Myocardial protection: the efficacy of an ultra-short-acting beta-blocker, esmolol, as a cardioplegic agent.

OBJECTIVE: During myocardial revascularization, some surgeons (particularly in the United Kingdom) use intermittent crossclamping with fibrillation as an alternative to cardioplegia. We recently showed that intermittent crossclamping with fibrillation has an intrinsic protection equivalent to that of cardioplegia. In this study we hypothesized that arrest, rather than fibrillation, during intermittent crossclamping may be beneficial. Because esmolol, an ultra-short-acting beta-blocker, is known to attenuate myocardial ischemia-reperfusion injury, we compared the protective effect of esmolol arrest with that of intermittent crossclamping with fibrillation and conventional cardioplegia (St Thomas' Hospital solution). METHODS: Isolated rat hearts were Langendorff perfused at either constant flow (14 mL/min) or constant pressure (75 mm Hg) with oxygenated Krebs-Henseleit bicarbonate buffer (37 degrees C), and left ventricular developed pressure was assessed. In study 1 (constant flow perfusion) 8 groups (n = 6 hearts per group) were studied: (1) 40 minutes of global ischemia; (2) 2 minutes of St Thomas' Hospital infusion and 40 minutes of ischemia; (3) multidose (every 10 minutes) infusions of St Thomas' Hospital solution during 40 minutes of ischemia; (4) 2 minutes of esmolol infusion and 40 minutes of ischemia; (5) multidose (every 10 minutes) esmolol infusions during 40 minutes of ischemia; (6) continuous infusion of esmolol for 40 minutes during coronary perfusion; (7) intermittent (4 x 10 minutes) ischemia with ventricular fibrillation; and (8) intermittent (4 x 10 minutes) ischemia preceded by intermittent esmolol administration. All protocols were followed by 60 minutes of reperfusion. Further experiments (study 2) examined the esmolol administration method in hearts perfused by constant pressure. RESULTS: An optimal arresting dose of 1.0 mmol/L esmolol was established. In study 1 recovery of left ventricular developed pressure (expressed as percentage of preischemic value) was 7% +/- 4%, 28% +/- 8%, 70% +/- 5%, 8% +/- 1%, 90% +/- 4%, 65% +/- 3%, 71% +/- 5%, and 76% +/- 5% in groups 1 to 8, respectively. Intermittent esmolol arrest with global ischemia provided equivalent myocardial protection to intermittent crossclamping with fibrillation, continuous esmolol perfusion, and multidose St Thomas' Hospital solution. Surprisingly, multidose esmolol infusion was more protective than all other treatments. In further experiments (study 2) optimal recovery was obtained with multiple esmolol infusions (by constant flow or constant pressure), but continuous esmolol infusion (at constant flow) was less effective than constant pressure infusion. CONCLUSIONS: Intermittent arrest with esmolol did not enhance protection of intermittent crossclamping with fibrillation; however, multiple esmolol infusions during global ischemia provided improved protection. Administration (constant flow or constant pressure) of arresting solutions influenced outcome only during continuous infusion. Multidose esmolol arrest may be a beneficial alternative to intermittent crossclamping with fibrillation or conventional cardioplegia.     

Age-related changes in the ability of hypothermia and cardioplegia to protect ischemic rabbit myocardium

Hypothermia combined with pharmacologic cardioplegia protects the globally ischemic adult heart, but this benefit may not extend to children; poor postischemic recovery of function and increased mortality may result when this method of myocardial protection is used in children. The relative susceptibilities to ischemia-induced injury modified by hypothermia alone and by hypothermia plus cardioplegia were assessed in isolated perfused immature (7- to 10-day-old) and mature (6- to 24-month-old) rabbit hearts. Hearts were perfused aerobically with Krebs-Henseleit buffer in the working mode for 30 minutes, and aortic flow was recorded. This was followed by 3 minutes of hypothermic (14 degrees C) coronary perfusion with either Krebs or St. Thomas' Hospital cardioplegic solution No. 2, followed by hypothermic (14 degrees C) global ischemia (mature hearts 2 and 4 hours; immature hearts 2, 4, and 6 hours). Hearts were reperfused for 15 minutes in the Langendorff mode and 30 minutes in the working mode, and recovery of postischemic function was measured. Hypothermia alone provided excellent protection of the ischemic immature rabbit heart, with recovery of aortic flow after 2 and 4 hours of ischemia at 97% +/- 3% and 93% +/- 4% (mean +/- standard deviation) of the preischemic value. Mature hearts protected with hypothermia alone recovered only minimally, with 22% +/- 16% recovery of preischemic aortic flow after 2 hours; none were able to generate flow at 4 hours. St. Thomas' Hospital solution No. 2 improved postischemic recovery of aortic flow after 2 hours of ischemia in mature hearts from 22% +/- 16% to 65% +/- 6% (p less than 0.05), but actually decreased postischemic aortic flow in immature hearts from 97% +/- 3% to 86% +/- 10% (p less than 0.05). To investigate any dose-dependency of this effect, we subjected hearts from both age groups to reperfusion with either Krebs solution or St. Thomas' Hospital solution No. 2 for 3 minutes every 30 minutes throughout a 2-hour period of ischemia. Reexposure to Krebs solution during ischemia did not affect postischemic function in either age group. Reexposure of immature hearts to St. Thomas' Hospital solution No. 2 caused a decremental loss of postischemic function in contrast to incremental protection with multidose cardioplegia in the mature heart. We conclude that immature rabbit hearts are significantly more tolerant of ischemic injury than mature rabbit hearts and that, unexpectedly, St. Thomas' Hospital solution No. 2 damages immature rabbit hearts.     

