Studies of controlled reperfusion after ischemia. XXI. Reperfusate composition: superiority of blood cardioplegia over crystalloid cardioplegia in limiting reperfusion damage--importance of endogenous oxygen free radical scavengers in red blood cells

Postischemic damage is caused partially by oxygen free radical-mediated injury. This study will show that (1) crystalloid cardioplegia with room air oxygen is deleterious because it is devoid of free radical scavengers and (2) blood cardioplegia limits damage because it contains endogenous free radical scavengers in red blood cells. METHODS: Thirty-two dogs underwent 2 hours of ligation of the left anterior descending coronary artery followed by 20 minutes of regional blood cardioplegic reperfusion on bypass. Ten dogs received only the blood cardioplegic solution (containing its endogenous free radical scavengers); five received initial blood cardioplegia (5 minutes) with endogenous free radical scavengers (catalase and glutathione peroxidase) blocked by aminotriazole and N-ethylmaleimide, respectively; 12 received initial crystalloid cardioplegic solution oxygenated by room air (oxygen tension = 150 mm Hg); seven without and five with exogenous free radical scavengers (superoxide dismutase, catalase, coenzyme Q10); five received initial deoxygenated crystalloid cardioplegic solution (oxygen tension = 6 mm Hg); and five received deoxygenated crystalloid cardioplegic solution. RESULTS: Blood cardioplegia with endogenous free radical scavengers produced the best recovery of systolic shortening (69% systolic shortening) and resulted in the least histochemical damage (11% triphenyltetrazolium chloride nonstaining). The worst recovery and most damage occurred if blood cardioplegia was preceded by oxygenated crystalloid cardioplegia (3% systolic shortening, 48% triphenyltetrazolium chloride nonstaining; p less than 0.05 versus blood cardioplegia) or if free radical scavengers were blocked in the initial period of blood cardioplegia (3% systolic shortening, 41% triphenyltetrazolium chloride nonstaining; p less than 0.05 versus blood cardioplegia). Conversely, deoxygenation or supplementation of oxygenated crystalloid cardioplegic solution with exogenous free radical scavengers restored 60% systolic shortening (p less than 0.05 versus oxygenated crystalloid cardioplegia) and 54% systolic shortening (p less than 0.05 versus oxygenated crystalloid cardioplegia) and reduced damage to 34% and 21% (both p less than 0.05 versus oxygenated crystalloid cardioplegia). CONCLUSION: Blood cardioplegic solutions containing their own endogenous free radical scavengers are superior to crystalloid cardioplegic solutions, because they limit oxygen-mediated perfusion damage and restore contractile function. Initial crystalloid cardioplegic washout negates the salutary effect of blood cardioplegia. Exogenous free radical scavenger supplementation or deoxygenation of the cardioplegic reperfusate is necessary only if crystalloid cardioplegia is used.     

Studies of controlled reperfusion after ischemia. XIX. Reperfusate composition: benefits of blood cardioplegia over fluosol DA cardioplegia during regional reperfusion--importance of including blood components in the initial reperfusate

HYPOTHESIS: Initial reoxygenation with blood cardioplegic solution produces better regional recovery than with Fluosol DA cardioplegic solution (Green Cross Corporation, Osaka, Japan) because blood cardioplegia ensures delivery of important blood components (i.e., plasma and red blood cells) that limit reperfusion damage. METHODS: Twenty-five dogs underwent 2 hours of ligation of the left anterior descending coronary artery followed by controlled reperfusion at 50 mm Hg through an internal mammary graft on total vented bypass. Five dogs received normal blood reperfusion, 10 dogs received a 20-minute reperfusion with Fluosol DA 20% cardioplegic solution, and 10 others received a blood cardioplegic reperfusate of identical composition (i.e., pH, calcium, potassium, glucose, osmolarity). Regional oxygen consumption was measured during reperfusion, and segmental shortening (ultrasonic crystals), tissue water content, and histochemical damage (triphenyltetrazolium chloride stain) were assessed 2 hours later. RESULTS: Reperfusion with normal blood failed to restore contractile function (3% systolic shortening), caused severe edema (81% water content), and caused marked histochemical damage (48% triphenyltetrazolium chloride nonstaining). Hearts reperfused with Fluosol DA cardioplegic solution did not take up as much oxygen as hearts receiving blood cardioplegic reperfusion (37 versus 54 ml/100 gm, p less than 0.05). Blood cardioplegia was superior to Fluosol DA cardioplegia in recovery of segmental contractility (69% versus 34% systolic shortening, p less than 0.05), produced less edema (79.5% versus 80.9% water content, p less than 0.05), and produced less histochemical damage with triphenyltetrazolium chloride (11% versus 40% area of nonstaining/area at risk, p less than 0.05). CONCLUSIONS: Initial reperfusion with a blood cardioplegic solution ensures better oxygen utilization, superior recovery of regional contractility, and less tissue damage than Fluosol DA cardioplegic reperfusion. These data emphasize the importance of including blood components (plasma or red blood cells) in the oxygenated cardioplegic reperfusate to limit reperfusion injury.     

