Effects of diltiazem cardioplegia on global function, segmental contractility, and the area of necrosis after acute coronary artery occlusion and surgical reperfusion

We investigated the effects of diltiazem cardioplegia on myocardial function and infarct size in the region of the left anterior descending artery after acute occlusion and reperfusion during cardiopulmonary bypass. Sheep (30 kg) were subjected to 1 hour of regional myocardial ischemia by occlusion of the left anterior descending artery and assigned to a control (n = 8) or experimental group (n = 5). Control animals were placed on cardiopulmonary bypass and the heart arrested with potassium cardioplegia. The left anterior descending artery was released and two additional doses of 100 ml of cardioplegic solution were infused during the total cross-clamp time of 30 minutes. The animals were then weaned from bypass after 1 hour and beating, working reperfusion maintained for an additional 4 hours. The experimental group followed the same protocol except that the cardioplegic solution contained diltiazem (1.4 mg/L). Segmental myocardial function was determined by pairs of ultrasonic crystals in the area at risk, control segment, and minor axis. Global contractility was determined from maximum derivative of left ventricular pressure and cardiac output. The area at risk was determined by injecting monastral blue dye into the left atrium with the left anterior descending artery briefly reoccluded, and the area of necrosis was determined by measuring with a planimeter non-triphenyltetrazolium chloride stained areas in the sectioned left ventricle. After 5 hours of reperfusion, not only did the diltiazem group demonstrate better global contractility as defined by the derivative of left ventricular pressure (1853 +/- 292 versus 979 +/- 191, p = 0.05) but, in addition, the systolic shortening in the ischemic area improved significantly when compared with the control group (9.4 +/- 4 versus 2.13 +/- 0.77, p = 0.05). The group receiving diltiazem cardioplegia had an area of necrosis to area at risk ratio of 31.4% +/- 3%, which was significantly better than this ratio in the control group of 60.75% +/- 7% (p = 0.01). Diltiazem cardioplegia results in improved global and segmental contractility and limits the infarct size after occlusion of the left anterior descending artery and surgical reperfusion.     

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.     

Controlled reperfusion following regional ischemia

The ability to reverse acute coronary occlusion with fibrinolytic agents and percutaneous transluminal angioplasty has increased interest in the revascularization of ischemic myocardium. This study defines changes in global ventricular function, mass, and compliance during acute coronary occlusion and following reperfusion with blood in the beating and arrested heart. In 17 dogs on cardiopulmonary bypass, the proximal left anterior descending coronary artery was occluded for 45 minutes. In 12 dogs, flow was reestablished by releasing the coronary snare in the beating heart. In the other 5 dogs, the snare was released during a continuous 10-minute infusion of blood potassium cardioplegia in the arrested heart. Coronary occlusion resulted in significant decreases in stroke work index and left ventricular (LV) mass, but compliance was unchanged. Reperfusion in the beating heart increased LV mass compared with the values measured before ischemia (104 +/- 5 versus 95 +/- 5 gm; p less than 0.05) and decreased LV compliance (39 +/- 4 versus 53 +/- 4 ml at LV end-diastolic pressure of 8 mm Hg; p less than 0.05). In contrast, with blood cardioplegia-based reperfusion in the arrested heart, LV mass and LV compliance remained unchanged from control values. We conclude that revascularization of acutely ischemic myocardium in the beating heart further impairs LV function by increasing LV mass and decreasing compliance. This damage can be avoided by reperfusion with blood cardioplegia in the arrested heart.     

The effect of age on cerebral blood flow during hypothermic cardiopulmonary bypass