Cardioplegia-induced damage to ischemic immature myocardium is independent of oxygen availability

The known benefits of hypothermic pharmacological cardioplegia in protecting the ischemic adult heart may not extend to children. Protection of the ischemic immature rabbit heart with hypothermic Krebs-Henseleit bicarbonate buffer is better than with hypothermic St. Thomas' II cardioplegic solution. We investigated whether the availability of oxygen in the preischemic perfusate is responsible for the increased tolerance to ischemia of immature (7- to 10-day-old) hearts perfused with Krebs buffer in comparison with St. Thomas' II solution immediately before ischemia. After obtaining preischemic control data in the "working" mode, we perfused hearts (n = 8 per group) for 3 minutes with hypothermic (14 degrees C) Krebs buffer or hypothermic St. Thomas' II solution saturated with 0%, 25%, or 95% oxygen. This was followed by 2 hours of global ischemia at 14 degrees C. Hearts were reperfused for 15 minutes in the Langendorff mode and 35 minutes in the working mode, and recovery of function was measured. For preischemic oxygen concentrations of 0%, 25%, and 95%, recovery of aortic flow in hearts protected by hypothermia alone during ischemia was 74% +/- 9%, 82% +/- 4%, and 99% +/- 2% of preischemic values, respectively. In hearts protected by hypothermia plus cardioplegia, the values were 69% +/- 6%, 72% +/- 3%, and 86% +/- 5%, respectively. Thus, at equal oxygen concentrations, recovery of postischemic function was better in hearts protected by hypothermia alone compared with hypothermia plus cardioplegia. We conclude that factors other than oxygen availability are responsible for the damaging effect of St. Thomas' II solution on the ischemic immature rabbit heart.     

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.     

K(ATP) channel opener protects neonatal rabbit heart better than St. Thomas' solution

OBJECTIVES: Myocardial protection with ATP-sensitive potassium channel (K(ATP) channel) openers is as effective as St. Thomas' cardioplegia (StTCP) in adult rabbit hearts. This study compares the effectiveness of the K(ATP) channel opener pinacidil to StTCP in protecting neonatal rabbit hearts exposed to global ischemia. METHODS: Seventeen neonatal rabbit hearts (7-9 days old) perfused with Krebs-Henseleit buffer (KHB) on a Langendorff apparatus underwent 90 min of normothermic ischemia. Six (ischemia control) received no pretreatment before or during ischemia. Six others (pinacidil) received a 3-min infusion of 50 microM pinacidil in KHB without StTCP at the onset of ischemia. Five others (StTCP) received a 3-min infusion of StTCP at the onset of ischemia. After 60 min of KHB reperfusion, recovery of left ventricular (LV) performance and coronary flow (CF) were measured and compared to preischemia. A paired t test was used for comparison between drug-treated and untreated groups. RESULTS: Pinacidil-treated hearts had significantly better recovery of left ventricular developed pressure (47 +/- 3.8 mmHg vs 32 +/- 2.5 mmHg, P < 0.05), contractility (+dP/dt(max); 885.4 +/- 74 mmHg vs 643.7 +/- 65 mmHg, P < 0.05), left ventricular end diastolic pressure (10.5 +/- 0.9 mmHg vs 17.4 +/- 1.2 mmHg P < 0.05), compliance (-dP/dt(max); 994.2 +/- 86 mmHg vs 673.6 +/- 69 mmHg, P < 0.05), and CF (5.9 +/- 0.4 ml/min vs 4.2 +/- 0.2 ml/min, P < 0.05) compared to ischemic control. StTCP only improved the recovery of -dP/dt(max) (877.4 +/- 73 mmHg/s vs 673.6 +/- 69 mmHg/s, P < 0.05) and CF (5.7 +/- 0.3 ml/min vs 4.2 +/- 0.2 ml/min, P < 0.05) compared to control. CONCLUSIONS: Pinacidil pretreatment provided superior recovery of systolic performance compared to St. Thomas' cardioplegia solution in neonatal hearts. Myocardial protection by pretreatment with the K(ATP) channel opener pinacidil may be a new strategy for myocardial protection during pediatric cardiac surgery.     

