C) ischemic arrest (from 24.1% +/- 4.4% and 35.9% +/- 4.1% in the unmodified cardioplegia group to 62.6% +/- 4.7% and 71.0% +/- 3.0%, respectively, p less than 0.001). Adenosine triphosphate at its optimal concentration (0.1 mmol/L) also reduced creatine kinase leakage by 39% (p less than 0.001). Postischemic arrhythmias were also significantly reduced, which obviated the need for electrical defibrillation and reduced the time to return of regular rhythm from 7.9 +/- 2.0 minutes in the control group to 3.5 +/- 0.4 minutes in the adenosine triphosphate group. Under more clinically relevant conditions of hypothermic ischemia (20 degrees C, 270 minutes) with multidose (every 30 minutes) cardioplegia, adenosine triphosphate addition improved postischemic recovery of aortic flow and cardiac output from control values of 26.8% +/- 8.4% and 35.4% +/- 6.3% to 58.0% +/- 4.7% and 64.4% +/- 3.7% (p less than 0.01), respectively, and creatine kinase leakage was significantly reduced. Parallel hypothermic ischemia studies (270 minutes, 20 degrees C) using the previously demonstrated optimal creatinine phosphate concentration (10.0 mmol/L) gave nearly identical improvements in recovery and enzyme leakage. The combination of the optimal concentrations of adenosine triphosphate and creatine phosphate resulted in even greater myocardial protection; aortic flow and cardiac output improved from their control values of 26.8% +/- 8.4% and 35.4% +/- 6.3% to 79.7% +/- 1.1 and 80.7% +/- 1.0% (p less than 0.001), respectively. In conclusion, both extracellular adenosine triphosphate and creatine phosphate alone markedly improve the cardioprotective properties of the St. Thomas' Hospital cardioplegic solution during prolonged hypothermic ischemic arrest, but together they act additively to provide even greater protection.     

Improved myocardial recovery after cardioplegic arrest with an oxygenated crystalloid solution

Possible enhancement of myocardial protection by oxygenation of a crystalloid cardioplegic solution was evaluated in a three-part study. In Part I, canine hearts underwent ischemia followed by heterogeneous cardioplegic arrest for 45 to 60 minutes. Oxygenation led to improved recovery in the left anterior descending region (47% versus 86% recovery, p less than 0.05) (15 minutes of ischemia) and in the circumflex region (9.5% versus 52% recovery, p less than 0.05) (30 minutes of ischemia). Part II was a blind prospective randomized study in 12 patients. It examined creatine kinase, myoglobin, and lactate as well as coronary sinus flow, oxygen consumption, and cardiac work 1 hour after aortic cross-clamping during atrial and during ventricular pacing. No significant difference was demonstrable between control and oxygenated solutions. In Part III, 57 coronary bypass patients were protected with a nonoxygenated solution while 94 patients received an identical oxygenated solution. Twelve-hour creatine kinase levels were similar in the nonoxygenated (9.5 +/- 16 IU, +/- standard deviation) and oxygenated (11 +/- 22 IU) groups if the cross-clamp interval was 28 minutes or less. In patients subjected to longer than 28 minutes of arrest, the 12 hour creatine kinase MB levels were more than twice as high in the nonoxygenated group (26.5 +/- 26 IU) compared to the oxygenated group (9.9 +/- 14 IU, p less than 0.05). In this canine model of heterogeneous cardioplegia and in the routine conduct of coronary bypass operations, oxygenated crystalloid cardioplegia is superior to an identical nonoxygenated solution.     

Enhanced myocardial preservation by nicotinic acid, an antilipolytic compound. Improved cardiac performance after hypothermic cardioplegic arrest

The effect of nicotinic acid, an antilipolytic drug, on myocardial preservation was studied on the basis of cardiac performance after 2 hours of cardioplegic arrest. Isolated in situ pig hearts were subjected to 120 minutes of hypothermic potassium (35 mEq) crystalloid cardioplegic arrest followed by 60 minutes of reperfusion. The experimental group received nicotinic acid 0.08 mmol/L 15 minutes before cardioplegic arrest, whereas the control group received 15 minutes of unmodified perfusion. There was a marked decline in myocardial creatine phosphate levels during cardioplegic arrest in both groups that returned to the baseline level during reperfusion without a significant intergroup difference, and adenosine triphosphate levels remained stable throughout the experiment in both groups. Myocardial oxygen consumption during reperfusion was significantly higher in hearts treated with nicotinic acid, which was consistent with a significantly greater cardiac contractile force as evaluated by isovolumetric left ventricular pressure measurements. There appeared to be less cardiac membrane damage as measured by creatine kinase release during reperfusion, which was significantly inhibited by treatment with nicotinic acid. The present study supports the conclusion that nicotinic acid improves cardiac performance after hypothermic cardioplegic arrest.     