Cerebral blood flow was measured in 20 patients by xenon 133 clearance methodology during nonpulsatile hypothermic cardiopulmonary bypass to determine the effect of age on regional cerebral blood flow during these conditions. Measurements of cerebral blood flow at varying perfusion pressures were made in patients arbitrarily divided into two age groups at nearly identical nasopharyngeal temperature, hematocrit value, and carbon dioxide tension and with equal cardiopulmonary bypass flows of 1.6 L/min/m2. The range of mean arterial pressure was 30 to 110 mm Hg for group I (less than or equal to 50 years of age) and 20 to 90 mm Hg for group II (greater than or equal to 65 years of age). There was no significant difference (p = 0.32) between the mean arterial pressure in group I (54 +/- 28 mm Hg) and that in group II (43 +/- 21 mm Hg). The range of cerebral blood flow was 14.8 to 29.2 ml/100 gm/min for group I and 13.8 to 37.5 ml/100 gm/min for group II. There was no significant difference (p = 0.37) between the mean cerebral blood flow in group I (21.5 +/- 4.6 ml/100 gm/min) and group II (24.3 +/- 8.1 ml/100 gm/min). There was a poor correlation between mean arterial pressure and cerebral blood flow in both groups: group I, r = 0.16 (p = 0.67); group II, r = 0.5 (p = 0.12). In 12 patients, a second cerebral blood flow measurements was taken to determine the effect of mean arterial pressure on cerebral blood flow in the individual patient. Changes in mean arterial pressure did not correlate with changes in cerebral blood flow (p less than 0.90). We conclude that age does not alter cerebral blood flow and that cerebral blood flow autoregulation is preserved in elderly patients during nonpulsatile hypothermic cardiopulmonary bypass.     

Measurement of regional myocardial blood flow. Application of the electrolytic hydrogen clearance method in man

To assess myocardial perfusion intraoperatively and to evaluate the adequacy of coronary bypass grafting, we measured regional myocardial blood flow by the electrolytic hydrogen clearance method in 49 patients. Group I comprised 10 patients with nonischemic heart disease and group II, 39 patients with ischemic heart disease undergoing coronary bypass grafting. Group II was subdivided according to the percent stenosis of the coronary arteries supplying the ventricular regions: group IIa, less than 75% stenosis; group IIb, greater than or equal to 75% stenosis. Mean myocardial blood flows were 154 +/- 7, 145 +/- 5, and 98 +/- 9 ml/min/100 gm in groups I, IIa, and IIb, respectively (p less than 0.01, group IIb versus groups I and IIa). Mean blood flows were 161 +/- 19, 159 +/- 12, 78 +/- 12, and 59 +/- 15 ml/min/100 gm in areas of the left anterior descending coronary artery with less than 50%, 75%, 90%, and 99% stenosis in group II. In areas with a totally occluded left anterior descending coronary artery with collaterals, mean flow was 90 +/- 15 ml/min/100 gm. The mean myocardial blood flows were 40 +/- 7 and 100 +/- 14 ml/min/100 gm in areas with anterior Q wave and non-Q wave infarction, respectively (p less than 0.01). After cardiopulmonary bypass, the mean flow increased from 99 +/- 11 to 150 +/- 7 ml/min/100 gm in the grafted areas in group IIb (p less than 0.01), but it did not change in group I or IIa. The electrolytic hydrogen clearance method provided quantitative evaluation of myocardial perfusion and recovery from hypoperfusion by coronary bypass grafting. This method was especially useful in patients undergoing mammary artery grafting.     

Studies of controlled reperfusion after ischemia. XX. Reperfusate composition: detrimental effects of initial asanguineous cardioplegic washout after acute coronary occlusion

This study tests whether initial asanguineous washout of potentially toxic substances that accumulate during ischemia improves recovery produced by blood cardioplegic reperfusion and evaluates the role of plasma versus whole blood cardioplegia. METHODS: Twenty-four dogs underwent 2 hours of occlusion of the left anterior descending coronary artery and 20 minutes of blood cardioplegic reperfusion on total vented bypass. In 13 dogs, a 5-minute infusion of either a crystalloid (n = 7) or plasma (n = 6) cardioplegic solution (containing the same pH, calcium potassium, and osmolarity as blood cardioplegia) was given immediately before reoxygenation with blood cardioplegia. Regional oxygen uptake and coronary vascular resistance were measured during controlled reperfusion, and segmental shortening (ultrasonic crystals), tissue water content, and histochemical damage (triphenyltetrazolium chloride stain) were assessed 1 hour after bypass was discontinued. RESULTS: Asanguineous cardioplegic washout before reoxygenation with blood cardioplegic solution resulted in a progressive (+42%) increase in coronary vascular resistances (from 123 to 176 units, p less than 0.05) and low oxygen utilization during 20 minutes of blood cardioplegic reperfusion (29 ml/100 gm, p less than 0.05); coronary vascular resistance remained low throughout blood cardioplegic reperfusion without washout (from 109 to 98 units), and oxygen utilization was 54 ml/100 gm (p less than 0.05). Neither plasma nor crystalloid washout restored substantial regional systolic shortening (3% systolic shortening versus 73% systolic shortening with blood cardioplegia), and asanguineous washout caused more myocardial edema (81.1% +/- 80.9% versus 79.5% water content, p less than 0.05) and produced extensive transmural triphenyltetrazolium chloride damage (48% +/- 41% versus 8% nonstaining in area at risk, p less than 0.05) than initial blood cardioplegic reperfusion. CONCLUSION: Asanguineous cardioplegic washout before blood cardioplegic reperfusion limits oxygen utilization during subsequent controlled reperfusion, restricts early recovery of systolic shortening, allows more myocardial edema, and produces extensive histochemical damage, which may be avoided by initial reoxygenation with blood cardioplegia. The red blood cells appear more important than the plasma components of blood cardioplegia.     

Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury

BACKGROUND: In clinical trials, perioperative intravenous Na(+)/H(+) exchange isoform-1 (NHE1) inhibitors were only moderately effective in high-risk patients undergoing surgical reperfusion (GUARDIAN trial). However, effective myocardial concentrations of NHE1 inhibitor may not have been achieved by parenteral administration alone. We tested the hypothesis that increasing doses of NHE1 inhibitor EMD 87580 ((2-methyl-4,5-di-(methylsulfonyl)-benzoyl)-guanidine) delivered in blood cardioplegia (BCP) and by parenteral route at reperfusion reduce myocardial injury after surgical reperfusion of evolving infarction. METHODS: Twenty-six anesthetized dogs underwent 75 minutes of left anterior descending coronary artery occlusion, followed by cardiopulmonary bypass and 60 minutes of arrest with multidose 10 degrees C BCP. In the control group (n = 8), BCP was not supplemented. In the three EMD-BCP groups, BCP was supplemented with 10 micromol/L EMD 87580 (EMD-10, n = 5), 20 micromol/L EMD 87580 (EMD-20, n = 5), or 20 micromol/L EMD 87580 combined with an immediate reperfusion bolus (5 mg/kg intravenously) (EMD-20R, n = 8). The left anterior descending coronary artery occlusion was released just before the second infusion of BCP. Reperfusion continued for 120 minutes after discontinuation of cardiopulmonary bypass. RESULTS: Postischemic systolic and diastolic function in the area at risk was dyskinetic in all groups. Infarct size (percentage of area at risk) was not significantly reduced in the EMD-10 (26.2% +/- 3.6%) and EMD-20 (22.5% +/- 2.4%) groups versus control (30.7% +/- 2.4%); however, infarct size was significantly reduced in the EMD-20R group (16.1% +/- 2.8%, p = 0.003). Edema in the area at risk in the EMD-10 (81.1% +/- 0.5% water content), EMD-20 (81.7% +/- 0.3%), and EMD-20R (81.9% +/- 0.3%) groups was less than in controls (83.2% +/- 0.2%), (p < 0.056). Neutrophil accumulation (myeloperoxidase activity) in postischemic area-at-risk myocardium was less in the EMD-20R group versus the control group (5.3 +/- 0.7 versus 8.7 +/- 1.4 absorbance units x min(-1) x g(-1); p = 0.05), which suggests an attenuated postischemic inflammatory response. CONCLUSIONS: Optimal delivery of NHE1 inhibitor to the heart through combined cardioplegia and parenteral routes significantly attenuates myocardial injury after surgical reperfusion of regional ischemia. Timing, dose, and mode of delivery of NHE1 inhibitors are important to their efficacy.     

Pulmonary artery perfusion with protective solution reduces lung injury after cardiopulmonary bypass