Protection of the immature heart. Temperature-dependent beneficial or detrimental effects of multidose crystalloid cardioplegia in the neonatal rabbit heart

There are conflicting reports of the detrimental or beneficial effects of hypothermic cardioplegia in the immature heart. We therefore investigated the temperature-dependence of myocardial protection and the ability of single-dose and multidose infusions of cardioplegic solution to protect the immature heart during hypothermic ischemia. Isolated, working hearts (n = 6 per group) from neonatal rabbits (aged 7 to 10 days) were perfused aerobically (37.0 degrees C) for 20 minutes before infusion (2 minutes) with either perfusion fluid (noncardioplegia control) or St. Thomas' Hospital cardioplegic solution and ischemic arrest (for 4, 6, and 18 hours) at various temperatures between 10.0 degrees and 30.0 degrees C. Hearts arrested with cardioplegic solution received either one preischemic infusion only (single-dose cardioplegia) or repeated infusions at intervals of 60 or 180 minutes (multidose cardioplegia). Ischemic arrest with single-dose cardioplegia for 4 hours at 10.0 degrees, 20.0 degrees, 22.5 degrees, 25.0 degrees, 27.5 degrees, and 30.0 degrees C resulted in 96.0% +/- 4.3%, 96.6 +/- 2.5%, 87.0% +/- 3.8%, 71.8% +/- 10.0% (p less than 0.05 versus 10.0 degrees C group), 35.1% +/- 10.3% (p less than 0.01 versus 10.0 degrees C group), and 3.0% +/- 1.9% (p less than 0.04 versus 10.0 degrees C group) recovery of preischemic cardiac output, respectively. With 6 hours of ischemia at 20.0 degrees C, single-dose cardioplegia significantly (p less than 0.01) increased the recovery of cardiac output from 20.9% +/- 13.1% (control) to 76.4% +/- 4.4%, whereas multidose cardioplegia (infusion every 60 minutes) further increased recovery to 97.8% +/- 3.8% (p less than 0.01 versus control and single-dose cardioplegia). In contrast, after 6 hours of ischemia at 10.0 degrees C, cardiac output recovered to 93.4% +/- 1.2% (control) and 92.3% +/- 3.1% (single-dose cardioplegia), whereas multidose cardioplegia reduced recovery to 76.9% +/- 2.2% (p less than 0.01 versus both groups). This effect was confirmed after 18 hours of ischemia at 10.0 degrees C; single-dose cardioplegia significantly increased the recovery of cardiac output from 24.5% +/- 10.9% (control) to 62.9% +/- 13.3% (p less than 0.05), whereas multidose cardioplegia reduced recovery to 0.8% +/- 0.4% (p less than 0.01 versus single-dose cardioplegia) and elevated coronary vascular resistance from 8.90 +/- 0.56 mm Hg.min/ml (control) to 47.83 +/- 9.85 mm Hg.min/ml (p less than 0.01). This effect was not reduced by lowering the infusion frequency (from every 60 to every 180 minutes).(ABSTRACT TRUNCATED AT 400 WORDS)     

Temperature-response studies of the detrimental effects of multidose versus single-dose cardioplegic solution in the rabbit heart