Studies of controlled reperfusion after ischemia. XXII. Reperfusate composition: effects of leukocyte depletion of blood and blood cardioplegic reperfusates after acute coronary occlusion

OBJECTIVES: This study evaluates the role of leukocyte depletion during initial reoxygenation with normal blood and blood cardioplegic reperfusates in limiting reperfusion damage. METHODS: Twenty-eight dogs underwent 2 hours of ligation of the left anterior descending coronary artery. The initial reperfusate (37 degrees C) was delivered on total vented bypass to the left anterior descending artery by a calibrated pump via an internal mammary artery graft at 50 mm Hg for 20 minutes. Eight dogs received normal (normokalemic, nonenriched) blood reperfusion (leukocyte count 8000/mm3) and six were reperfused with leukocyte-depleted normal blood (leukocyte count less than 100/mm3). Of 14 dogs reperfused with substrate-enriched (hyperkalemic) blood cardioplegic solution, six received a cardioplegic solution with a leukocyte count less than 100/mm3. RESULTS: Leukocyte depletion of normal blood reduced reperfusion-induced arrhythmias from 63% to 17% (p less than 0.05). Coronary vascular resistance at initial reperfusion was low and remained low during substrate-enriched blood cardioplegic reperfusion with both normal and reduced leukocyte counts. In contrast, coronary vascular resistance rose 63% with normal blood reperfusion, and this increase was avoided by leukocyte depletion (2.6 versus 4.0 mm Hg x ml/min, p less than 0.05). Coronary vascular resistance after 20 minutes was, however, higher than that with blood cardioplegia with normal or decreased leukocyte counts. Negligible functional recovery followed reperfusion with normal blood and leukocyte-depleted blood (12% and 6% of control systolic shortening). In contrast, substantial segmental recovery followed blood cardioplegic reperfusion (73% systolic shortening, p less than 0.05) but was not improved by leukopheresis (81% systolic shortening). Leukocyte depletion of normal blood reperfusate reduced histochemical damage from 53% to 38% (p less than 0.05), but the least histochemical damage followed blood cardioplegic reperfusion with a normal or reduced leukocyte count (8% or 11%, p less than 0.05). CONCLUSIONS: These findings suggest an important role for leukocytes in reperfusion damage, but reperfusate leukocyte filtration alone is inferior to blood cardioplegic reperfusion. Leukocyte depletion of blood cardioplegic solutions seems unnecessary after only 2 hours of ischemia.     

Studies of controlled reperfusion after ischemia. XVII. Reperfusion conditions: controlled reperfusion through an internal mammary artery graft--a new technique emphasizing fixed pressure versus fixed flow