BACKGROUND: The inflammatory response and higher temperature of lung tissue during cardiopulmonary bypass can result in lung injury. This study was to evaluate the protective effect of pulmonary perfusion with hypothermic antiinflammatory solution on lung function after cardiopulmonary bypass. METHODS: Twelve adult mongrel dogs were randomly divided into two groups. The procedure was carried out through a midline sternotomy, cardiopulmonary bypass was established using cannulas placed in the ascending aorta, superior vena cava, and right atrium near the entrance of the inferior vena cava. After the ascending aorta was clamped and cardioplegic solution infused, the right lung was perfused through a cannula placed in the right pulmonary artery with 4 degrees C lactated Ringer's solution in the control group (n = 6) and with 4 degrees C protective solution in the antiinflammation group (n = 6). Antiinflammatory solution consisted of anisodamine, L-arginine, aprotinin, glucose-insulin-potassium, and phosphate buffer. Plasma malondialdehyde, white blood cell counts, and lung function were measured at different time point before and after cardiopulmonary bypass; lung biopsies were also taken. RESULTS: Peak airway pressure increased dramatically in the control group after cardiopulmonary bypass when compared with the antiinflammation group at four different time points (24 +/- 1, 25 +/- 2, 26 +/- 2, 27 +/- 2 cm H2O versus 17 +/- 2, 18 +/- 1, 17 +/- 1, 18 +/- 1 cm H2O; all p < 0.01). Pulmonary vascular resistance increased significantly in the control group than in the antiinflammation group at 5 and 60 minutes after cardiopulmonary bypass (1,282 +/- 62 dynes x s x cm(-5) versus 845 +/- 86 dynes x s x cm(-5) and 1,269 +/- 124 dynes x s x cm(-5) versus 852 +/- 149 dynes x s x cm(-5), p < 0.05). Right pulmonary venous oxygen tension (PvO2) in the antiinflammation group was higher than in the control group at 60 minutes after cardiopulmonary bypass (628 +/- 33.3 mm Hg versus 393 +/- 85.9 mm Hg, p < 0.05). The ratio of white blood cells in the right atrial and the right pulmonary venous blood was lower in the antiinflammation group than in the control group at 5 minutes after the clamp was removed (p < 0.05). Malondialdehyde were lower in the antiinflammation group at 5 and 90 minutes after the clamp was removed (p < 0.01 and p < 0.05, respectively). Histologic examination revealed that the left lung from both groups had marked intraalveolar edema and abundant intraalveolar neutrophils, whereas the right lung in the control group showed moderate injury and the antiinflammation group had normal pulmonary parenchyma. CONCLUSIONS: Pulmonary artery perfusion using hypothermic protective solution can reduce lung injury after cardiopulmonary bypass.     

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.     

Pathophysiology of chronic cyanosis in a canine model. Functional and metabolic response to global ischemia

To investigate the pathophysiology of chronic cyanosis, we subjected 14 adult mongrel dogs to diversion of the inferior vena cava to the right inferior pulmonary vein. This produced a mean oxygen tension of 42 +/- 2 mm Hg and a calculated right-to-left shunt of 52.0% +/- 3.9%. These animals (Group C) and 15 normal dogs (Group N) were subjected to cardiopulmonary bypass with 20 minutes of normothermic global ischemia. Functional indices studied were rate of rise of left ventricular pressure and the end-systolic pressure/volume ratio. Metabolic status was assessed by obtaining transmural myocardial biopsy specimens for measurement of adenosine triphosphate content. Myocardial blood flow was measured with radiolabeled microspheres. There were no significant differences between Group C and Group N in either functional index or blood flow measurement prior to global ischemia. At 45 minutes after ischemia, Group N animals had a significantly greater rate of rise of left ventricular pressure (at a left ventricular end-diastolic pressure of 0, 5, 10, and 15 mm Hg, p less than 0.025 to 0.05) and subendocarial perfusion (endocardial/epicardial flow ratio 0.961 +/- 0.037 versus 0.815 +/- 0.021, p less than 0.01). At 90 minutes after ischemia, Group N animals exhibited a significantly higher end-systolic pressure/volume ratio (4.9 +/- 0.7 versus 3.0 +/- 0.4 mm Hg/ml, p less than 0.05), rate of rise of left ventricular pressure (at an end-diastolic pressure of 0 to 20 mm Hg, p less than 0.005 to 0.05), and endocardial/epicardial flow ratio (1.065 +/- 0.046 versus 0.829 +/- 0.059, p less than 0.01). No differences in adenosine triphosphate content were found at any sampling period. The Group C left ventricles exhibited no hypertrophy but were significantly dilated compared to Group N (38.8 +/- 0.3 versus 30.1 +/- 0.2 mm, p less than 0.05). Inferior vena cava to pulmonary vein diversion produces cyanosis with left ventricular dilatation but without hypertrophy. It is proposed that abnormal loading characteristics of the left ventricle are responsible for the functional derangements that result from global ischemia.     