Both single-dose and multidose cardioplegia are protective in the ischemic adult heart under normothermic and hypothermic conditions, but in the hypothermic neonatal rabbit heart single-dose cardioplegia only is protective, whereas multidose cardioplegia is damaging. The present studies in the isolated perfused working heart from neonatal rabbits (aged 7 to 10 days) were designed to characterize the interrelationships between temperature, frequency of cardioplegic infusion, and tissue protection. Hearts (n = 8/group) were subjected to 1, 1.5, 1.5, 3, 10, 12, or 18 hours of ischemia at 37.0 degrees, 34.5 degrees, 32.0 degrees, 28.0 degrees, 20.0 degrees, 15.0 degrees, or 10.0 degrees C, respectively. These times were selected to achieve approximately 55% to 75% recovery of cardiac output in hearts during normothermic reperfusion when single-dose (2 minutes) St. Thomas' Hospital cardioplegic solution was given at the onset of each ischemic period. Under these conditions actual recoveries of cardiac output were 55.7% +/- 5.6%, 68.5% +/- 6.8%, 73.8% +/- 4.1%, 54.6% +/- 5.3%, 56.3% +/- 7.5%, 59.5% +/- 7.7%, and 81.3% +/- 2.3% of the preischemic control values, respectively. By contrast, with multidose cardioplegia (given every 60 minutes in the 3- to 18-hour experiments and every 30 minutes in the 1- and 1.5-hour experiments) there was a temperature-dependent loss of protection when compared with single-dose cardioplegia; the recoveries of cardiac output were 75.7% +/- 1.5%, 78.4% +/- 4.8%, 65.0% +/- 5.8%, 36.7% +/- 5.8%, 34.6% +/- 7.5%, 25.9% +/- 6.0%, and 9.6% +/- 6.4%, respectively. These results were reflected in other indices of cardiac function and in changes in vascular resistance during cardioplegic infusion and reperfusion. To ascertain whether the progressive loss of protection was related to the degree of hypothermia or the duration of ischemia (which had to be increased as the temperature was lowered to permit a 55% to 75% recovery in the single-dose cardioplegia group), we conducted studies at a fixed temperature (20 degrees C) with variable durations of ischemia (6, 8, 10, and 12 hours). Finally, multidose and single-dose cardioplegia at 10.0 degrees, 20.0 degrees, and 37.0 degrees C were compared with hypothermia alone. We concluded that in the neonatal (in contrast to the adult) rabbit heart the protective properties of multidose cardioplegia relative to single-dose cardioplegia are progressively lost.(ABSTRACT TRUNCATED AT 400 WORDS)     

Is protection of ischemic neonatal myocardium by cardioplegia species dependent?

Hypothermia combined with pharmacologic cardioplegia protects the globally ischemic adult heart, but this benefit may not extend to children, resulting in poor postischemic recovery of function and increased mortality. The relative susceptibilities to ischemia modified by hypothermia alone and by hypothermia plus cardioplegia were assessed in isolated perfused neonatal (3- to 4-day-old) rabbit and pig hearts. Hearts were perfused aerobically with Krebs buffer solution in the working mode for 30 minutes and aortic flow was recorded. This was followed by 3 minutes of hypothermic (14 degrees C) coronary perfusion with either Krebs or St. Thomas' Hospital cardioplegic solution No. 2 followed by hypothermic (14 degrees C) global ischemia (rabbits 2, 4, and 6 hours; pigs 2 and 4 hours). Hearts were reperfused for 15 minutes in the Langendorff mode and 30 minutes in the working mode, and recovery of postischemic aortic flow was measured. Hypothermia alone provided excellent protection of the ischemic neonatal rabbit heart, with recovery of aortic flow after 2 and 4 hours of ischemia at 91% +/- 4% and 87% +/- 5% (mean +/- standard deviation) of its preischemic value. Recovery after 6 hours of ischemia was depressed to 58% +/- 9% of its preischemic value. Ischemic neonatal pig hearts protected with hypothermia alone recovered 94% +/- 3% of preischemic aortic flow after 2 hours; none was able to generate flow after 4 hours. St. Thomas' Hospital solution No. 2 decreased postischemic aortic flow after 4 hours of ischemia in rabbit hearts from 87% +/- 5% to 70% +/- 7% (p less than 0.05, hypothermia alone versus hypothermia plus cardioplegia) but improved postischemic recovery of aortic flow in pig hearts after 4 hours of ischemia from 0 to 73% +/- 13% (p less than 0.0001, hypothermia alone versus hypothermia plus cardioplegia). This effect was dose related in both species. We conclude that the neonatal pig heart is more susceptible to ischemia modified by hypothermia alone than the neonatal rabbit and that St. Thomas' Hospital solution No. 2 improves postischemic recovery of function in the neonatal pig but decreases it in the neonatal rabbit. This species-dependent protection of the neonatal heart may be related to differences in the extent of myocardial maturity at the time of study.     

