Biochemical Changes of Ischemia

Normothermic ischemic arrest by aortic cross-clamping, a widely used clinical technique, is associated with metabolic changes in the myocardium that are incompletely understood. The effects of aortic cross-clamping on glycolytic pathways as well as associated morphological changes are discussed. Emphasis is placed on the conservation of high-energy phosphate moieties during the period of cross-clamping as well as during reperfusion. A marked reduction in total high-energy phosphates (62%) and glycogen (63%) and an increase in lactate production (243%) denote a shift to anaerobic metabolism during the period of arrest. Despite reperfusion, total high-energy nucleotides remained depressed. The data suggest that persistent abnormal myocardial carbohydrate metabolism and low levels of high-energy nucleotides prevent recovery of contractility following normothermic ischemic arrest and reperfusion.     

Fluosol-Da: An Artificial Blood for Total Cardiopulmonary Bypass

The isolated, in situ pig heart model was used to determine if Fluosol could support myocardial function during cardiopulmonary bypass. Fourteen pigs were utilized; 7 underwent studies of myocardial metabolism (coronary blood flow and vascular resistance, myocardial oxygen consumption and extraction, lactate extraction, and adenosine triphosphate and creatine phosphate levels), and 7 underwent studies of myocardial contractility and compliance (intraventricular balloon measurements). Each study was carried out utilizing one hour of control hemic perfusion, followed by one hour of Fluosol perfusion, and followed by a third hour of a return of hemic perfusion.The results documented that in the vented, beating, nonischemic heart, myocardial metabolism and functional measurements are maintained during an hour of Fluosol perfusion. However, because of an increased level of ionized calcium during Fluosol perfusion, myocardial functional measurements document significantly increased contractility. The increased contractility is associated with an increase in anaerobic metabolism. The latter contributes to a decline in the high-energy phosphate level following a return of hemic perfusion as the heart recovers from the increased work load placed on it during Fluosol perfusion.It is concluded that there is sufficient oxygen-carrying capacity in Fluosol-DA to maintain cardiac function during perfusion in the large animal model. However, the carrier solution for the Fluosol must be adjusted to appropriate electrolyte content to avoid adverse effects on the myocardium.     

Depletion of myocardial high energy phosphates by induction of ventricular fibrillation prior to cardioplegic arrest

The effects of a short period of ventricular fibrillation on myocardial high energy phosphates were assessed in two groups of rats. Group 1 underwent hypothermic crystalloid cardioplegia infusion and aortic cross-clamping. In Group 2, cardioplegia and cross-clamping were preceded by ten seconds of induced ventricular fibrillation. In rat hearts that had undergone ventricular fibrillation, adenosine triphosphate levels averaged only 70% (p less than .0001) and creatine phosphate levels averaged only 60% (p less than .0005) of levels measured following standard cardioplegic arrest without ventricular fibrillation. These findings are of potential importance in both routine cardiac surgical procedures and in organ procurement.     

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.     

Myocardial energy depletion during profound hypothermic cardioplegia for cardiac operations

Myocardial biopsy specimens were taken from 10 patients undergoing aortic valve replacement using extracorporeal circulation and continuous perfusion blood cardioplegia at extremely low myocardial temperature (10 degrees C). They were analyzed for adenosine triphosphate, creatine phosphate, creatine, and lactate before, after 10 minutes, and after 60 minutes of cardioplegia. Patient inclusion criteria were heart volume less than 700 ml/m2 body surface area and no significant coronary atherosclerosis as judged from preoperative angiograms. The profound hypothermic cardioplegia resulted in a smaller intramyocardial lactate accumulation but a greater decrease in adenosine triphosphate and creatine phosphate than a moderate reduction of myocardial temperature (15 degrees C) as previously reported in a similar patient group. This suggests that at the lower temperature energy-generating processes are thwarted more than energy consumption. In addition, the profound hypothermic cardioplegia led to a reduction of the myocardial pool of total creatine, which may delay restitution of myocardial high-energy phosphate and function after cardioplegia.     