Two-dimensional echocardiography in dogs. Variation of left ventricular mass, geometry, volume, and ejection fraction on cardiopulmonary bypass

Quantitative two-dimensional echocardiography was evaluated in 39 open-chest dogs placed on cardiopulmonary bypass. The correlation coefficient of left ventricular end-diastolic volume against postmortem pressure-volume curves was r = 0.89 to 0.93 (347 measurements in 15 dogs, 0 to 24 mm Hg). Ejection fraction was validated against roller pump flow and echo left ventricular end-diastolic volume (r = 0.83, n = 13). Left ventricular mass in vivo was compared with postmortem left ventricular mass (r = 0.81 in 21 early studies, r = 0.91 in 10 later studies with updated equipment) and was found to increase with ischemic injury as well as cardiopulmonary bypass with hemodilution. Left ventricular mass increased (p less than 0.001) from 119 +/- 5 (standard error of the mean) to 138 +/- 6 gm (n = 23) after 2 1/2 hours on cardiopulmonary bypass and moderate hemodilution. With the addition of ischemic arrest, left ventricular mass increased from 119 +/- 7 to 148 +/- 11 gm (p less than 0.01, n = 8), and myocardial water content increased by 2.0% +/- 0.4%, which accounted for at least 65% of the observed mass change. Mean left ventricular wall thickness increased from 13.8 to 15.5 mm (p = 0.02) after ischemia. Ventricular shape became more spherical with increasing left ventricular end-diastolic pressure. We conclude that two-dimensional echocardiography can be reliably used for accurate, serial measurements in physiological studies. The demonstrated variability in left ventricular mass is important, yet frequently ignored. Recognizing left ventricular mass changes may facilitate the detection of myocardial injury reflected as edema.     

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.     

Leukocyte depletion results in excellent heart-lung function after 12 hours of storage

Extended preservation of the heart-lung block for 12 hours in a bovine model of heart-lung transplantation was achieved using donor core cooling, static hypothermic storage, and reperfusion on cardiopulmonary bypass with leukocyte-depleted (LD) blood. Orthotopic heart-lung transplantation was performed with (n = 4, LD group) or without (n = 4, control group) LD blood during cardiopulmonary bypass. Postoperative measurements of cardiopulmonary function were made at 2, 4, and 6 hours after reperfusion. Only 2 animals (50%) of the control group survived more than 2 hours, whereas all animals in the LD group survived the study period. Arterial oxygen tension on 100% oxygen was 535.63 +/- 64.96 mm Hg and 146.45 +/- 90.9 mm Hg in the LD and control groups, respectively, at 2 hours (p less than 0.5) and 524.3 +/- 73.32 and 147.9 +/- 255.67 mm Hg at 6 hours. Pulmonary artery systolic pressure-to-systemic pressure ratio was 0.49 +/- 0.08 and 0.62 +/- 0.35 at 2 and 6 hours in the LD group. Extravascular lung water was 17.81 +/- 0.02 mL/kg (control group) and 11.28 +/- 9.15 mL/kg (LD group) at 2 hours. At reperfusion, the mean neutrophil count was 27 +/- 27 and 764 +/- 635 x 10(9)/L in the LD and control groups, respectively. This novel approach of leukocyte depletion during reperfusion after heart-lung preservation resulted in excellent cardiac and pulmonary protection.     

The safety and efficacy of ten percent pentastarch as a cardiopulmonary bypass priming solution. A randomized clinical trial.