Comparison of the protective properties of four clinical crystalloid cardioplegic solutions in the rat heart

Although few surgeons dispute the benefits of high-potassium crystalloid cardioplegia, objective comparison of the efficacy of various formulations is difficult in clinical practice. We compared four commonly used cardioplegic solutions in the isolated rat heart (N = 6 for each solution) subjected to 180 minutes of hypothermic (20 degrees C) ischemic arrest with multidose cardioplegia (3 minutes every half-hour). The clinical solutions studied were St. Thomas' Hospital solution, Tyers' solution, lactated Ringer's solution with added potassium, and a balanced saline solution with glucose and potassium. Postischemic recovery of function was expressed as a percentage of preischemic control values. Release of creatine kinase during reperfusion was measured as an additional index of protection. St. Thomas' Hospital solution provided almost complete recovery of all indexes of cardiac function following ischemia including 88.1 +/- 1.6% recovery of aortic flow, compared with poor recovery for the Tyers', lactated Ringer's, and balanced saline solutions (20.6 +/- 6.5%, 12.5 +/- 6.4%, and 9.6 +/- 4.2%, respectively) (p less than 0.001). Spontaneous defibrillation was rapid (less than 1 minute) and complete (100%) in all hearts in the St. Thomas' Hospital solution group, but much less satisfactory with the other formulations. Finally, St. Thomas' Hospital solution had a low postischemic level of creatine kinase leakage, contrasting with significantly higher enzyme release in the other solutions tested (p less than 0.001). Although differences in composition are subtle, all potassium crystalloid cardioplegic solutions are not alike in the myocardial protection they provide. Comparative studies under controlled conditions are important to define which formulation is superior for clinical application.     

Protection of the immature myocardium. An experimental evaluation of topical cooling, single-dose, and multiple-dose administration of St. Thomas' Hospital cardioplegic solution

Low cardiac output in infants after cardiac operations continues to be a problem, yet little experimental work has been done to evaluate the various methods of protecting the immature myocardium. In this study, we have used an isolated working heart model to test three methods of myocardial protection in 3- to 4-week-old rabbit hearts: (1) topical cooling, (2) single-dose cardioplegia plus topical cooling, and (3) multiple-dose cardioplegia plus topical cooling. Myocardial temperature was maintained at 10 degrees C during ischemia, and St. Thomas' Hospital solution was used for cardioplegia. Sets of 18 hearts were subjected to 60, 90, or 120 minutes of ischemia, and within each set six hearts were protected by all three methods. After 90 and 120 minutes of ischemia, the percent recovery of aortic flow (expressed as mean +/- standard error of the mean) was lower in hearts protected with multiple-dose cardioplegia plus topical cooling (61.5% +/- 4.8%, 50.7% +/- 14.2%) than in those protected with topical cooling (92.4% +/- 5.7%, 94.3% +/- 12.8%) or single-dose cardioplegia plus topical cooling (86.4% +/- 5.3%, 90.2 +/- 3.6%). However, adenosine triphosphate, creatine phosphate, and glycogen levels were adequately preserved in all groups. Both topical cooling and single-dose cardioplegia provide effective protection for the immature rabbit heart during ischemia, but multiple-dose cardioplegia plus topical cooling results in inadequate preservation of hemodynamic function, despite adequate preservation of myocardial high-energy phosphate stores.     

Protection of the myocardium during global ischemia. Is crystalloid cardioplegia effective in the immature myocardium?

In pediatric cardiac operations, a high proportion of hospital deaths are believed to result from inadequate myocardial protection during the period of global ischemia. To investigate whether this may be due to an inherently lower resistance to myocardial ischemia or to the failure of conventional cardioplegia to afford adequate protection in the immature heart, we have conducted a series of studies with isolated hearts from neonatal (3 to 5 days old, body weight 6.3 to 13.4 gm) and adult (84 to 112 days old, 260 to 340 gm) rats. The efficacy of cardioplegia was assessed in neonatal hearts (n = 6 per group) subjected to various durations of normothermic ischemia, with and without a 2-minute preischemic infusion of the St. Thomas' Hospital cardioplegic solution. At all times studied, the use of cardioplegia resulted in a greater postischemic recovery of left ventricular developed pressure and first derivative of left ventricular pressure. After periods of ischemia lasting 30, 60, 90, 120, and 150 minutes in the absence of cardioplegia, left ventricular developed pressure recovered to 80% +/- 10%, 66% +/- 11%, 53% +/- 7%, 33% +/- 6%, and 21% +/- 4% of preischemic values, respectively; in the presence of cardioplegia, the values were 89% +/- 6%, 83% +/- 8%, 74% +/- 6% (p less than 0.05), 58% +/- 5% (p less than 0.05), and 41% +/- 7% (p less than 0.05), respectively. The corresponding values for first derivative of left ventricular pressure were 78% +/- 9%, 67% +/- 12%, 54% +/- 7%, 30% +/- 5%, and 19% +/- 3% in the absence of cardioplegia and 92% +/- 7%, 88% +/- 8%, 75% +/- 8%, 56% +/- 5% (p less than 0.05) and 39% +/- 6% (p less than 0.05) in the presence of cardioplegia. In the noncardioplegia groups, 90% of hearts exhibited ischemic contracture (mean time to onset = 24.7 +/- 1.1 minutes), whereas in the cardioplegia groups, only 63% exhibited contracture, and of a significantly delayed onset (37.0 +/- 1.5 min, p less than 0.05). Adult hearts (n = 5) subjected to 30 minutes of normothermic ischemic arrest, in the absence of cardioplegia, recovered 36% +/- 7% of the preischemic left ventricular developed pressure and 37% +/- 9% of the preischemic first derivative of left ventricular pressure on reperfusion; 100% of these hearts exhibited some degree of contracture (mean time to onset = 15.4 +/- 1.1 minutes) by the end of the ischemic period.(ABSTRACT TRUNCATED AT 400 WORDS)     