This study tests the usefulness of delivering a controlled reperfusate through an internal mammary graft after acute ischemia by applying a percutaneous technique of mammary artery cannulation and compares reperfusion at fixed pressure versus fixed flow. Methods: Twenty-one dogs underwent 2 hours of ligation of the left anterior descending coronary artery followed by regional controlled revascularization on total vented bypass. A reperfusion catheter was introduced percutaneously from the brachial artery into the internal mammary artery. Five dogs received normal blood reperfusion at 50 mm Hg pressure, and eight dogs received a regional blood cardioplegic reperfusate at 50 mm Hg before reperfusion with normal blood. Eight additional dogs received regional cardioplegia at 30 ml/min for 20 minutes. Coronary vascular resistance, segmental shortening (ultrasonic crystals), tissue water content, and histochemical damage (triphenyltetrazolium chloride stain) were assessed. Results: Reperfusion with normal blood increased coronary vascular resistance progressively to 62% above initial values (p less than 0.05) and failed to restore regional contractility (9% +/- 6% systolic shortening, p less than 0.05). In contrast, coronary resistance remained low throughout blood cardioplegic reperfusion at fixed pressure and the reperfused muscle recovered immediate contractility (73% systolic shortening, p less than 0.05). Controlled reperfusion at a fixed flow rate resulted in pressure that ranged from 30 to 80 mm Hg, slightly less recovery of systolic shortening (57%), and less return of contractile reserve (81% versus 114%, p less than 0.05). Regional blood cardioplegic reperfusion limited edema formation (79.5 versus 82% water content, p less than 0.05) and histochemical damage (11% versus 50% area of necrosis/area at risk, p less than 0.05). Conclusion: An internal mammary artery graft can be used effectively in the setting of acute ischemia if a controlled blood cardioplegic reperfusate is delivered through it to ensure limitation of histochemical damage, low reflow phenomenon, and restoration of immediate segmental contractility. Controlled-pressure reperfusion seems superior to fixed-flow reperfusion. A technique is described that may allow preoperative insertion of the reperfusion catheter in the internal mammary artery in the catheterization laboratory.     

Myocardial protection during prolonged aortic cross-clamping. Comparison of blood and crystalloid cardioplegia

We compared the ability of blood and crystalloid cardioplegia to protect the myocardium during prolonged arrest. Twelve dogs underwent 180 minutes of continuous arrest. Group I (six dogs) received 750 ml of blood cardioplegic solution (potassium chloride 30 mEq/L) initially and every 30 minutes. Group II (six dogs) received an identical amount of crystalloid cardioplegic solution (potassium chloride 30 mEq, methylprednisolone 1 gm, and 50% dextrose in water 16 ml/L of electrolyte solution). Temperature was 10 degrees C and pH 8.0 in both groups. Studies of myocardial biochemistry, physiology, and ultrastructure were completed before arrest and 30 minutes after normothermic reperfusion. Biopsy specimens for determination of adenosine triphosphate were obtained before, during, and after the arrest interval. Regional myocardial blood flow, total coronary blood flow, and myocardial oxygen consumption were statistically unchanged in Group I (p greater than 0.05). Total coronary blood flow rose 196% +/- 49% in Group II (p less than 0.005), and left ventricular endocardial/epicardial flow ratio fell significantly in this group from 1.51 +/- 0.18 to 0.8 +/- 0.09, p less than 0.01 (mean +/- standard error of the mean. The rise in myocardial oxygen consumption was not significant in this group (34% +/- 36%, p greater than 0.05). Ventricular function and compliance were statistically unchanged in both groups. In Group II, adenosine triphosphate fell 18% +/- 3.4% (p less than 0.005) after 30 minutes of reperfusion; it was unchanged in Group I. Ultrastructural appearance in both groups correlated with these changes. We conclude that blood cardioplegia offers several distinct advantages over crystalloid cardioplegia during prolonged arrest.     

Studies of retrograde cardioplegia. I. Capillary blood flow distribution to myocardium supplied by open and occluded arteries