Captopril-induced glutamate release at the start of reperfusion after cold cardioplegic storage of pig hearts

OBJECTIVE: We sought to evaluate the effects of captopril on glucose-related metabolism during hypothermic cardioplegic storage and subsequent reperfusion. METHODS: We compared hearts from control pigs with hearts from pigs treated with increasing oral doses of captopril for 3 weeks (12.5-150 mg daily), an intravenous bolus (25 mg) before operation, and captopril-containing cardioplegic solution (1 mg/L). The hearts were excised after infusion of cold crystalloid cardioplegic solution and stored in saline solution (4 degrees C-6 degrees C). In one series we studied myocardial blood flow and arteriovenous differences in oxygen, glucose, lactate, glutamate, and alanine during 60 minutes of postcardioplegic blood reperfusion. In this series captopril-treated hearts were reperfused with captopril-containing blood (1 mg/L). In another series we obtained biopsy specimens from the left ventricle throughout 30 hours of hypothermic cardioplegic storage and monitored tissue content of energy-rich phosphates, glycogen, glutamate, and alanine. RESULTS: Captopril increased glutamate and alanine release 11- to 17-fold at the start of reperfusion (P <.001). Furthermore, captopril increased myocardial oxygen and glucose uptake during reperfusion (P <.001 for both), whereas lactate release and myocardial blood flow were unaffected by captopril. At the start of reperfusion, there was a positive correlation between glutamate release and glucose uptake in captopril-treated hearts (r = 0.66, P =.05). We found no statistically significant differences between captopril and control hearts in tissue content of adenosine triphosphate, glycogen, glutamate, alanine, or lactate during 30 hours of cardioplegic storage. CONCLUSIONS: The metabolic effects of captopril are strictly related to reperfusion, during which oxidative metabolism of glucose is improved. The captopril-induced increase in glutamate and alanine release at the start of reperfusion after cardioplegic storage may reflect a switch in metabolism of glucose-related amino acids.     

Effect of an oxygen-enriched solution and multiple dosing of antegrade crystalloid cardioplegic solution on myocardial metabolism during coronary artery bypass graft operations.

The metabolic effect of excessive oxygenation and frequency of administration of antegrade crystalloid cardioplegic solution was assessed in 33 patients undergoing routine coronary artery bypass graft operations. Four patient groups were designed in which the initial aortic root injection was 1000 ml and then 100 ml administered through the vein grafts after completion of each distal anastomosis. The groups were divided as follows: group 1, single dose, normally oxygenated cardioplegic solution infused via the aortic root; group 2, single dose, high oxygen content cardioplegic solution infused via the aortic root; group 3, normally oxygenated cardioplegic solution with additional 250 ml doses via the aortic root every 20 minutes; group 4, high oxygen content cardioplegic solution with additional 250 ml doses via the aortic root every 20 minutes. In all groups myocardial mean septal temperature showed an immediate fall to approximately 11 degrees C with the initial aortic root doses and then a gradual rewarming to approximately 20 degrees C during the crossclamp period (mean 58.6 minutes). Metabolic parameters measured or calculated from the coronary sinus effluent were myocardial oxygen extraction, lactate production, base deficit, inorganic phosphate, glucose, potassium, creatine kinase (total and myocardial band fraction), and catecholamine production. There was no statistically significant difference in any of these determinations between each patient group. Furthermore, myocardial recovery, myocardial performance, and postoperative recovery characteristics were not different. We conclude that single or multidose aortic root crystalloid cardioplegic solution (either oxygen enriched or normally oxygenated) is equally effective in routine coronary artery bypass graft operations when septal temperatures are maintained between 15 degrees and 21 degrees C for a total arrest time of 60 minutes or less. In this study, increasing the volume cardioplegic solution given in multiple doses appeared to offer no significant metabolic or functional advantage in patients without complications who had satisfactory left ventricular function.     