Lowering the calcium concentration in St. Thomas' Hospital cardioplegic solution improves protection during hypothermic ischemia

The concentration of calcium (1.2 mmol/L) in clinical St. Thomas' Hospital cardioplegic solution was chosen several years ago after dose-response studies in the normothermic isolated heart. However, recent studies with creatine phosphate in St. Thomas' Hospital solution demonstrated that additional myocardial protection during hypothermia resulted principally from its calcium-lowering effect in the solution. The isolated working rat heart model was therefore used to establish the optimal calcium concentration in St. Thomas' Hospital solution during lengthy hypothermic ischemia (20 degrees C, 300 minutes). The calcium content of standard St. Thomas' Hospital solution was varied from 0.0 to 1.5 mmol/L in eight treatment groups (n = 6 for each group). During ischemia, hearts were exposed to multidose cardioplegia (3 minutes every 30 minutes). Postischemic recovery of function was expressed as a percentage of preischemic control values. Release of creatine kinase and the time to return of sinus rhythm during the reperfusion period were also measured. These dose-response studies during hypothermic ischemia revealed a broad range of acceptable calcium concentrations (0.3 to 0.9 mmol/L), which appear optimal in St. Thomas' Hospital solution at 0.6 mmol/L. This concentration improved the postischemic recovery of aortic flow from 22.0% +/- 5.9% with control St. Thomas' Hospital solution (calcium concentration 1.2 mmol/L) to 86.0% +/- 4.0% (p less than 0.001). Other indices of functional recovery showed similar dramatic results. Creatine kinase release was reduced 84% (p less than 0.01) in the optimal calcium group. Postischemic reperfusion arrhythmias were diminished with the loser calcium concentration, with a significant decrease in the time between initial reperfusion until the return of sinus rhythm. In contrast, acalcemic St. Thomas' Hospital solution precipitated the calcium paradox with massive enzyme release and no functional recovery. Unlike prior published calcium dose-response studies at normothermia, these results demonstrate that the optimal calcium concentration during clinically relevant hypothermic ischemia is considerably lower than that of normal serum ionized calcium (1.2 mmol/L) and appears ideal at 0.6 mmol/L to realize even greater cardioprotective and antiarrhythmic effects with St. Thomas' Hospital solution.     

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.     

Protection of the neonatal heart following normothermic ischemia: a comparison of oxygenated saline and oxygenated versus nonoxygenated cardioplegia

Optimal methods of myocardial preservation in the neonate remain unknown. Hypothermia and cardioplegia have been shown to protect neonatal hearts, but few studies have examined the effects of cardioplegia when administered at normothermia. Accordingly, the role of 37 degrees C St. Thomas' cardioplegic solution in protecting the neonatal heart during 1 hour of ischemia in an isolated working rabbit heart model was examined. Both oxygenated and nonoxygenated cardioplegic solutions (CSs) were evaluated and compared with an oxygenated physiological saline solution (PSS). Following ischemia, control hearts were characterized by severely impaired left ventricular function, whereas all three treatment groups recovered well, indicating that the treatments provided substantial protection. Aortic flow recovered to 62, 63, and 57% of preischemic values for the oxygenated CS, nonoxygenated CS, and oxygenated PSS groups, respectively. Similarly, rate of change of pressure recovered to 76, 80, and 76% of preischemic values for oxygenated CS, nonoxygenated CS, and oxygenated PSS groups. All values were significantly greater than those for the control group. Recovery of developed pressure was significantly improved in all three groups. End-diastolic pressure rose markedly following ischemia in control hearts, was not increased after ischemia in hearts receiving oxygenated and nonoxygenated CS, but was increased in the oxygenated PSS group. These data indicate that crystalloid cardioplegia and oxygenated PSS provide substantial protection in neonatal rabbit hearts, even when delivered at 37 degrees C. No additional benefit was seen when the cardioplegic solution was oxygenated. Therefore, either method of balancing the oxygen supply/demand ratio appears to be beneficial: supplying oxygen intermittently during ischemia (oxygenated PSS group) or decreasing oxygen demand during the ischemic period (cardioplegia groups).     

