Adenosine cardioplegia. Adenosine versus potassium cardioplegia: effects on cardiac arrest and postischemic recovery in the isolated rat heart

Adenosine is a potential cardioplegic agent by virtue of its specific inhibitory properties on nodal tissue. We tested the hypothesis that adenosine could be more effective than potassium in inducing rapid cardiac arrest and enhancing postischemic hemodynamic recovery. Isolated rat hearts were perfused with Krebs-Henseleit buffer or cardioplegic solutions to determine the time to cardiac arrest and the high-energy phosphate levels at the end of cardioplegia. Cardioplegic solutions contained adenosine 10 mmol/L, potassium 20 mmol/L, or adenosine 10 mmol/L + potassium 20 mmol/L and were infused at a rate of 2 ml/min for 3 minutes at 10 degrees C. Both time taken and total number of beats to cardiac arrest during 3 minutes of cardioplegia were reduced by adenosine 10 mmol/L and adenosine 10 mmol/L + potassium 20 mmol/L when compared with potassium 20 mmol/L alone (p less than 0.001). Tissue phosphocreatine was conserved by adenosine 10 mmol/L when compared with potassium 20 mmol/L, being 7.1 +/- 0.2 (mumol/gm wet weight (n = 7) and 6.0 +/- 0.3 mumol/gm wet weight (n = 5), respectively (p less than 0.05). Postischemic hemodynamic recovery was tested in isolated working rat hearts. After initial cardiac arrest, the cardioplegic solution was removed with Krebs-Henseleit buffer at a rate of 2 ml/min for 3 minutes at 10 degrees C, and thereafter total ischemia was maintained for 30 or 90 minutes at 10 degrees C before reperfusion. Adenosine 10 mmol/L enhanced recovery of aortic output when compared with potassium 20 mmol/L or adenosine 10 mmol/L + potassium 20 mmol/L, the percentage recovery after 30 minutes of ischemia being 103.0% +/- 4.4% (n = 6), 89.0% +/- 5.8% (n = 6), and 86.6% +/- 4.3% (n = 6), respectively (p less than 0.05 for comparison between adenosine 10 mmol/L and potassium 20 mmol/L). Thus adenosine cardioplegia caused rapid cardiac arrest and improved postischemic recovery when compared with potassium cardioplegia and with a combination of these two agents.     

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.     

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.     

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)     

Enhancement of low coronary reflow improves postischemic myocardial function.

The effect of reperfusion coronary vasodilatation on postischemic myocardial mechanical function has been investigated in the isolated working rat heart. After a working period to assess control function, all the hearts were subjected to a single infusion (10 ml) of St. Thomas' Hospital cardioplegic solution No. 1 at 4 degrees C and were kept immersed in the same solution for 4 hours at 4 degrees C. Then hearts (six in each group) were initially reperfused at 37 degrees C for 10 minutes, either with ordinary reperfusate (Krebs-Henseleit bicarbonate buffer) or with reperfusate containing additional coronary dilator. After this period, all hearts were subjected to a further 5 minutes of ordinary reperfusate before being put back into the working mode to assess functional recovery. Mean reperfusion coronary flows and the steady coronary flow measured after 10 minutes of reperfusion in ml/min +/- SEM were--Krebs (control): 17.4 +/- 0.39 and 13.4 +/- 0.40; adenosine (3.75 mumol/L): 19.9 +/- 0.6 and 16.7 +/- 0.8; papaverine (0.05 mmol/L): 21.8 +/- 2.3 and 17.3 +/- 1.8; dipyridamole (2 mmol/L): 20.7 +/- 1.7 and 17.9 +/- 1.0; nitroglycerin (15 mg/L): 20.5 +/- 0.45 and 19.9 +/- 1.4; diltiazem (0.05 mmol/L): 19.6 +/- 2.98 and 17.7 +/- 1.8; calcitonin gene-related peptide (0.03 mmol/L): 20.8 +/- 0.69 and 18.0 +/- 1.3; 5-hydroxytryptamine (0.01 mmol/L): 19.2 +/- 0.53 and 16.9 +/- 0.80. Mean postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were expressed as percent of preischemic control +/- SEM were--Krebs: 54.1 +/- 2.8, 69.1 +/- 2.8, and 53.9 +/- 3.0; adenosine: 78.0 +/- 5.6, 89.5 +/- 2.9, and 69.1 +/- 1.9; papaverine: 81.8 +/- 3.9, 91.8 +/- 3.1, and 71.0 +/- 4.1; dipyrdamole: 67.3 +/- 3.3, 84.3 +/- 2.3, and 75.0 +/- 2.7; nitroglycerin: 83.1 +/- 4.8, 79.7 +/- 2.7, and 69.0 +/- 0.5; diltiazem: 76.5 +/- 3.7, 85.9 +/- 2.9, and 73.3 +/- 1.7; calcitonin gene-related peptide: 79.5 +/- 3.6, 90.0 +/- 4.9, and 75.4 +/- 3.9; 5-hydroxytryptamine: 71.6 +/- 3.2, 85.5 +/- 3.5, and 67.9 +/- 4.8. There was a positive correlation between mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure. Mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were significantly greater in groups reperfused with vasodilators (p < 0.05) compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