The effect of temperature and hematocrit level of oxygenated cardioplegic solutions on myocardial preservation

The ideal temperature and hematocrit level of blood cardioplegia has not been clearly established. This study was undertaken (a) to determine the optimal temperature of blood cardioplegia and (b) to study the effect of hematocrit levels in blood cardioplegia. A comparison of myocardial preservation was done among seven groups of animals on the basis of variations in hematocrit levels and temperature of oxygenated cardioplegic solution. The experimental protocol consisted of a 2-hour hypothermic cardioplegic arrest followed by 1 hour of normothermic reperfusion. Group 1 received oxygenated crystalloid cardioplegic solution at 10 degrees C. Groups 2 through 7 received oxygenated blood cardioplegic solution with the following hematocrit values and temperatures: (2) 10%, 10 degrees C; (3) 10%, 20 degrees C; (4) 10%, 30 degrees C; (5) 20%, 10 degrees C; (6) 20%, 20 degrees C; and (7) 20%, 30 degrees C. Parameters studied include coronary blood flow, myocardial oxygen extraction, myocardial oxygen consumption, and myocardial high-energy phosphate levels of adenosine triphosphate and creatine phosphate during control (prearrest), arrest, and reperfusion. Myocardial oxygen consumption at 30 degrees C during arrest was significantly higher than at 10 degrees C and 20 degrees C, which indicates continued aerobic metabolic activity at higher temperature. Myocardial oxygen consumption and the levels of adenosine triphosphate and creatine phosphate during reperfusion were similar in all seven groups. Myocardial oxygen extraction (a measure of metabolic function after ischemia) during initial reperfusion was significantly lower in the 30 degrees C blood group than in the 10 degrees C blood group at either hematocrit level and in the oxygenated crystalloid group, which suggests inferior preservation. The hematocrit level of blood cardioplegia did not affect adenosine triphosphate or myocardial oxygen consumption or extraction. It appears from this study that blood cardioplegia at 10 degrees C and oxygenated crystalloid cardioplegia at 10 degrees C are equally effective. Elevating blood cardioplegia temperature to 30 degrees C, however, reduces the ability of the solution to preserve metabolic function regardless of hematocrit level. Therefore, the level of hypothermia is important in blood cardioplegia, whereas hematocrit level has no detectable impact, and cold oxygenated crystalloid cardioplegia is as effective as hypothermic blood cardioplegia.     

Long-term preservation of explanted hearts perfused with L-aspartate-enriched cardioplegic solution. Improved function, metabolism, and ultrastructure.

The effects of supplementing oxygenated St. Thomas' Hospital cardioplegic solution No. 2 with L-aspartate and/or D-glucose for the long-term preservation of excised rat hearts were determined with isolated working heart preparations. Left ventricular function was assessed at 37 degrees C with a crystalloid perfusate, before cardioplegic arrest and after 20 hours of low-flow perfusion (1.5 ml/min) with continuing arrest at 4 degrees C, and after this period, again at 37 degrees C with a crystalloid perfusate. Four groups (n = 8/group) of hearts were studied with four cardioplegic solutions: St. Thomas' Hospital solution alone, St. Thomas' Hospital solution with aspartate 20 mmol/L, St. Thomas' Hospital solution with glucose 20 mmol/L, and St. Thomas' Hospital solution plus both aspartate and glucose (20 mmol/L each). The addition of glucose to St. Thomas' Hospital solution made no significant difference in the recovery of aortic flow rates (17.7% +/- 8.6% and 21.6% +/- 7.8% of prearrest values), but when aspartate or aspartate and glucose were present, hearts showed significant improvements (89.8% +/- 5.2% and 85.0% +/- 6.2%, respectively). These improvements were associated with a reduction in the decline of myocardial high-energy phosphates during reperfusion, a reduction in cellular uptake of Na+ and Ca++, and a reduction in ultrastructural damage. These results indicate that low-flow perfusion with St. Thomas' Hospital solution plus aspartate can considerably extend the duration of safe storage of explanted hearts.     