This study defines the nutritive (i.e., capillary) distribution of blood cardioplegic solutions delivered via retrograde and antegrade techniques to muscle supplied by open and occluded coronary arteries where myocardial segments are in jeopardy of inadequate cardioplegic protection. Open-chest anesthetized dogs were studied by mixing radioactive microspheres (15 +/- 5 microns) with a blood cardioplegic solution and administering cardioplegia either into the coronary sinus or into the proximal aorta with the left anterior descending coronary artery open or occluded (30% +/- 2% area at risk). Nutritive flow (i.e., percentage of delivered 15 microns microspheres trapped in myocardial capillaries) during retrograde infusions averaged 65% versus 87% with antegrade cardioplegia (p less than 0.05). Retrograde and antegrade cardioplegic nutritive flow to all left ventricular regions was comparable with the left anterior descending coronary artery open (65 versus 82 ml/100 gm/min, p greater than 0.05), and both methods provided preferential hyperperfusion of subendocardial muscle (endocardial/epicardial ratios 1.6 and 1.5, respectively). Nutritive flow to muscle supplied by the occluded left anterior descending coronary artery was preserved better by retrograde than antegrade cardioplegia (35 versus 5 ml/100 gm/min, p less than 0.05). Preferential subendocardial hyperperfusion was maintained during retrograde cardioplegia (52 ml/100 gm/min, endocardial/epicardial ratio 1.6), but flow was redistributed away from subendocardial muscle with antegrade cardioplegia (less than 2 ml/100 gm/min, endocardial/epicardial, 0.29, p less than 0.05). Left ventricular flow was reduced markedly during retrograde infusion with the left anterior descending coronary artery open or occluded (23 and 12 ml/100 gm/min), but septal cooling was superior to antegrade cardioplegia (15 degrees +/- 1 degree C versus 20% +/- 3%, p less than 0.05) despite near-normal antegrade septal flow (the left anterior descending coronary artery was ligated beyond the first septal branch). Right ventricular nutritive flow was only 7 ml/100 gm/min during retrograde coronary sinus perfusion and was maintained normally with antegrade cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Overdose reperfusion of blood cardioplegic solution. A preventable cause of postischemic myocardial depression

Reperfusion of warm blood cardioplegic solution is useful in minimizing reperfusion damage after ischemia. This study tests the hypothesis that overzealous administration of blood cardioplegic solution at reperfusion counteracts these benefits and can lead to a prevalence of depressed ventricular performance and mortality similar to that seen after normal blood reperfusion. Thirty-one dogs underwent 45 minutes of 37 degrees C global ischemia on vented bypass. Six received normal blood reperfusion and 25 were reperfused with a warm aspartate/glutamate-enriched blood cardioplegic solution; of these, eight received high-dose (3600 +/- 600 ml) and 17 received limited-dose (1180 +/- 120 ml) blood cardioplegic reperfusion over 10 to 20 minutes. High-dose blood cardioplegic perfusion (5100 +/- 200 ml) without prior ischemia was tested in an additional five dogs. High-dose blood cardioplegia without preceding ischemia did not alter ventricular function (peak stroke work index 96% of control). After ischemia, normal blood reperfusion (no cardioplegia) resulted in marked left ventricular dysfunction (peak stroke work index 36% of control, p less than 0.05 versus control) and a 33% mortality rate (2/6 died). High-dose cardioplegic reperfusion yielded marginal recovery of stroke work index (40% of control, p less than 0.05 versus control) and a 25% mortality rate (2/8 died). In contrast, limited-dose reperfusion of blood cardioplegic solution allowed 100% survival (17/17) and restored stroke work index to 90% of control (1.3 versus 1.45 gm.m/kg). We conclude that reperfusion damage can be avoided by initial reoxygenation with limited doses of substrate-enriched blood cardioplegic solution. Conversely, high-dose reperfusion of blood cardioplegic solution offsets this benefit, reduces recovery substantially, and may be lethal.     

Cardioplegia for the immature myocardium. A comparative study in the neonatal rabbit

This study examined the effect of hypothermia (15 degrees C) alone or combined with various cardioplegic solutions on functional recovery of the neonatal heart after 120 minutes of global ischemia in an isolated working rabbit heart model. Control hearts were preserved with hypothermia alone, and groups 1 to 6 were given different hyperkalemic crystalloid cardioplegic solutions. Each cardioplegic solution differed in Na+ and Ca++ content. Aortic flow, coronary flow, cardiac output, heart rate, peak systolic pressure, and stroke work were measured before ischemia and after 35 and 45 minutes of reperfusion. There were no statistical differences in hemodynamic recovery in the six groups in which cardioplegia was used. However, hearts preserved with multidose hyperkalemic cardioplegia showed significantly better recovery of cardiac output (86% versus 75%; p less than 0.05), coronary flow (88% versus 72%; p less than 0.05), and stroke work (86% versus 75%; p less than 0.05) than those preserved with hypothermia alone. These results suggest that hypothermic hyperkalemic cardioplegia improves preservation of the neonatal rabbit heart but that variations in Ca++ and Na+ content appear not to provide further myocardial protection.     