Cardioprotective effects of carnitine in extensive aortocoronary bypass grafting: a double-blind, randomized, placebo-controlled clinical trial

The cardioprotective effects of carnitine were tested in patients undergoing multiple aortocoronary bypass grafting. Intermittent aortic cross-clamping at 28 degrees C was used. Mean total cross-clamping time was 30 +/- 11 min. Patients were randomized into three groups: a control group receiving placebo (group 1), a group pretreated with 3 g carnitine intravenously before cardiopulmonary bypass (CPB) (group 2), and a group pretreated with 6 g carnitine intravenously (group 3). The markers of myocardial ischemia included levels of adenosine triphosphate, its catabolites, and creatine phosphate in transmural left ventricular biopsy specimens taken at the beginning and end of CPB, as well as hemodynamic recovery during weaning from CPB and for the next 24 h. The intravenous infusion of carnitine (3 or 6 g) had no hemodynamic effect. At the end of CPB myocardial tissue levels of adenosine triphosphate and creatine phosphate did not differ significantly among the groups (P greater than 0.05). Recovery of cardiac function during weaning from CPB and for the following 24 h was similar in all three groups (P greater than 0.05). It is concluded that pretreatment with carnitine neither facilitates weaning from cardiopulmonary bypass in patients undergoing aortocoronary bypass surgery nor favorably affects hemodynamic function during the next 24 h.     

Beneficial effects of potassium cardioplegia during intermittent aortic cross-clamping and reperfusion

Aortic cross-clamping is an essential adjunct to a variety of cardiac surgical procedures requiring a quiet flaccid heart and avoidance of systemic air embolism. The consequences of excluding the heart from perfusion, oxygen, and substrate are time dependent and lead ultimately to irreversible damage of the myocardium. The goal of complete preservation of myocardial function and metabolism during ischemia has not been realized even with the best clinically applicable techniques. The present study was designed to evaluate the effects of sequential aortic cross-clamping interrupted by reperfusion similar to that used in clinical practice. The advantages of induced cardiac arrest with potassium chloride solution at the onset of aortic cross-clamping were assessed in a second group of animals. A total of 27 mongrel dogs supported by normothermic cardiopulmonary bypass was subjected to four aortic cross-clamp periods interrupted by 5-min reper-fusion periods. The study included an evaluation of left ventricular performance using an isovolumic balloon technique and an assessment of myocardial metabolism using “stop-freeze” biopsies and biochemical assay for ATP, ADP, AMP, and creatine phosphate. The data demonstrate that repeated induction of ischemic arrest results in profound depletion of adenine nucleo-tides and severe depression of contractility. Using potassium-induced cardiac arrest, normal contractile function is preserved along with conservation of adenine nucleo-tides, suggesting that even at normothermia, preservation of the heart during ischemia can be achieved.     

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.     

Adenosine for cardioplegic induction: a comparison with St Thomas solution

OBJECTIVE: To determine if quicker cardiac standstill obtained by adding adenosine to potassium crystalloid cardioplegia translated into better myocardial preservation and cardiac function in the early postoperative period compared with the same cardioplegia without adenosine. DESIGN: A prospective study. SETTING: Cardiac center of a teaching institute. PARTICIPANTS: Sixty consecutive patients with left main vessel or triple-vessel disease undergoing coronary artery bypass surgery under moderate hypothermia. INTERVENTIONS: The study comprised two groups of patients. Group N (n = 15) was the control group, given St Thomas cardioplegic solution after aortic cross-clamping, without adenosine; whereas group A (n = 45) received 250 microg/kg of adenosine into the aortic root after aortic cross-clamping, followed by the same St Thomas cardioplegia as in group N. The two groups were otherwise similar in all aspects of perfusion management. MEASUREMENTS AND MAIN RESULTS: Time taken to achieve cardiac standstill after aortic cross-clamping was significantly greater, 18.7+/-3.1 seconds, in the control group compared with the adenosine group, 3.4+/-0.9 seconds (p<0.001). The quicker arrest of the adenosine group led to better postoperative function, in the form of higher cardiac index (p<0.01), lower filling pressures (pulmonary artery wedge pressure) (p<0.05), and lower mean pulmonary artery pressure (p<0.05) at 6 hours. In the adenosine group, only 3 of 45 (6.6%) patients had elevated creatine phosphokinase (CPK) (MB) values greater than 50 U/L over preoperative CPK values compared with 3 of 15 (20%) in the control group (p<0.01). CONCLUSIONS: Injection of 250 microg/kg of adenosine into the aortic root before administration of cold crystalloid St Thomas cardioplegia solution after cross-clamping, in patients with severe coronary artery disease, produces significantly faster cardiac standstill, better myocardial preservation, and better cardiac function in the early postoperative period.     