The effectiveness of University of Wisconsin solution on prolonged myocardial protection as assessed by phosphorus 31-nuclear magnetic resonance spectroscopy and functional recovery.

The effectiveness of the University of Wisconsin solution on extended myocardial preservation was examined in this study using phosphorus 31-nuclear magnetic resonance spectroscopy. Isolated perfused rat hearts were arrested and stored in four preservation solutions: group 1, modified Krebs-Henseleit solution; group 2, modified St. Thomas' Hospital solution; group 3, oxygenated modified St. Thomas' Hospital solution containing 11 mmol/L glucose; and group 4, University of Wisconsin solution. The changes in myocardial high energy phosphate profiles and the intracellular pH values were measured during 12 hours of cold (4 degrees C) global ischemia and 90 minutes of normothermic reperfusion. Following ischemia, the hearts were assessed for hemodynamic recovery and myocardial water content. During ischemia, adenosine triphosphate depletion was observed in all groups; however, after 5 hours of ischemia, the adenosine triphosphate levels were significantly higher in group 3 compared with the other groups (adenosine triphosphate levels at 6 hours in mumol/gm dry weight: group 3, 7.6; group 4, 3.2; group 2, < 1; p < 0.025). The tissue water content at the end of ischemia was lower with the University of Wisconsin solution compared with the modified St. Thomas' Hospital solution or the oxygenated modified St. Thomas' Hospital solution (in ml/gm dry weight: group 4, 3.0; group 2, 4.4; group 3, 3.9; p < 0.05). The adenosine triphosphate repletion during reperfusion was greater with the University of Wisconsin solution compared with the modified St. Thomas' Hospital solution or the oxygenated modified St. Thomas' Hospital solution (12 mumol/gm dry weight in group 4; 8.1 in group 2; 9.0 in group 3; p < 0.05). Similar findings were obtained for the recovery of left ventricular pressure (in percent of preischemic control: group 4, 70%; group 2, 42%; group 3, 52%; p < 0.01) and coronary flow (group 4, 61%; group 2, 49%; group 3, 49%; p < 0.05). These data suggest that preservation with the University of Wisconsin solution affords improved hemodynamic recovery, enhanced adenosine triphosphate repletion, and reduced tissue edema upon reperfusion; however, oxygenated St. Thomas' Hospital solution with glucose is associated with the preservation of higher myocardial adenosine triphosphate levels during prolonged cold global ischemia. In conclusion, these data indicate that the University of Wisconsin solution might improve graft tolerance of ischemia in clinical heart transplantation.     

Effect of multidose cardioplegia and cardioplegic solution buffering on myocardial tissue acidosis

Multidose administration of cardioplegic solution during cardiac operation is intended to maintain both electromechanical arrest of the heart and myocardial hypothermia as well as to remove accumulated metabolites of anaerobic glycolysis. This study was conducted to assess the effect of multidose infusion of three different types of cardioplegic solution on tissue acidosis during global myocardial ischemia. Three groups of five dogs each were placed on cardiopulmonary bypass and the aorta was cross-clamped for 3 hours. The hearts were maintained at a constant temperature (20 degrees C) and cardioplegic solution was infused at an initial dose of 500 ml and five supplementary doses of 250 ml administered every 30 minutes. Group 1 received a crystalloid solution weakly buffered with sodium bicarbonate, Group 2 received a blood-based solution, and Group 3 received a crystalloid solution strongly buffered with histidine (Bretschneider's solution). The buffering capacities of the solutions used in Groups 2 and 3 were 40 and 60 times, respectively, that of the solution used in Group 1. The average myocardial tissue pH at the end of 3 hours of ischemia was 6.54 +/- 0.07 in Group 1, 7.23 +/- 0.05 in Group 2, and 7.19 +/- 0.06 in Group 3 (Group 1 significantly lower than Groups 2 and 3). Multidose infusion of a cardioplegic solution with low buffering capacity was unable to prevent the progressive development of tissue acidosis during 3 hours of ischemia. However, the multidose infusion of either blood-based or crystalloid solutions with high buffering capacity completely prevented any further reduction of tissue pH after the first 30 minutes of ischemia.     