Surgical revascularization of acute (1 hour) coronary occlusion: blood versus crystalloid cardioplegia

This study compares blood versus crystalloid cardioplegia in restoring contractile function, and high-energy phosphate and tissue water content in a myocardial segment after 1 hour of coronary artery occlusion. Anesthetized dogs underwent instrumentation with the chest open to measure left ventricular and aortic pressures, and systolic shortening in the myocardium perfused by the left anterior descending coronary artery (LAD) was measured with ultrasonic crystals. In 21 dogs, the LAD was occluded for an hour, thereby replacing systolic shortening with passive lengthening averaging -28.7 +/- 6.2% of control shortening in both groups. The dogs were then placed on total bypass, and arrest was achieved with multidose crystalloid (N = 10) or blood cardioplegia (N = 11). The ligatures were released just prior to the second infusion of cardioplegic solution. Postischemic subendocardial levels of adenosine triphosphate were comparably depleted with crystalloid and blood cardioplegia (55.2% and 44.0%, respectively, of control). Subendocardial increases in water content were similar for crystalloid (3.62%) and blood (3.16%) cardioplegia. Recovery of segmental shortening was significantly greater with blood than crystalloid cardioplegia (31.5 +/- 8.2% versus 4.9 +/- 6.6% of control, respectively). We conclude that the composition and the delivery of blood cardioplegia used in this study restore greater postischemic function than crystalloid cardioplegia in acute evolving myocardial infarction.     

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.     

Asanguineous reperfusion in a canine model of cardiopulmonary bypass and controlled postischemic work

This study was designed to test the hypothesis that asanguineous reperfusion with a standard crystalloid cardioplegic solution results in improved myocardial salvage after a period of global ischemia. Four groups of 6 dogs each were placed on cardiopulmonary bypass. Control group A (work only) performed two hours of controlled work by contracting against a saline-filled left intraventricular balloon. Control group B (ischemia only) underwent 45 minutes of global normothermic ischemia before simple blood reperfusion while supported on bypass. Groups C and D were subjected to ischemia and reperfusion as in group B, followed by controlled work stress as in group A. Group D, however, received 500 mL of St. Thomas' Hospital solution immediately before blood reperfusion. Morphological analysis showed no significant injury in groups A and B, whereas group C had 11.4% +/- 2.4% necrosis of heart mass versus 2.5% +/- 1.1% in group D (p less than 0.001). Biochemical data from left ventricular biopsies showed no significant differences between groups B, C, and D. Functional analyses showed deterioration of diastolic compliance in group C (p less than 0.05), although a significant difference in systolic functional indexes could not be detected. Myocardial protection and salvage was improved by initial reperfusion with an asanguineous cardioplegic solution versus reperfusion with blood alone.     

The effect of oxygen free radical scavengers on the recovery of regional myocardial function after acute coronary occlusion and surgical reperfusion

This study investigated the effects of the oxygen free radical scavengers superoxide dismutase and catalase, the peroxide ion inhibitor, in crystalloid potassium cardioplegic solution on infarct size and global and regional myocardial function after occlusion of the left anterior descending artery and surgical reperfusion in young sheep on cardiopulmonary bypass. After 1 hour of occlusion, the animals were randomized to receive either routine potassium cardioplegia or cardioplegia with superoxide dismutase and catalase. Global hemodynamics measured by maximum rate of pressure rise showed significant improvement after 5 hours of reperfusion in the group treated with superoxide dismutase and catalase (1843 +/- 163 versus 979 +/- 191, p less than 0.001). Regional myocardial function was measured by ultrasonic crystals implanted in the ischemic area and in a nonischemic control segment. The percent systolic shortening or bulging was calculated. At end of reperfusion in the animals treated with superoxide dismutase and catalase, there was active shortening in the ischemic area after reperfusion of +9.2% +/- 0.4% versus 2.1% +/- 0.8% in untreated animals (p less than 0.001). Infarct size measured by triphenyltetrazolium chloride staining showed significant difference (p less than 0.001) between animals treated with superoxide dismutase and catalase (0.9% +/- 0.1%) and control animals (61% +/- 70%). Superoxide dismutase and catalase given in the cardioplegic solution before reperfusion of an acutely ischemic area of myocardium enhances recovery of contractile function and results in a significant reduction in infarct size, which suggests improved salvage of the ischemic myocardium.     