Protection of the hypertrophied pig myocardium. A comparison of crystalloid, blood, and Fluosol-DA cardioplegia during prolonged aortic clamping

The myocardial protective effects of crystalloid, blood, and Fluosol-DA-20% cardioplegia were compared by subjecting hypertrophied pig hearts to 3 hours of hypothermic (10 degrees to 15 degrees C), hyperkalemic (20 mEq/L) cardioplegic arrest and 1 hour of normothermic reperfusion. Left ventricular hypertrophy was created in piglets by banding of the ascending aorta, with increase of the left ventricular weight-body weight ratio from 3.01 +/- 0.2 gm/kg (control adult pigs) to 5.50 +/- 0.2 gm/kg (p less than 0.001). An in vivo isolated heart preparation was established in 39 grown banded pigs, which were divided into three groups to receive aerated crystalloid (oxygen tension 141 +/- 4 mm Hg), oxygenated blood (oxygen tension 584 +/- 41 mm Hg), or oxygenated Fluosol-DA-20% (oxygen tension 586 +/- 25 mm Hg) cardioplegic solutions. The use of crystalloid cardioplegia was associated with the following: a low cardioplegia-coronary sinus oxygen content difference (0.6 +/- 0.1 vol%), progressive depletion of myocardial creatine phosphate and adenosine triphosphate during cardioplegic arrest, minimal recovery of developed pressure (16% +/- 8%) and its first derivative (12% +/- 7%), and marked structural deterioration during reperfusion. Enhanced oxygen uptake during cardioplegic infusions was observed with blood cardioplegia (5.0 +/- 0.3 vol%), along with excellent preservation of high-energy phosphate stores and significantly improved postischemic left ventricular performance (developed pressure, 54% +/- 4%; first derivative of left ventricular pressure, 50% +/- 5%). The best results were obtained with Fluosol-DA-20% cardioplegia. This produced a high cardioplegia-coronary sinus oxygen content difference (5.8 +/- 0.1 vol%), effectively sustained myocardial creatine phosphate and adenosine triphosphate concentrations during the extended interval of arrest, and ensured the greatest hemodynamic recovery (developed pressure, 81% +/- 6%, first derivative of left ventricular pressure, 80% +/- 10%) and the least adverse morphologic alterations during reperfusion. It is concluded that oxygenated Fluosol-DA-20% cardioplegia is superior to oxygenated blood and especially aerated crystalloid cardioplegia in protecting the hypertrophied pig myocardium during prolonged aortic clamping.     

Adenosine and lidocaine: a new concept in nondepolarizing surgical myocardial arrest, protection, and preservation

OBJECTIVE: Depolarizing potassium cardioplegia has been increasingly linked to left ventricular dysfunction, arrhythmia, and microvascular damage. We tested a new polarizing normokalemic cardioplegic solution employing adenosine and lidocaine as the arresting, protecting, and preserving cardioprotective combination. Adenosine hyperpolarizes the myocyte by A1 receptor activation, and lidocaine blocks the sodium fast channels. METHODS: Isolated perfused rat hearts were switched from the working mode to the Langendorff (nonworking) mode and arrested for 30 minutes, 2 hours, or 4 hours with 200 micromol/L adenosine and 500 micromol/L lidocaine in Krebs-Henseleit buffer (10 mmol/L glucose, pH 7.7, at 37 degrees C) or modified St Thomas' Hospital solution no. 2, both delivered at 70 mm Hg and 37 degrees C (arrest temperature 22 degrees C to 35 degrees C). RESULTS: Adenosine and lidocaine hearts achieved faster mechanical arrest in (25 +/- 2 seconds, n = 23) compared with St Thomas' Hospital solution hearts (70 +/- 5 seconds, n = 24; P=.001). After 30 minutes of arrest, both groups developed comparable aortic flow at approximately 5 minutes of reperfusion. After 2 and 4 hours of arrest (cardioplegic solution delivered every 20 minutes for 2 minutes at 37 degrees C), only 50% (4 of 8) and 14% (1 of 7) of St Thomas' Hospital solution hearts recovered aortic flow, respectively. All adenosine and lidocaine hearts arrested for 2 hours (n = 7) and 4 hours (n = 9) recovered 70% to 80% of their prearrest aortic flows. Similarly, heart rate, systolic pressures, and rate-pressure products recovered to 85% to 100% and coronary flows recovered to 70% to 80% of prearrest values. Coronary vascular resistance during delivery of cardioplegic solution was significantly lower (P <.05) after 2 and 4 hours in hearts arrested with adenosine and lidocaine cardioplegic solution compared with hearts arrested with St Thomas' Hospital solution. CONCLUSIONS: We conclude that adenosine and lidocaine polarizing cardioplegic solution confers superior cardiac protection during arrest and recovery compared with hyperkalemic depolarizing St Thomas' Hospital cardioplegic solution.     