St. Thomas' Hospital cardioplegic solution. Beneficial effect of glucose and multidose reinfusions of cardioplegic solution

The intention of this study was to determine whether glucose is beneficial in a cardioplegic solution when the end products of metabolism produced during the ischemic period are intermittently removed. The experimental model used was the isolated working rat heart, with a 3-hour hypothermic 10 degrees C cardioplegic arrest period. Cardioplegic solutions tested were the St. Thomas' Hospital No. 2 and a modified Krebs-Henseleit cardioplegic solution. Glucose (11 mmol/L) was beneficial when multidose cardioplegia was administered every 30 minutes. Including glucose in Krebs-Henseleit cardioplegic solution improved postischemic recovery of aortic output from 57.0% +/- 1.8% to 65.8% +/- 2.2%; p less than 0.025. The addition of glucose to St. Thomas' Hospital No. 2 cardioplegic solution improved aortic output from 74.6% +/- 1.9% to 87.4% +/- 1.9%; p less than 0.005. Furthermore, a dose-response curve showed that a glucose concentration of 20 mmol/L gave no better recovery than 0 mmol/L, and glucose in St. Thomas Hospital No. 2 cardioplegic solution was beneficial only in the range of 7 to 11 mmol/L. In addition, we showed that multidose cardioplegia was beneficial independent of glucose. Multidose St. Thomas' Hospital No. 2 cardioplegia, as opposed to single-dose cardioplegia, improved aortic output recovery from 57.4% +/- 5.2% to 74.6% +/- 1.9%; p less than 0.025, and with St. Thomas' Hospital No. 2 cardioplegic solution plus glucose (11 mmol/L) aortic output recovery improved from 65.9% +/- 2.9% to 87.4% +/- 1.9%; p less than 0.005. Hence, at least in this screening model, the St. Thomas' Hospital cardioplegic solution should contain glucose in the range of 7 mmol/L to 11 mmol/L, provided multidose cardioplegia is given. We cautiously suggest extrapolation to the human heart, on the basis of supporting clinical arguments that appear general enough to apply to both rat and human metabolisms.     

L-aspartate improves the functional recovery of explanted hearts stored in St. Thomas' Hospital cardioplegic solution at 4 degrees C

Explanted rat hearts were subjected to cardioplegic arrest by 3 minutes' perfusion with oxygenated St. Thomas' Hospital solution no. 2 and then were stored by immersion in the same solution at 4 degrees C. Prearrest and postischemic left ventricular functions were compared by means of an isolated working heart apparatus. Hearts (n = 8 per group) arrested and stored for up to 8 hours all resumed the spontaneous rhythm of contraction during reperfusion for 30 minutes at 37 degrees C. There was good recovery of aortic flow rate (105% +/- 3%) against a pressure of 100 cm H2O, of heart rate (102% +/- 2%), and of aortic pressure (86% +/- 5% of prearrest values). Hearts stored for 10 and 20 hours showed poor or no postischemic recovery of cardiac pump function (aortic flow, 16% +/- 11% and 0%, respectively). Enrichment of St. Thomas' Hospital solution with L-glutamate (20 mmol/L) also failed to improve functional recovery of hearts subjected to 10 hours of storage, but hearts treated with St. Thomas' Hospital solution containing L-aspartate (20 mmol/L) or L-aspartate plus L-glutamate (20 mmol/L each) reestablished aortic flow rates of 99% +/- 5% and 93% +/- 4%, respectively. These results indicate that the addition of L-aspartate to St. Thomas' Hospital solution improves the functional recovery and extends the safe preservation of explanted hearts stored at 4 degrees C.     

Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury

This study tests the hypothesis that aspartate enrichment of glutamate-blood cardioplegia improves metabolic and functional recovery after ischemic and reperfusion damage. Ischemic and reperfusion damage were produced in 15 dogs by 45 minutes of aortic clamping at 37 degrees C and 5 minutes of blood reperfusion, before 2 more hours of aortic clamping (simulated operation). Six received multidose blood cardioplegia at 4 degrees C. In nine others, the cardioplegic solution was infused at 37 degrees C for the first 5 minutes, followed by multidose infusions at 4 degrees C. Four received 26 mmol glutamate-enriched cardioplegic solution. In five, the glutamate (13 mmol) cardioplegic solution was enriched with aspartate (13 mmol). Oxygen uptake and ventricular function (stroke work index, left atrial pressure) were measured. These data suggest aspartate enrichment produced the highest oxygen uptake (32 +/- 4 versus 17 +/- 2 ml/100 gm for glutamate and 7 +/- 1 ml/100 gm for 4 degrees C blood cardioplegia). Complete functional recovery occurred in aspartate/glutamate-treated hearts (stroke work index 90% +/- 4%, left atrial pressure 12 +/- 2 mm Hg), whereas recovery was incomplete with both glutamate alone (stroke work index 66% +/- 14%, left atrial pressure 20 +/- 3 mm Hg) and 4 degrees C blood cardioplegia at low cardiac outputs. Eight of 10 hearts not receiving aspartate failed at high cardiac outputs. Aspartate enrichment of glutamate-blood cardioplegia improves recovery after severe ischemic/reperfusion damage by improving oxidative metabolism during cardioplegic infusion and during postischemic work.     

Myocardial protective effects of the class Ic antiarrhythmic agent flecainide

The class Ic antiarrhythmic agent flecainide has recently become available in this country for management of ventricular arrhythmias. The pharmacologic and electrophysiologic features of this class of drug--marked sodium channel blockade producing inhibition of phase 0 of the myocardial action potential, moderate blockade of slow inward (calcium) channels, and general lack of systemic toxicity--suggest that these agents may exert significant myocardial protective effects. This hypothesis was tested in isolated, perfused rat hearts subjected to 30 minutes of global normothermic ischemia followed by 30 minutes of reperfusion after pretreatment with (1) Krebs-Henseleit buffer (n = 7); (2) Krebs-Henseleit buffer with potassium adjusted to 20.9 mmol/L with potassium chloride (n = 10); and (3) Krebs-Henseleit buffer plus flecainide acetate 50 mg/L (0.12 mmol/L) (n = 11). Severity of ischemic injury was assessed by time to ischemic contracture: 9.9 +/- 1.3 (Krebs-Henseleit buffer), 18.4 +/- 1.1 (potassium chloride), and 25.4 +/- 1.0 (flecainide) minutes (mean +/- standard error of the mean) (p less than 0.05 among all groups). Functional recovery after ischemia and reperfusion was measured by developed pressure (expressed as percent of preischemic control): 19.6 +/- 5.4 (Krebs-Henseleit buffer), 70.8 +/- 3.2 (potassium chloride), and 67.3 +/- 2.7 (flecainide). These results suggest that class Ic agents afford significant myocardial protection from global normothermic ischemia.     