Ten percent pentastarch is a low-molecular-weight hydroxyethyl starch with greater oncotic pressure and shorter intravascular persistence than 6% hetastarch. To evaluate its safety and efficacy as a component of cardiopulmonary bypass priming solution, we prospectively studied 90 patients undergoing coronary artery bypass grafting or valve replacement necessitating cardiopulmonary bypass (bubble oxygenator and moderate systemic hypothermia). Sixty patients were randomized to receive 75 gm of either 10% pentastarch (group P) or 25% albumin (group A), and 30 patients received lactated Ringer's solution alone (group C). Intravascular colloid osmotic pressure during cardiopulmonary bypass was highest with either of the colloid primes (15-minute measurement: group P, 15.7 +/- 2.2 mm Hg (mean +/- standard deviation); group A, 15.2 +/- 2.0 mm Hg; group C, 11.3 +/- 1.7 mm Hg; p less than 0.05, groups P and A compared with group C). This was associated with a lower volume requirement during cardiopulmonary bypass to maintain the venous reservoir (group P, 333 +/- 318 ml; group A, 483 +/- 472 ml; group C, 1332 +/- 1013 ml; p less than 0.05, groups P and A compared with group C). Urine output during cardiopulmonary bypass was similar in each group. Net intraoperative fluid balance was lowest in the colloid groups (groups P and A, 5.7 +/- 1.4 L; group C, 6.9 +/- 1.3 L; p less than 0.05, groups P and A compared with group C). Cardiac index shortly after weaning from cardiopulmonary bypass was greatest in group P (group P, 3.2 +/- 0.9; group A, 2.8 +/- 0.8; group C, 2.7 +/- 0.6 dyne.sec.cm-5; p less than 0.05, group P compared with group C). Changes in alveolar-arterial oxygen gradients, shunt fraction, and effective compliance were similar in all groups. During cardiopulmonary bypass, pentastarch appeared to cause the greatest degree of hemodilution, as suggested by the lowest hemoglobin, factor VII and IX levels and platelet count. The activated partial thromboplastin time was significantly prolonged during and immediately after cardiopulmonary bypass in group P relative to groups A and C (p less than 0.05), although there were no significant differences in the activated clotting time before cardiopulmonary bypass, during cardiopulmonary bypass, or after heparin neutralization. As well, clinical indices of hemostasis, including mediastinal drainage, red cell, platelet, and fresh frozen plasma requirements, and reoperation for excessive postoperative bleeding, were similar. We conclude that pentastarch, when used in cardiopulmonary bypass prime, is as safe as either albumin or Ringer's solution alone.(ABSTRACT TRUNCATED AT 400 WORDS)     

Reversal of reperfusion injury after ischemic arrest with pressure-controlled intermittent coronary sinus occlusion

Recent experimental studies have shown that pressure-controlled intermittent coronary sinus occlusion effectively reduces both infarct size and myocardium at risk after coronary artery occlusion. This study was undertaken to determine whether this modality was equally effective in altering reperfusion damage after a period of ischemic arrest. Fourteen pigs were placed on cardiopulmonary bypass and subjected to 2 hours of ischemic arrest with multidose potassium crystalloid cardioplegia supplemented with topical and systemic hypothermia (28 degrees C). During arrest, the mid-left anterior descending artery was occluded with a snare, which was released immediately after aortic unclamping. In seven pigs, a 7F balloon-tipped catheter was positioned in the coronary sinus and pressure-controlled intermittent coronary sinus occlusion was performed for 60 minutes after aortic unclamping. Seven other pigs served as controls. Parameters measured included stroke work index, ejection fraction, and myocardial pH in the distribution of the distal left anterior descending artery. Pigs treated with pressure-controlled intermittent coronary sinus occlusion had a significantly higher myocardial pH (6.99 +/- 0.06 versus 6.67 +/- 0.05, p less than 0.01), ejection fraction (50% +/- 2% versus 33% +/- 6%, p less than 0.01), and stroke work index (0.87 +/- 0.07 versus 0.61 +/- 0.05 gm-m/kg, p less than 0.01) after 60 minutes of reperfusion compared with those of the group not treated in this way. We conclude that pressure-controlled intermittent coronary sinus occlusion effectively reverses reperfusion damage after periods of ischemic arrest.     

Effect of cardiopulmonary bypass and global ischemia on human and canine left ventricular mass: evidence for interspecies differences

Previous studies in dogs suggest that global ischemia with cardiopulmonary bypass causes increased left ventricular (LV) mass and water content. To investigate effects in humans, we developed a simplified method for mass determination by intraoperative two-dimensional echocardiography. LV mass was measured as echocardiographic short-axis myocardial area. This was validated by linear regression versus postmortem LV mass in 10 dogs (r = 0.89) and versus single-plane angiography in 18 patients (r = 0.73). According to this method, there was no change in LV mass (209 gm versus 208 gm; NS) at constant preload in 20 patients during routine operations (eight coronary revascularizations, 10 aortic valve replacements, and two mitral valve replacements). The same method used in 10 dogs after 2 hours of bypass, 60 minutes of normothermic global ischemia, and reperfusion revealed an LV mass increase from 113 +/- 13 gm (SE) to 150 +/- 16 gm (p less than 0.01) at matched preload. In addition, in 14 dogs after 2 hours of bypass alone, LV mass was unchanged (98 +/- 5 gm versus 101 +/- 5 gm; NS) at matched preload. Data recently derived from a separate study in our laboratory revealed a statistically significant increase in canine LV mass when conditions of human cardiopulmonary bypass and cardioplegic arrest were reproduced. We conclude that uncomplicated cardiac operations in humans do not alter LV mass. This supports the safety of crystalloid cardioplegia in humans. While present evidence is not conclusive, it appears that the threshold for edema formation after ischemic injury may be higher in humans than it is in dogs. The clinical relevance of studies of cardioplegia in edematous dog hearts thus deserves careful scrutiny.     