Studies of myocardial protection in the immature heart. V. Safety of prolonged aortic clamping with hypocalcemic glutamate/aspartate blood cardioplegia

This study tests the hypothesis that multidose, hypocalcemic aspartate/glutamate-enriched blood cardioplegia provides safe and effective protection during prolonged aortic clamping of immature hearts. Of 17 puppies (6 to 8 weeks of age, 3 to 5 kg) placed on vented cardiopulmonary bypass, five were subjected to 60 minutes of 37 degrees C global ischemia without cardioplegic protection and seven underwent 120 minutes of aortic clamping with 4 degrees C multidose aspartate/glutamate-enriched blood cardioplegia ([Ca++] = 0.2 mmol/L), preceded and followed by 37 degrees C blood cardioplegic induction and reperfusion. Five puppies underwent blood cardioplegic perfusion for 10 minutes without intervening ischemia to assess the effect of the cardioplegic solution and the delivery techniques. Left ventricular performance was assessed 30 minutes after bypass was discontinued (Starling function curves). Hearts were studied for high-energy phosphates and tissue amino acids. One hour of normothermic ischemia resulted in profound functional depression, with peak stroke work index only 43% of control (0.7 +/- 0.1 versus 1.7 +/- 0.2 gm x m/kg, p less than 0.05). There was 70% depletion of adenosine triphosphate (7.6 +/- 1 versus control 20.3 +/- 1 mumol/gm dry weight, p less than 0.05) and 75% glutamate loss (6.6 +/- 1 versus control 26.4 +/- 3 mumol/gm, p less than 0.05). In contrast, after 2 hours of aortic clamping with multidose blood cardioplegia preceded and followed by 37 degrees C blood cardioplegia, there was complete recovery of left ventricular function (peak stroke work index 1.6 +/- 0.2 gm x m/kg) and maintenance of adenosine triphosphates, glutamate, and aspartate levels at or above control levels adenosine triphosphate 18 +/- 2 mumol/gm, aspartate 21 +/- 1 versus control 2 mumol/gm, and glutamate 25.4 +/- 2 mumol/gm). Puppy hearts receiving blood cardioplegic perfusion without ischemia had complete recovery of control stroke work index. We conclude that methods of myocardial protection used in adults, with amino acid-enriched, reduced-calcium blood cardioplegia, can be applied safely to the neonatal heart and allow for complete functional and metabolic recovery after prolonged aortic clamping.     

Cold blood as the vehicle for potassium cardioplegia

Cold blood with potassium, 34 mEq/L, was compared with cold blood and with a cardioplegic solution. Three groups of 6 dogs had 2 hours of aortic cross-clamp while on total bypass at 28 degrees C with the left ventricle vented. An initial 5-minute coronary perfusion was followed by 2 minutes of perfusion every 15 minutes for the cardioplegic solution (8 degrees C) and every 30 minutes for 3 minutes with cold blood or cold blood with potassium (8 degrees C). Hearts receiving cold blood or cold blood with potassium had topical cardiac hypothermia with crushed ice. Peak systolic pressure, rate of rise of left ventricular pressure, maximum velocity of the contractile element, pressure volume curves, coronary flow, coronary flow distribution, and myocardial uptake of oxygen, lactate, and pyruvate were measured prior to ischemia and 30 minutes after restoration of coronary flow. Myocardial creatine phosphate (CP), adenosine triphosphate (ATP), and adenosine diphosphate (ADP) were determined at the end of ischemia and after recovery. Changes in coronary flow, coronary flow distribution, and myocardial uptake of oxygen and pyruvate were not significant. Peak systolic pressure and lactate uptake declined significantly for hearts perfused with cold blood but not those with cold blood with potassium. ATP and ADP were lowest in hearts perfused with cardioplegic solution, and CP and ATP did not return to control in any group. Heart water increased with the use of cold blood and cardioplegic solution. Myocardial protection with cold blood with potassium and topical hypothermia has some advantages over cold blood and cardioplegic solution.     