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)     

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.     

Comparison of ischemic vulnerability and responsiveness to cardioplegic protection in crystalloid-perfused versus blood-perfused hearts.

The possibility of differences between crystalloid-perfused and blood-perfused hearts in their vulnerability to ischemia and responsiveness to protective interventions has been investigated in isolated rabbit hearts perfused with bicarbonate buffer or arterial blood. In preliminary studies with 165 minutes of aerobic perfusion at constant perfusion pressure (55 +/- 3 mm Hg), the stability of left ventricular developed pressure was significantly better in blood-perfused hearts. In subsequent studies, hearts were subjected to 20 minutes of aerobic perfusion (coronary flow, 2.0 +/- 0.3 ml/min/gm wet weight in blood-perfused hearts versus 11.3 +/- 3.0 ml/min/gm wet weight in crystalloid-perfused hearts; left ventricular developed pressure, 90 +/- 4 and 91 +/- 2 mm Hg, respectively) followed by 30, 45, 60, 75, 90, or 105 minutes of normothermic global ischemia and 40 minutes of reperfusion (n = 4 per group). In the buffer-perfused groups the postischemic recoveries of left ventricular developed pressure were 74% +/- 6%, 45% +/- 7%, 39% +/- 6% 32%, +/- 5%, 27% +/- 4%, and 12% +/- 3% of preischemic control, respectively. In blood-perfused groups they were consistently greater (91% +/- 3%, 55% +/- 5%, 46% +/- 5%, 45% +/- 1%, 33% +/- 2%, and 19% +/- 3%, respectively). In further studies, hearts (n = 5 per group) were perfused with buffer (groups 1 and 2) or blood (groups 3 and 4), and each was subjected to 60 minutes of normothermic global ischemia, with (groups 2 and 4) or without (groups 1 and 3) a 3-minute preischemic infusion of St. Thomas' Hospital cardioplegic solution. After 60 minutes of reperfusion, the postischemic recoveries of left ventricular developed pressure in groups 1, 2, 3, and 4 were 32% +/- 3%, 44% +/- 4%, 43% +/- 7%, and 72% +/- 6%, respectively, with coronary flow recovering to 64% +/- 7%, 82% +/- 4%, 82% +/- 4%, and 110% +/- 5%, respectively. Left ventricular end-diastolic pressures were 20 +/- 5, 24 +/- 7, 15 +/- 4, and 4 +/- 3 mm Hg, and tissue water contents were 4.76 +/- 0.11, 4.87 +/- 0.55, 3.93 +/- 0.05, and 3.68 +/- 0.02 ml/gm dry weight, respectively. In conclusion, compared with crystalloid perfusion, the blood-perfused rabbit heart has a greater resistance to ischemia, a superior response to cardioplegic protection, and a lower tissue water content.     

Calcium content of St. Thomas' II cardioplegic solution damages ischemic immature myocardium

Clinical application of hypothermic pharmacologic cardioplegia in pediatric cardiac surgery is less than satisfactory, despite its well known benefits in adults. Protection of the ischemic immature rabbit heart with hypothermia alone is better than with hypothermic St. Thomas' II cardioplegic solution. Control of cellular calcium is a critical component of cardioplegic protection. We determined whether the existing calcium content of St. Thomas' II solution (1.2 mmol/L) is responsible for suboptimal protection of the ischemic immature rabbit heart. Modified hypothermic St. Thomas' II solutions (calcium content, 0 to 2.4 mmol/L) were compared with hypothermic Krebs bicarbonate buffer in protecting ischemic immature (7- to 10-day-old) hearts. Hearts (n = 6 per group) underwent aerobic "working" perfusion with Krebs buffer, and cardiac function was measured. The hearts were then arrested with a 3-minute infusion of either cold (14 degrees C) Krebs buffer (1.8 mmol calcium/L) as hypothermia alone or cold St. Thomas' II solution before 6 hours of hypothermic (14 degrees C) global ischemia. Hearts were reperfused, and postischemic enzyme leakage and recovery of function were measured. A bell-shaped dose-response profile for calcium was observed for recovery of aortic flow but not for creatine kinase leakage, with improved protection at lower calcium concentrations. Optimal myocardial protection occurred at a calcium content of 0.3 mmol/L, which was better than with hypothermia alone and standard St. Thomas' II solution. We conclude that the existing calcium content of St. Thomas' II solution is responsible, in part, for its damaging effect on the ischemic immature rabbit heart.