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.     

Studies of controlled reperfusion after ischemia. XVIII. Reperfusion conditions: attenuation of the regional ischemic effect by temporary total vented bypass before controlled reperfusion

This study tests the hypothesis that total vented bypass can attenuate the regional ischemic effect during a defined time interval before controlled blood cardioplegic reperfusion. Thirty-three dogs underwent 2 or 4 hours of occlusion of the left anterior descending coronary artery and then received a regional blood cardioplegic reperfusate on total vented bypass. Cardiopulmonary bypass and reperfusion were started after 2 hours of ischemia in eight dogs, and after 4 hours of ischemia in 25 others. Among the 25 dogs, seven had total vented bypass started after the first 2 hours of the 4 hours of regional ischemia. Segmental shortening (ultrasonic crystals), tissue water content (wet/dry weight), and histochemical damage (triphenyltetrazolium chloride stain) were assessed 2 hours after reperfusion. Dogs reperfused after 2 hours of ischemia recovered 73% +/- 8% of control systolic shortening and sustained only 11% triphenyltetrazolium chloride nonstaining. Dogs undergoing 4 hours of regional ischemia, but with total vented bypass 2 hours before reperfusion had improved recovery of systolic shortening (49% versus 31%, p less than 0.05), limited epicardial edema (79.6% versus 81.1% water content, p less than 0.05), and reduced histochemical damage (24% versus 39% triphenyltetrazolium chloride nonstaining, p less than 0.05). These findings imply that institution of total vented bypass during ischemia attenuates the infarct process, increases regional recovery of contractility, limits edema and restricts histochemical damage, and may be a useful adjunct to myocardial salvage when controlled reperfusion can be provided.     

Studies of controlled reperfusion after ischemia. XXIII. Deleterious effects of simulated thrombolysis preceding simulated coronary artery bypass grafting with controlled blood cardioplegic reperfusion

This study tests whether simulated thrombolysis before controlled reperfusion (i.e., simulated coronary artery bypass) causes reperfusion injury that obviates the benefits of subsequent controlled reperfusion and results in unnecessary ventricular arrhythmias. Fifteen dogs underwent acute occlusion of the left anterior descending coronary artery. In 10 dogs we simulated thrombolysis after 1 hour of ischemia (delivering 10% to 15% of control flow at 5 ml/min), followed 1 hour later by either normal blood reperfusion at systemic pressure (to simulate percutaneous transluminal coronary angioplasty) in five dogs or regionally controlled blood cardioplegic reperfusion on bypass in five others to simulate coronary bypass. In five dogs ischemia was prolonged to 2 hours, and the initial reperfusate was blood cardioplegic solution on total vented bypass (to simulate primary coronary bypass). All hearts receiving simulated thrombolysis (100%) after 1 hour of ischemia had reperfusion-induced ventricular fibrillation. All hearts treated by simulated angioplasty recovered regional contractility (56% of control systolic shortening), whereas there was no (0%) recovery of spontaneous contractility after subsequent blood cardioplegic reperfusion, and only two (40%) dogs had contractile reserve capacity (6% +/- 49%). Conversely, surgically controlled blood cardioplegic reperfusion without preceding low-flow normal blood reperfusion after 2 hours of ischemia resulted in no ventricular arrhythmias (0%; p less than 0.05 versus simulated coronary artery bypass after simulated thrombolysis), 72% +/- 7% (p less than 0.05 versus simulated coronary artery bypass after simulated thrombolysis) recovery of regional contractility (ultrasonic crystals), and 114% +/- 11% (p less than 0.05 versus simulated coronary artery bypass after simulated thrombolysis) recovery of contractile reserve with calcium chloride stimulation. We conclude that controlled reperfusion (simulating coronary artery bypass) with blood cardioplegic solution produces immediate functional recovery and avoids the ventricular fibrillation that follows simulated thrombolysis despite the need for prolonged ischemic time. Preceding controlled reperfusion by normal blood reperfusion (simulated thrombolysis) shortens the ischemic time but nullifies immediate functional recovery possible by simulated coronary bypass and produces unnecessary arrhythmias.     