Temperature-specific effects of adjuvant diltiazem therapy on myocardial energetics following potassium cardioplegic arrest

Adjuvant slow calcium channel blockade theoretically minimizes the calcium influx attendant to potassium-induced cardioplegic arrest, particularly if clinically acceptable levels of cardiac hypothermia are not maintained. The present study assessed the efficacy of diltiazem therapy in ameliorating perturbations of myocardial oxygen consumption that could be attributable to postischemic intracellular calcium accumulation. In 30 canine hearts, myocardial oxygen consumption was determined during incremental isovolumic pressure-volume loading before and 30 minutes after 2 hours of either 20 or 28 degrees C potassium cardioplegic arrest. The intracoronary perfusate in randomized hearts was modified by the addition of diltiazem, 150 micrograms/kg. Although systolic performance (as defined by peak developed pressure as compared with balloon volume curves) was unchanged after 20 degrees C ischemia, adjuvant diltiazem therapy prevented the 44 +/- 2% (p less than .01) decrease in peak developed pressure after 28 degrees C arrest. Moreover, the 39% augmentation of postischemic myocardial oxygen consumption at specific peak developed pressure following both 20 and 28 degrees C ischemia was attenuated with diltiazem only after the warmer ischemic interval. This difference was characterized by a larger (35 +/- 2 vs. 26 +/- 2%; p less than .025) decrease in postischemic oxygen extraction despite a comparable hyperemia. These data suggest that adjuvant diltiazem therapy during potassium-induced cardioplegic arrest preserves energy-efficient pump function only after warmer ischemia, thereby limiting the clinical application of this myoprotective regimen.     

Effect of sodium aspartate on the recovery of the rat heart from long-term hypothermic storage.

We have investigated the reported ability of aspartate to enhance greatly the cardioprotective properties of the St. Thomas' Hospital cardioplegic solution after prolonged hypothermic storage. Rat hearts (n = 8 per group) were excised and subjected to immediate arrest with St. Thomas' Hospital cardioplegic solution (2 minutes at 4 degrees C) with or without addition of monosodium aspartate (20 mmol/L). The hearts were then immersed in the same solution for 8 hours (4 degrees C) before heterotopic transplantation into the abdomen of homozygous rats and reperfusion in vivo for 24 hours. The hearts were then excised and perfused in the Langendorff mode (20 minutes). Addition of aspartate to St. Thomas' Hospital cardioplegic solution gave a small but significant improvement in left ventricular developed pressure, which recovered to 82 +/- 3 mm Hg compared with 70 +/- 2 mm Hg in control hearts (p less than 0.05). However, coronary flow and high-energy phosphate content were similar in both groups. In subsequent experiments hearts (n = 8 per group) were excised, arrested (2 minutes at 4 degrees C) with St. Thomas' Hospital cardioplegic solution containing a 0, 5, 10, 20, 30, 40, or 50 mmol/L concentration of aspartate, stored for 8 hours at 4 degrees C, and then reperfused for 35 minutes. A bell-shaped dose-response curve was obtained, with maximum recovery in the 20 mmol/L aspartate group (cardiac output, 48 +/- 5 ml/min versus 32 +/- 5 ml/min in the aspartate-free control group; p less than 0.05). However, additional experiments showed that a comparable improvement could be achieved simply by increasing the sodium concentration of St. Thomas' Hospital cardioplegic solution by 20 mmol/L. Similarly, if sodium aspartate (20 mmol/L) was added and the sodium content of the St. Thomas' Hospital cardioplegic solution reduced by 20 mmol/L, no significant protection was observed when recovery was compared with that of unmodified St. Thomas' Hospital cardioplegic solution alone. In still further studies, hearts (n = 8 per group) were perfused in the working mode at either high (greater than 80 ml/min) or low (less than 50 ml/min) left atrial filling rates. Under these conditions, if functional recovery was expressed as a percentage of preischemic function, artifactually high recoveries could be obtained in the low-filling-rate group. In conclusion, assessment of the protective properties of organic additives to cardioplegic solutions requires careful consideration of (1) the consequences of coincident changes in ionic composition and (2) the characteristics of the model used for assessment.     

Polarized arrest with warm or cold adenosine/lidocaine blood cardioplegia is equivalent to hypothermic potassium blood cardioplegia