Fatty acids suppress recovery of heart function after hypothermic perfusion

Working rat hearts were perfused for 15 minutes at 37 degrees C before switching to a Langendorff perfusion (60 mm Hg aortic pressure) at 10 degrees C for 40 minutes of hypothermic arrest. Ventricular function was allowed to recover for 15 minutes at 37 degrees C by reestablishing the prehypothermic conditions. The perfusate was Krebs-Henseleit bicarbonate buffer containing 3% bovine serum albumin and either glucose (11 mmol/L) or glucose (11 mmol/L) plus palmitate (1.2 mmol/L) and gassed with 95% O2 and 5% CO2. In hearts receiving glucose alone as substrate, coronary flow was maintained constant during the 40 minutes of hypothermic arrest and returned to prehypothermic rates with rewarming. Ventricular function, as estimated by peak systolic pressure and heart rate, recovered to the prehypothermic level. When palmitate was added, coronary flow decreased continuously throughout the hypothermic perfusion (22% decrease by 40 minutes), and ventricular pressure development was lower throughout the rewarming perfusion. Tissue levels of adenosine triphosphate and creatine phosphate were well maintained and long-chain acyl coenzyme A and acyl carnitine decreased during hypothermia regardless of the substrate provided. With rewarming, tissue levels of adenosine triphosphate and creatine phosphate decreased in those hearts receiving palmitate. Omission of fatty acid either during hypothermia or during the first 5 minutes of rewarming improved recovery of function. Addition of oxfenicine to inhibit fatty acid oxidation, or inhibition of Ca2+ overload by verapamil and low perfusate Ca2+, prevented the effects of palmitate on ventricular function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retrograde coronary sinus perfusion prevents infarct extension during intraoperative global ischemic arrest

To determine whether continuous infusion of cardioplegia retrograde through the coronary sinus could improve the salvage of infarcting myocardium, 54 pigs were utilized in a region at risk model. All hearts underwent 30 minutes of reversible coronary artery occlusion, and were divided into six groups. Group 1 served as controls and underwent two hours of coronary reflow without global ischemic arrest. The remaining five groups were subjected to 45 minutes of cardioplegia-induced hypothermic arrest followed by two hours of normothermic reflow. Group 2 had a single infusion of crystalloid cardioplegia, and Group 3 received an oxygenated perfluorocarbon cardioplegic solution initially and again after 20 minutes of ischemia. After initial cardiac arrest with crystalloid cardioplegia, all hearts in Groups 4, 5, and 6 underwent a continuous infusion of a cardioplegic solution retrograde through the coronary sinus. Group 4 received a nonoxygenated crystalloid cardioplegic solution, Group 5 received an oxygenated crystalloid cardioplegic solution, and Group 6 received an oxygenated perfluorocarbon cardioplegic solution. With results expressed as the percent of infarcted myocardium within the region at risk, Group 2 hearts, which received only antegrade cardioplegia, had a mean infarct size of 44.8 +/- 6.3%, a 2.2-fold increase over controls (p less than 0.05). While antegrade delivery of oxygenated perfluorocarbon cardioplegia (Group 3) and coronary sinus perfusion with nonoxygenated crystalloid cardioplegia (Group 4) limited infarct size to 33.6 +/- 4.7% and 35.3 +/- 5.4%, respectively, only oxygenated cardioplegia delivered retrograde through the coronary sinus (Groups 5 and 6) completely prevented infarct extension during global ischemic arrest.(ABSTRACT TRUNCATED AT 250 WORDS)     

Magnesium ion is beneficial in hypothermic crystalloid cardioplegia

The role of magnesium ion and its relation to the calcium concentration of cardioplegic solutions was reexamined in this study. Isolated rat hearts were used with an oxygenated modified Krebs-Henseleit bicarbonate buffer as perfusion medium. The hearts were arrested for 20 minutes at 37 degrees C or 90 minutes at 24 degrees C. Treatment groups received one dose of nine possible cardioplegic solutions containing magnesium (0, 1.2, or 15 mmol/L) and calcium (0.05, 1.5, or 4.5 mmol/L). Ninety-six percent of the 75 magnesium-treated hearts recovered, regardless of the calcium concentration, in contrast to a 52% recovery rate in the 69 hearts that did not receive magnesium. The addition of 15 mmol/L Mg2+ to a cardioplegic solution containing no magnesium but 0.05 mmol/L Ca2+ significantly increased (p less than 0.01) the percent recovery of the following parameters of cardiac function: systolic pressure, 74% to 93% (37 degrees C), 64% to 98% (24 degrees C); cardiac output, 76% to 101% (37 degrees C), 71% to 102% (24 degrees C); stroke work, 64% to 104% (37 degrees C), 52% to 99% (24 degrees C); and adenosine triphosphate level, 75% to 83% (37 degrees C), 58% to 90% (24 degrees C). There were significant reductions (p less than 0.03) in percent recovery (37 degrees C and 24 degrees C) of cardiac output, stroke work, and adenosine triphosphate level in the groups that contained 0 or 15 mmol/L Mg2+ as the calcium concentration was increased from 0.05 to 4.5 mmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)