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.     

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.     

Resuscitation of injured myocardium with adenosine and biventricular assist

Recovery of energy metabolism and contractility in stunned myocardium requires several days, even when mechanical circulatory support is employed. This double-blind study was undertaken to determine if myocardial recovery could be accelerated by intracoronary infusion of adenosine during reperfusion. Ten mongrel dogs were subjected to 45 minutes of global normothermic ischemia while on biventricular support with centrifugal pumps. During initial reperfusion, 20 minutes later, and at hourly intervals for 4 hours, dogs received 100 mL/min of unaltered blood or blood enriched with adenosine (0.2 mmol/L) into the coronary arteries for 5 minutes. Circulatory support was discontinued after 4 hours or sooner if the first time derivative of left ventricular pressure exceeded 2,000 mm Hg/s. Animals that received adenosine were weaned sooner (72 +/- 27 versus 216 +/- 54 minutes) and had higher systolic pressure (110 +/- 21 versus 57 +/- 36 mm Hg), lower left ventricular end-diastolic pressure (23.8 +/- 4.8 versus 34.0 +/- 7.2 mm Hg), and higher first time derivative of left ventricular pressure (3,407 +/- 812 versus 1,510 +/- 1376 mm Hg/s) than controls at the completion of the experiment (p less than 0.05). Final myocardium adenosine triphosphate levels were higher in the adenosine group (20.0 +/- 3.6 versus 14.2 +/- 4.0 mumol/g protein; p less than 0.05). Determination of infusion and coronary sinus blood concentrations demonstrated a 90% uptake of adenosine. All adenosine animals survived, but 2 of 5 control animals died within 1 hour of weaning. Reperfusion with adenosine-enriched blood accelerated recovery of ischemic myocardium and should be considered for patients requiring mechanical circulatory support after a heart operation.     

Rapid cooling contracture of the myocardium. The adverse effect of prearrest cardiac hypothermia

Hypothermic total circulatory arrest for repair of congenital heart lesions in neonates requires a period of rapid core cooling on cardiopulmonary bypass during which the myocardium is also exposed to hypothermic perfusion. Myocardial hypothermia in the nonarrested state results in an increase in contractility due to elevation of intracellular calcium levels. This study was designed to test the hypothesis that rapid myocardial cooling before cardioplegic ischemic arrest results in damage, with impaired recovery during reperfusion. Two groups of 10 rabbit hearts were perfused on an isolated Langendorff apparatus. Group N (normothermia) was perfused at 37 degrees C before 2 hours of cardioplegic ischemic arrest at 10 degrees C. Group C (cooling) was perfused at 15 degrees C in the unarrested state for 20 minutes before the same cardioplegic arrest conditions as group N. Left ventricular isovolumic pressure measurements, biochemical measurements from right ventricular biopsy specimens, and ventricular necrosis as defined by tetrazolium staining were used to compare the groups at 30 and 60 minutes of normothermic reperfusion. Developed pressure at a constant volume was preserved in group N at 90.7 +/- 4.5 mm Hg versus 76.9 +/- 6.3 in group C after reperfusion (p less than 0.05). Diastolic compliance showed significant deterioration in group C, with marked elevation of diastolic pressure during reperfusion (group N = 6.8 +/- 2.5 mm Hg versus group C = 38.9 +/- 6.1 after reperfusion; p less than 0.001). Adenosine triphosphate levels were significantly higher in group N both at end-ischemia and after reperfusion versus group C (group N = 17.0 +/- 1.1 nmol/mg protein versus group C = 7.7 +/- 1.0 after reperfusion; p less than 0.001). Group N had 0.4% +/- 0.4% necrosis of ventricular mass versus 19.3% +/- 2.2% with prearrest cooling in group C (p less than 0.0001). These results indicate that, when combined with cardioplegic ischemic arrest, rapid myocardial cooling in the unarrested state results in significant damage. The mechanism may be related to the cytosolic calcium loading effect of hypothermia that is not relieved during the subsequent period of cardioplegic arrest. Although hypothermia is an essential component to ischemic preservation, rapid cooling contracture can adversely influence cardioplegic myocardial protection.