Effects of Delay in Administration of Potassium Cardioplegia to the Isolated Rat Heart

Ischemic injury to the heart in the period between aortic cross-clamping and administration of cardioplegic solution was evaluated in the normothermic rat heart model. After isolation and control perfusion with oxygenated Krebs-Henseleit bicarbonate buffer, the hearts were given lactated Ringer's cardioplegic solution (30 mEq of K⁺ per liter) for 2 minutes at three different intervals following aortic clamping: no delay, 2-minute delay, and 5-minute delay. Thereafter, the hearts were left unper-fused and the time to initiation of ischemic contracture was recorded. Adenosine triphosphate (ATP) and creatine phosphate levels were measured in all groups prior to and at the conclusion of cardioplegia administration.A 2-minute delay in the administration of cardioplegic solution resulted in significantly lower (p < 0.001) ATP levels that were restored after 2 minutes of cardioplegia administration. Contracture times were not significantly altered. A 5-minute delay resulted in significantly shorter (p < 0.001) contracture times and significantly lower (p < 0.001) ATP levels that were not restored to preischemic levels by 2 minutes of cardioplegia administration.The fate of the myocardium may be insensitive to events that occur during the earliest moments of ischemia provided that rapid administration of oxygenated potassium cardioplegia follows the ischemic period and restores preischemic high-energy phosphate stores. However, there is a critical ischemic time during the initial interval before cardioplegia that is associated with an impaired ability of the myocardium to tolerate subsequent ischemia.     

The effect of amino acids on the ischemic heart. Improvement of oxygenated crystalloid cardioplegic solution by an enriched branched chain amino acid formulation

This study was designed to test the effect of glucose and a formulation enriched with branched chain amino acids as additives to oxygenated crystalloid cardioplegic solution in the ischemic heart. Energy-depleted isolated working rat hearts were subjected to 68 minutes of normothermic global ischemia during which oxygenated cardioplegic solution was used to protect them. The hearts were then reperfused in the nonworking mode for 10 minutes and for a further 30 minutes in the working mode. The hearts were randomly divided into three groups, in which various oxygenated cardioplegic solutions were perfused. Group 1 (control) was subjected to modified St. Thomas' Hospital cardioplegic solution and groups 2 and 3 to the same solution with the addition of glucose (11.1 mmol/L) and glucose (11.1 mmol/L) and branched chain amino acids, respectively. Recovery of aortic flow, coronary flow, cardiac output, aortic pressure, adenosine triphosphate, creatine phosphate, and oxygen consumption was significantly better in group 2 than in group 1. In addition, recovery of aortic flow, coronary flow, cardiac output, aortic pressure, stroke volume, minute work, adenosine triphosphate, and creatine phosphate was found to be significantly enhanced in group 3. Release of adenine catabolites and lactic dehydrogenase from these hearts during postischemic reperfusion was significantly decreased. Thus, during global ischemia in the energy-depleted heart, the presence of glucose and branched chain amino acids in oxygenated crystalloid cardioplegic solution enhanced myocardial protection.     

Myocardial adenine nucleotide metabolism in pediatric patients during hypothermic cardioplegic arrest and normothermic ischemia

Quantitative assessment of high-energy phosphate levels, including degradation or utilization during ischemia, has not previously been performed in infants and children. Animal experiments suggest that high-energy phosphate metabolism varies with maturation. To help answer these questions, 24 patients aged 2 months to 8 years underwent myocardial biopsy immediately after the institution of cardiopulmonary bypass (16 to 20 degrees C). Additional samples were obtained at 16 and 45 minutes after aortic cross-clamping and administration of cardioplegia (St. Thomas's solution) (in vivo ischemia). Seven patients also underwent major myocardial resection. Resected specimens were placed in a 37 degrees C bath and divided into equal-sized samples that were removed at ten-minute intervals (in vitro ischemia). All samples were immersed in liquid nitrogen and analyzed for adenine nucleotide pool metabolites using high-performance liquid chromatography. Levels of adenosine triphosphate were high before cross-clamping but diminished during the period of protected ischemia. Adenosine triphosphate loss was much more pronounced in patients less than 18 months old (p less than 0.05) and was associated with accumulation of adenosine monophosphate and inosine, a finding not seen in patients more than 18 months old (p less than 0.05). The same trends documented during in vivo ischemia were noted during in vitro ischemia. Immaturity of 5'-nucleotidase results in accumulation of adenosine monophosphate during ischemia. It is known that 5'-nucleotidase is present in neonatal myocardial cell membranes and absent from the cytosol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Noncoronary collateral myocardial blood flow.