Intraoperative myocardial protection: a comparison of blood and asanguineous cardioplegia

Cardiac arrest was achieved in 84 patients using asanguineous cardioplegia and in 97 patients using cold blood potassium cardioplegia. The patient groups were similar in age, sex ratio, and preoperative risk factors. Other than the cardioplegic solution used, the conduct of each operation was identical. There were no differences in mean total pump time (118 minutes for the asanguineous cardioplegia group versus 117 minutes for the cold blood cardioplegia group) or cross-clamp time (73.5 versus 70 minutes, respectively). However, the blood cardioplegia group had a greater number of distal anastomoses per patient (3.9 versus 3.7; p less than 0.05). Myocardial protection was assessed clinically and by serial electrocardiograms. Cellular integrity was determined by release of the myocardial isoenzyme of serum creatine kinase (CK-MB). Cellular morphology was studied in 6 randomly selected patients in each group by electron microscopic examination of left ventricular myocardial samples obtained before and after bypass. Three patients given blood cardioplegia and 5 given asanguineous cardioplegia required intraaortic balloon counterpulsation at termination of bypass. There were no ultrastructural changes in either group. Electrocardiographic changes (Minnesota code) occurred in 12 of 84 patients receiving asanguineous cardioplegia versus 12 of 97 patients receiving cold blood potassium cardioplegia. To maintain a satisfactory cardiac index (greater than 2.0 L/min/m2), 38 of 84 patients given asanguineous cardioplegia versus 25 of 97 patients given blood cardioplegia required inotropic support up to 24 hours postoperatively (p less than 0.05). Infarct size determined from CK-MB release was significantly greater (p less than 0.05) in patients given asanguineous cardioplegia (36.27 gm-equivalents) than in those given blood cardioplegia (26.7 gm-equivalents).(ABSTRACT TRUNCATED AT 250 WORDS)     

High-volume crystalloid cardioplegia. An improved method of myocardial preservation

Controlled metabolic studies were used to gauge the relative efficacy of three cardioplegic techniques in 41 patients undergoing multiple coronary artery bypass grafts. Normal-volume (1,946 +/- 155 ml) crystalloid cardioplegia (NVCC) (14 patients) was compared to high-volume (4,961 +/- 282 ml) crystalloid cardioplegia (HVCC) (14 patients) and to blood cardioplegia (BC) (1,672 +/- 127 ml) (13 patients). Measurements of coronary blood flow, coronary vascular resistance, coronary arteriovenous oxygen difference, myocardial oxygen consumption and extraction, and myocardial lactate and potassium extraction and release were all measured in the isolated, vented, paced, beating heart, before and for 20 minutes after a 1 hour arrest interval during which revascularization was completed. Additionally, during administration of the cardioplegic solution, infusion flow rate, myocardial oxygen consumption and extraction, and lactate and potassium release and uptake were noted. The results indicate that during cardioplegic administration, myocardial oxygen consumption is 1 ml O2/min with crystalloid infusion and 2.6 ml O2/min during BC infusion. The volume of crystalloid solution administered contributed to increased oxygen utilization during HVCC compared to NVCC, whereas BC promoted the highest oxygen utilization of the three groups. Potassium absorption was nearly three times greater during BC than during crystalloid administration. During myocardial reperfusion, oxygen extraction was maintained at prearrest levels only in the HVCC group. Following both NVCC and BC, oxygen extraction was depressed during the first 5 minutes of reperfusion, and the difference between the latter two groups and HVCC was significant (p less than 0.01). The rapid recovery in normal metabolic function seen with HVCC allows early discontinuation of cardiopulmonary bypass without myocardial metabolic depression.     