BACKGROUND: Hypothermic depolarizing hyperkalemic (K + 20 mEq/L) blood cardioplegia is the "gold standard" in cardiac surgery. K + has been associated with deleterious consequences, eg, intracellular calcium overload. This study tested the hypothesis that elective arrest in a polarized state with adenosine (400 micromol/L via adenosine triphosphate-sensitive potassium channel opening) and the Na + channel blocker lidocaine (750 micromol/L) as the arresting agents in blood cardioplegia provides cardioprotection comparable to standard hypothermic K + -blood cardioplegia. METHODS: Anesthetized dogs were placed on cardiopulmonary bypass and assigned to 1 of 3 groups receiving antegrade cardioplegia delivered every 20 minutes for 1 hour of arrest: cold (10 degrees C) K + -blood cardioplegia (n = 6), cold (10 degrees C) adenosine/lidocaine blood cardioplegia (n = 6), or warm (37 degrees C) adenosine/lidocaine blood cardioplegia (n = 6). After an hour of arrest, cardiopulmonary bypass was discontinued, and reperfusion was continued for 120 minutes. RESULTS: Time to arrest was longer with cold and warm adenosine/lidocaine blood cardioplegia (175 +/- 19 seconds and 143 +/- 19 seconds, respectively) compared with K + -blood cardioplegia (27 +/- 2 seconds; P < .001). Postcardioplegia left ventricular systolic function (slope of the end-systolic pressure/dimension relationship) was comparable among the 3 groups (K + -blood cardioplegia, 15.2 +/- 2.1 mm Hg/mm; cold adenosine/lidocaine blood cardioplegia, 15.9 +/- 3.4 mm Hg/mm; warm adenosine/lidocaine blood cardioplegia, 14.1 +/- 2.8 mm Hg/mm; P = .90). Plasma creatine kinase activity in cold and warm adenosine/lidocaine blood cardioplegia was similar to that in K + -blood cardioplegia at 120 minutes of reperfusion (cold adenosine/lidocaine blood cardioplegia, 11.5 +/- 2.1 IU/g protein; warm adenosine/lidocaine blood cardioplegia, 10.1 +/- 0.9 IU/g protein; K + -blood cardioplegia, 7.6 +/- 0.8 IU/g protein; P = .17). Postcardioplegia coronary artery endothelial function was preserved in all groups. CONCLUSIONS: Intermittent polarized arrest with warm or cold adenosine/lidocaine blood cardioplegia provided the same degree of myocardial protection as intermittent hypothermic K + -blood cardioplegia in normal hearts.     

Role of potassium concentration in cardioplegic solutions in mediating endothelial damage

We studied the effect of potassium concentration in cardioplegic solutions on endothelial function by examining its influence on 5-hydroxytryptamine- (5-HT) and nitroglycerin-induced vasodilation in the isolated rat heart. Forty-eight rat hearts were perfused on a modified Langendorff preparation. After a baseline record of increase in coronary flow induced by 10(-7) M 5-HT and 10 micrograms/mL nitroglycerin, the hearts were perfused for 30 or 60 minutes with either St. Thomas' solution or Bretschneider solution containing 20 mmol/L of potassium or for 30 minutes with either solution containing 30 mmol/L of potassium (n = 8 in each). Initially, 5-HT and nitroglycerin caused a 39.0% +/- 3.3% and 39.7% +/- 2.8% increase in coronary flow, respectively. After 30 or 60 minutes' perfusion with St. Thomas' solution containing 20 mmol/L of potassium, there was little change in the response to 5-HT or nitroglycerin (5-HT, 43.1% +/- 4.1%; nitroglycerin, 38% +/- 3.2%). Similarly, perfusion with Bretschneider solution (20 mmol/L K+) for 30 or 60 minutes did not alter the degree of vasodilation (5-HT, 39.2% +/- 2.9%; nitroglycerin, 38.0% +/- 3.3%). However, perfusion with St. Thomas' solution containing 30 mmol/L of potassium for 30 minutes abolished the endothelial-dependent 5-HT-induced vasodilation (5-HT, -1.6% +/- 1.4%; nitroglycerin, 36.9% +/- 2.2%). Perfusion with Bretschneider solution (30 mmol/L K+) gave similar results (5-HT, -2.1% +/- 1.2%; nitroglycerin, 36.4% +/- 1.7%). We conclude that the concentration of potassium in cardioplegic solutions plays a critical role in causing functional endothelial damage.     

Long-term myocardial preservation: effects of hyperkalemia, sodium channel, and Na/K/2Cl cotransport inhibition on extracellular potassium accumulation during hypothermic storage.