This study shows that noncoronary collateral flow occurs in normal hearts after chronic coronary occlusion and with left ventricular hypertrophy in variable amounts (0.2 to 16 ml/100 gm/min). Luminal--left ventricular flow is greatest when the heart is arrested by aortic cross-clamping, falls significantly when perfusion pressure is lowered to 50 mm Hg, and increases slightly when blood viscosity is reduced (hemodilution). Our findings indicate that the heart which is arrested by aortic cross-clamping may not be anoxic.     

Inhibition of phosphodiesterase type III before aortic cross-clamping preserves intramyocardial cyclic adenosine monophosphate during cardiopulmonary bypass

Inotropes are often used to treat myocardial dysfunction shortly after cardiopulmonary bypass (CPB). beta-Adrenergic agonists improve contractility, in part by increasing cyclic adenosine monophosphate (cAMP) production, whereas phosphodiesterase type III inhibitors prevent its breakdown. CPB is associated with abnormalities at the beta-receptor level and diminished adenyl cyclase activity, both of which tend to decrease cAMP. These effects may be increased in the presence of preexisting myocardial dysfunction. We tested the hypothesis that inhibition of phosphodiesterase type III before global myocardial ischemia and pharmacologic arrest results in the preservation of intramyocardial cAMP concentration during CPB. Twenty adult patients undergoing coronary artery bypass grafting with CPB were studied. After CPB was instituted, a myocardial biopsy was obtained from the apex of the left ventricle. Patients were randomized to receive either placebo or milrinone (50 micro/kg) through the bypass pump 10 min before aortic cross-clamping. Another myocardial biopsy was performed adjacent to the left ventricular apex just before weaning from CPB. Myocardial cAMP concentration was determined by radioimmunoassay. Myocyte protein content was determined by the Bradford method by using a commercial kit. There were no significant demographic differences between the groups; however, patients in the Milrinone group had a lower left ventricular ejection fraction than placebo (41% +/- 13% vs 53% +/- 7%; P < 0.05). Patients who received milrinone had larger cAMP concentrations at the end of CPB compared with placebo (21 +/- 12.5 pmol/mg protein versus 12.8 +/- 2.2 pmol/mg protein; P < 0.05). The administration of milrinone before aortic cross-clamping is associated with increased intramyocardial cAMP concentration at the end of CPB. IMPLICATIONS: The administration of a single dose of milrinone before aortic cross-clamping resulted in significantly larger intramyocardial cyclic adenosine monophosphate concentration in myocardial biopsy specimens compared with controls.     

The time course of myocardial high-energy phosphate degradation during potassium cardioplegic arrest

Myocardial high-energy phosphate and glucose-6-phosphate levels were determined in the in vivo pig heart model during ischemic arrest and reperfusion to determine the effectiveness of potassium cardioplegia in myocardial protection. Thirty-five pigs were divided into six experimental groups consisting of 2-hour normothermic arrest, 2-hour hypothemic arrest, 2-hour normothermic cardioplegic arrest, and 1-, 2-, and 3-hour hypothermic cardioplegic arrest. Myocardial biopsies from the left ventricle were obtained prior to arrest, every 30 minutes during the arrest interval, and at 30 and 60 minutes of reperfusion. The measurement of adenosine triphosphate and creatine phosphate showed that (1) cardioplegic arrest requires hypothermia to preserve high-energy phosphate levels in myocardial tissue; (2) hypothermia, while not completely protective alone, is more effective than potassium cardioplegia alone in providing myocardial preservation during 2-hour ischemic arrest; (3) the combination of potassium cardioplegia and hypothermia is additive in providing an effective means of maintaining myocardial high-energy phosphate stores during 1, 2, and 3 hours of ischemic arrest; (4) myocardial reperfusion does not allow a return to preischemic adenosine triphosphate (ATP) levels after 2 hours of arrest, except following hypothermic cardioplegia; and (5) extension of the duration of ischemic arrest to 3 hours using hypothermic cardioplegia prevents recovery of high-energy phosphate stores to preischemic levels during reperfusion. Optimal preservation can be achieved during 2 hours of ischemic arrest by using hypothermic potassium cardioplegia. The effects of myocardial reperfusion, however, prevent full ATP and creatine phosphate (CP) recovery following 3 hours of arrest. No other technique studied was as effective in providing myocardial preservation.     