Diltiazem cardioplegia. A balance of risk and benefit

Calcium channel blockers may prevent myocardial injury during cardioplegia and reperfusion. A prospective, randomized trial was instituted to evaluate the hemodynamic and myocardial metabolic recovery in 40 patients undergoing elective aorta-coronary bypass with either diltiazem in crystalloid potassium cardioplegia (n = 20) or crystalloid potassium cardioplegia (n = 20). In a preliminary trial, doses between 150 and 250 micrograms/kg reduced the period of heart block after cross-clamp removal (90 +/- 110 minutes) from that found with higher doses and improved myocardial metabolism. In the randomized trial, diltiazem cardioplegia (150 micrograms/kg) produced coronary vasodilatation during cardioplegia and produced less reactive hyperemia during reperfusion. Myocardial oxygen extraction was lower and myocardial lactate production was less after diltiazem cardioplegia during reperfusion. Tissue adenosine triphosphate and creatine phosphate concentrations were preserved better after diltiazem cardioplegia. The postoperative creatine kinase MB levels were less (p less than 0.05) after diltiazem cardioplegia, which indicated less myocardial injury. Postoperative volume loading demonstrated that systolic function (the relation between systolic blood pressure and end-systolic volume index) was depressed after diltiazem cardioplegia compared to crystalloid cardioplegia, but cardiac index was higher because afterload (mean arterial pressure) was lower and preload (end-diastolic volume index) was higher. Diltiazem cardioplegia preserved high-energy phosphates, improved postoperative myocardial metabolism, and reduced ischemic injury after elective coronary bypass. However, diltiazem was a potent negative inotrope and produced prolonged periods of electromechanical arrest. Diltiazem cardioplegia may be of value in patients with severe ischemia but should be used with caution in patients with ventricular dysfunction, and a dose-response relation must be established at each institution before clinical use.     

Improved myocardial recovery after cardioplegic arrest with an oxygenated crystalloid solution

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

Atrial activity during cardioplegia and postoperative arrhythmias

Cardioplegia provides excellent protection for the left ventricle, but the right atrium may be poorly protected. Myocardial temperatures, right atrial electrical activity, and postoperative arrhythmias were assessed in 103 patients participating in two consecutive randomized trials comparing blood cardioplegia (n = 36), crystalloid cardioplegia (n = 38), and diltiazem crystalloid cardioplegia (n = 29). Both right atrial and right ventricular temperatures were significantly warmer (p less than 0.05) during delivery of the blood cardioplegic solution than during delivery of either the crystalloid or the diltiazem crystalloid cardioplegic solutions; the aortic root temperatures were 9 degrees +/- 2 degrees C with blood cardioplegia and 5 degrees + 1 degrees C with both crystalloid and diltiazem crystalloid cardioplegia. Atrial activity during cardioplegic arrest was greatest with blood cardioplegia (12 +/- 3 beats/min), lower with crystalloid cardioplegia (10 +/- 2 beats/min), and minimal with diltiazem crystalloid cardioplegia (5 +/- 1 beats/min, p less than 0.05). Perioperative ischemic injury (by creatine kinase MB isoenzyme analysis) was greatest with crystalloid cardioplegia (p less than 0.05). Postoperative supraventricular arrhythmias (both treated and untreated) were more frequent after crystalloid cardioplegia (crystalloid, 63%; blood, 40%; diltiazem, 47%; p less than 0.05). Patients in whom supraventricular arrhythmias developed had significantly more postoperative ischemic injury (by creatinine kinase MB isoenzyme analysis, p less than 0.05). Blood cardioplegia reduced supraventricular arrhythmias by reducing ischemic injury despite warmer intraoperative temperatures and more right atrial activity. Diltiazem crystalloid cardioplegia reduced postoperative arrhythmias by improving intraoperative myocardial protection and suppressing intraoperative and postoperative atrial activity. Crystalloid cardioplegia cooled but did not arrest the right atrium intraoperatively, resulted in the most perioperative ischemic injury, and yielded the highest incidence of postoperative supraventricular arrhythmias.