OBJECTIVES: We previously demonstrated improved myocardial preservation with polarized (tetrodotoxin-induced), compared with depolarized (hyperkalemia-induced), arrest and hypothermic storage. This study was undertaken to determine whether polarized arrest reduced ionic imbalance during ischemic storage and whether this was influenced by Na+/K +/2Cl- cotransport inhibition. METHODS: We used the isolated crystalloid perfused working rat heart preparation (1) to measure extracellular K+ accumulation (using a K+-sensitive intramyocardial electrode) during ischemic (control), depolarized (K+ 16 mmol/L), and polarized (tetrodotoxin, 22 micromol/L) arrest and hypothermic (7.5 degrees C) storage (5 hours), (2) to determine dose-dependent (0.1, 1.0, 10 and 100 micromol/L) effects of the Na +/K+/2Cl- cotransport inhibitor, furosemide, on extracellular K+ accumulation during polarized arrest and 7.5 degrees C storage, and (3) to correlate extracellular K+ accumulation to postischemic recovery of cardiac function. RESULTS: Characteristic triphasic profiles of extracellular K+ accumulation were observed in control and depolarized arrested hearts; a significantly attenuated profile with polarized arrested hearts demonstrated reduced extracellular K+ accumulation, correlating with higher postischemic function (recovery of aortic flow was 54% +/-4% [P =.01] compared with 39% +/-3% and 32% +/-3% in depolarized and control hearts, respectively). Furosemide (0.1, 1.0, 10, and 100 micromol/L) modified extracellular K+ accumulation by -18%, -38%, -0.2%, and +9%, respectively, after 30 minutes and by -4%, -27%, +31%, and +42%, respectively, after 5 hours of polarized storage. Recovery of aortic flow was 53% +/-4% (polarized arrest alone), 56% +/-8%, 70% +/-2% (P =.04 vs control), 69% +/-4% (P =.04 vs control), and 65% +/-3% ( P =. 04 vs control), respectively. CONCLUSIONS: Polarized arrest was associated with a reduced ionic imbalance (demonstrated by reduced extracellular K+ accumulation) and improved recovery of cardiac function. Further attenuation of extracellular K + accumulation (by furosemide) resulted in additional recovery.     

Improved distribution of cardioplegia with pressure-controlled intermittent coronary sinus occlusion

Coronary occlusions may alter the distribution of antegrade cardioplegia and result in ischemic damage. This study was undertaken to determine whether pressure-controlled intermittent coronary sinus occlusion (PICSO) could improve antegrade cardioplegic delivery when coronary occlusions are present. Twenty pigs were subjected to 120 minutes of ischemic arrest with antegrade, multidose, potassium crystalloid cardioplegia. During arrest, the mid-left anterior descending artery was occluded with a snare, which was released on reperfusion. In 10 pigs, a balloon-tipped catheter was placed in the coronary sinus and PICSO was performed during each cardioplegia dose. PICSO-treated hearts had faster arrests (27 +/- 5 versus 102 +/- 21 [SE] seconds; p less than 0.02), as well as lower temperatures (18.4 +/- 1.0 versus 22.0 +/- 1.4 degrees C; p less than 0.05) and higher tissue pH (6.58 +/- 0.09 versus 6.31 +/- 0.09; p less than 0.05) just before aortic unclamping. Postischemic end-diastolic volume was unchanged with PICSO, but it decreased in non-PICSO-treated hearts. PICSO-treated hearts generated a higher postischemic stroke work index (0.70 +/- 0.08 versus 0.38 +/- 0.08 g-m/kg; end-diastolic volume, 60 ml; p less than 0.05). We conclude that PICSO improves cardioplegic distribution, thus reducing ischemic injury.     

Effects of oxygenated cardioplegic solutions on myocardial aerobic metabolism.