Nifedipine as an adjunct to St. Thomas' Hospital cardioplegia. A double-blind, placebo-controlled, randomized clinical trial

The cardioprotective effect of the addition of the slow calcium-channel blocker nifedipine to cardioplegic solution was tested in two double-blind placebo controlled randomized studies. The first study included 24 patients undergoing aortic-coronary bypass grafting, and the second included 24 patients undergoing aortic valve replacement. Nifedipine at a dose of 200 micrograms/L or placebo was added to St. Thomas' Hospital cardioplegic solution. The following markers of ischemia were used: adenosine triphosphate and its catabolites, creatine phosphate and inorganic phosphate, determined in transmural left ventricular biopsy specimens taken before, at the end of, and after aortic cross-clamping; hemodynamic recovery 15 minutes after cessation of cardiopulmonary bypass; clinical outcome in terms of the incidence of arrhythmias, low cardiac output, positive inotropic support immediately after operation, and follow-up at 15 months. The main difference between the two studies was that myocardial temperature during cross-clamping remained constant at 14 degrees C in coronary bypass grafting but increased to 25 degrees C in valve operations despite the application of the same amounts of cardioplegic solutions. This lower temperature resulted in better preservation of high-energy phosphates in coronary bypass operations as compared to the placebo group having valve replacement operations. According to analysis of variance, a drug effect could be demonstrated only in the aortic valve replacement study: Accumulation of breakdown products of the adenine nucleotide pool was less in the nifedipine group than in the placebo group (p less than 0.05). Adenosine triphosphate decreased only to 84% in the nifedipine group and to 72% in the placebo group. Despite this adenosine triphosphate-sparing effect, weaning from cardiopulmonary bypass was more difficult in the nifedipine group. Left ventricular stroke work index 15 minutes after bypass was decreased to 72% of the prebypass value in the nifedipine group (t test, p less than 0.01) and only to 86% in the placebo group (p = NS). In contrast, after the patients were admitted to the intensive care unit, the incidence of low cardiac output tended to be lower in the nifedipine group than in the placebo group: 33% versus 58% (p = NS). In conclusion, ischemia-induced degradation of nucleotides as it occurs when myocardial cooling is inadequate can be prevented by the addition of nifedipine to the St. Thomas' Hospital cardioplegic solution. This effect, however, is not associated with an improved clinical outcome.     

Functional evaluation of normothermic intermittent coronary perfusion

The myocardial contractility of papillary muscle from rabbit hearts was used to evaluate various techniques of normothermic intermittent coronary perfusion. A progressive decline of the myocardial contractility was noted as aortic cross-clamping and coronary reperfusion were repeated. After a net anoxic period of 90 minutes, the contractility fell to 58.67, 60.2, and 40 percent of the base line when single aortic cross-clamping time was 5, 10, and 15 minutes, respectively, interrupted by 5 minutes of reperfusion. Repeated application of single cross-clamping of 20 minutes or longer was not tolerated by the rabbit hearts. When the heart was reperfused for 10 minutes, between 15 minute periods of anoxia, the final recovery of contractility was 62 percent. Normothermic intermittent coronary perfusion has a significant adverse effect on the myocardial contractility. If this technique is to be used, single anoxic times should not be longer than 15 minutes and the heart must be reperfused for at least 10 minutes.     

MB creatine kinase and the evaluation of myocardial injury following aortocoronary bypass operation

Myocardial injury was studied in 104 patients undergoing coronary artery grafting without cold chemical cardioplegia using the quantity of the isoenzyme MB of the creatine kinase liberated as an indicator. This method of evaluation, which is said to permit comparison of different techniques of myocardial protection, allowed us to consider the relative importance of several factors believed to have an influence on intraoperative myocardial injury. Indices of significance were duration of symptoms before operation, presence of chronic arterial hypertension, and the type of antiangina treatment employed. Other operative factors included severity of the arterial lesions, number of anastomoses performed, and duration of extracorporeal circulation and of aortic cross-clamping.     

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.     

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.