Oxygenated cardioplegic solutions can deliver sufficient oxygen to support aerobic metabolism of heart tissue during cardiac arrest, but little is known about oxygen use after cardioplegic solution infusion. Exhaustion of myocardial oxygen stores after infusion of oxygenated crystalloid cardioplegic solution or Krebs-Henseleit buffer was measured in rat hearts. Since nicotinamide adenine dinucleotide accumulates when mitochondria become anaerobic, the epicardium was monitored during perfusion and ischemia. As ischemia progressed, nicotinamide adenine dinucleotide fluorescence increased, indicating exhaustion of oxygen. After buffer perfusion, at 37 degrees C, 50% of peak fluorescence was seen at 13 +/- 1 seconds and 90% at 37 +/- 3 seconds. Oxygenated cardioplegic solution increased these intervals to 57 +/- 6 and 114 +/- 9 seconds, respectively. Oxygenated cardioplegic solution at 10 degrees C increased the time to 50% fluorescence to 238 +/- 12 seconds and to 90% to 320 +/- 14 seconds. Differences between buffer and cardioplegic solution were less at 10 degrees C. Aerobic metabolism was completely abolished 6 minutes after infusion of 10 degrees C oxygenated cardioplegic solution. Maintenance of continuous aerobic metabolism during surgical cardiac arrest would require frequent administration of oxygenated crystalloid cardioplegic solution.     

Purine-enriched asanguineous cardioplegia retards adenosine triphosphate degradation during ischemia and improves postischemic ventricular function

Myocardial dysfunction after induced ischemic arrest is an important problem in cardiac surgery. Adenosine-5'-triphosphate content in myocardial tissue remains depressed for days after ischemia, perhaps because of reperfusion washout of diffusable purine substrates. Left ventricular function is also depressed after ischemia, but its relationship to absolute tissue adenosine triphosphate content is unclear. We tested the hypothesis that arresting hearts with a cardioplegic solution containing adenosine, hypoxanthine, and ribose would result in improved tissue adenosine triphosphate content and left ventricular function after 1 hour of normothermic global ischemia in dogs supported by cardiopulmonary bypass. Animals with ischemic arrest initiated with a crystalloid cardioplegic solution containing adenosine 100 mumol/L, hypoxanthine 100 mumol/L, and ribose 2 mmol/L demonstrated significant improvement (p less than 0.05) during postischemic reperfusion. A significant correlation (p less than 0.05) existed between myocardial adenosine triphosphate content and the recovery of left ventricular function. These experiments demonstrate that an asanguineous cardioplegic solution containing adenosine, hypoxanthine, and ribose maintains myocardial adenosine triphosphate content during ischemia and reperfusion and enhances functional recovery during the postischemic period.     

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.     

Pretreatment with nicardipine preserves ventricular function after hypothermic ischemic arrest

Calcium antagonists have a protective effect on postischemic myocardial function when included in normothermic cardioplegia solutions. This effect varies with the calcium antagonist, but is generally lost under hypothermic conditions. The hypothesis tested was that a calcium antagonist would increase postischemic myocardial performance if given before the onset of hypothermic arrest. Isolated working rat hearts were used with an oxygenated modified Krebs-Henseleit buffer solution as a perfusion media. Rats were pretreated with 1 of 9 doses of a nicardipine solution (0 to 100 micrograms/kg, intraperitoneally) 20 minutes before excision of the heart. Nicardipine is a light-stable, water-soluble calcium antagonist with minimal myocardial depressant effects. The hearts were arrested for 25 minutes at 37 degrees C or 93 minutes at 24 degrees C with 20 mL of cardioplegia solution containing 0.05 mmol/L CaCl2. Postischemic performance and adenosine triphosphate content were used as determinants of efficacy. Eighty-three percent of 101 treated hearts recovered in contrast to a mortality of 50% in the 24 nontreated hearts. Pretreatment with 25 micrograms/kg significantly increased (p less than 0.05) the percent recovery (compared with the nontreated group) of the following variables of cardiac function: systolic pressure, 74% to 96% (37 degrees C), 76% to 90% (24 degrees C); cardiac output, 61% to 90% (37 degrees C), 62% to 84% (24 degrees C); stroke work, 49% to 95% (37 degrees C), 50% to 92% (24 degrees C); and adenosine triphosphate, 76% to 87% (37 degrees C), 58% to 68% (24 degrees C). Progressive increases in postischemic function at 37 degrees and 24 degrees C were seen as the dose of nicardipine was increased from 0 to 25 micrograms/kg and decreased function was seen with a pretreatment dose greater than 25 micrograms/kg of nicardipine. Pretreatment with nicardipine significantly improved postischemic myocardial performance under hypothermic conditions and should be administered or at least not discontinued before cardiac operations.