Granulocyte and eicosanoid gradients across the coronary circulation during myocardial reperfusion in cardiac surgery

Polymorphonuclear granulocytes (PMN) and eicosanoids such as leukotrienes have been suggested as possible mediators of myocardial ischemia-reperfusion injury. We have investigated the gradients of PMN, 6-keto-PGF1 alpha (a stable metabolite of prostacyclin) and leukotriene B4 (LTB4) across the coronary circulation during myocardial reperfusion after cold, cardioplegic arrest in cardiac surgery. Baseline values in arterial blood were 4.4 +/- 0.4 x 10(9)/l, 59 +/- 6 pg/ml and 149 +/- 27 pg/ml (mean +/- SEM) for PMN, 6-keto-PGF1 alpha and LTB4, respectively. They were significantly elevated during cardiopulmonary bypass (CPB). There was a positive correlation between the number of circulating PMN and LTB4 at all sample times during cardiopulmonary bypass (P less than 0.05). At 5 min reperfusion (CPB time: 122 +/- 8 min) PMN, 6-keto-PGF1 alpha and LTB4 were 6.2 +/- 0.5 x 10(9)/l, 696 +/- 117 pg/ml and 280 +/- 60 pg/ml, respectively. The PMN in coronary sinus blood were significantly lower (P less than 0.001) than in arterial blood at 5 min reperfusion, but not at 15 and 30 min. The concentrations of 6-keto-PGF1 alpha and LTB4 were significantly elevated in coronary sinus blood as compared to arterial blood after reperfusion for 5 min (P less than 0.05). Thereafter, no significant gradients were found across the heart, except at 30 min reperfusion when LTB4 was significantly lower in coronary sinus blood. Neither PMN sequestration nor 6-keto-PGF1 alpha and LTB4 production were significantly correlated to aortic cross clamp time.(ABSTRACT TRUNCATED AT 250 WORDS)     

The heart produces but the lungs consume proinflammatory cytokines following cardiopulmonary bypass.

OBJECTIVE: Proinflammatory cytokines, such as interleukin-6 (IL-6), and soluble adhesion molecules, such as E-selectin, may play an important role in patient response to cardiopulmonary bypass (CPB). We sought to define whether the heart and the lungs serve as important sources of these inflammatory mediators under clinical conditions of myocardial revascularization using CPB and cardioplegic arrest. METHODS: Plasma levels of IL-6 and E-selectin were measured in coronary sinus (CS), arterial, pulmonary arterial (PA) and left atrial (LA) blood samples taken from 12 consecutive patients (68.3 +/- 11 years; five females) undergoing coronary artery bypass grafting (CABG). Blood samples were collected preoperatively, after reperfusion, and 1, 6, 12 and 18 h following surgery. CS and LA blood was drawn using transcutaneous catheters. PA artery blood was obtained through a Swan-Ganz catheter. Cytokine levels were determined by standard enzyme linked immunosorbent assay (ELISA) technique. RESULTS: A mean of 3.8 +/- 1 coronary anastomoses were performed. The CPB time and aortic X-clamp time were 91 +/- 15 and 45 +/- 10 min, respectively. IL-6 levels increased significantly after CPB and peaked 6 h postoperatively. There was also a significant increase of E-selectin levels with an onset at 1 h and a peak at 12 h postoperatively. At all time points the IL-6 and E-selectin concentrations were significantly higher in the CS than in arterial blood. In contrast, the levels of both mediators measured in the LA were significantly lower than those in the PA. CONCLUSION: The reperfusion of ischemic myocardium during CABG results in a significant increase in plasma levels of IL-6 and E-selectin. Our data indicate that the myocardium, but not the lungs, is a predominant source of IL-6 and E-selectin release following CPB. The lungs may consume rather than release those mediators during reperfusion. Not the CPB per se, but the myocardial ischemia seems to be crucial in the pathogenesis of the inflammatory response observed following open heart surgery.     

IL-8 concentration in coronary sinus blood during early coronary reperfusion after ischemic arrest.

OBJECTIVE: Activation of the inflammatory response is an important factor contributing to complications of cardiopulmonary bypass. Increased level of proinflammatory cytokine - IL-8 has been reported during coronary artery bypass grafting (CABG) operations with the use of cardiopulmonary bypass. The aim of this study was to find out whether the heart is the main source of IL-8 during early coronary reperfusion. METHODS: IL-8 concentration in coronary sinus before clamping and 5, 10, and 15 min after declamping of the aorta as well as in radial artery blood before clamping and 10 min after declamping of the aorta, was assessed in 30 patients undergoing CABG surgery. RESULTS: We observed increase in IL-8 concentration in coronary sinus blood after declamping of the aorta, however no difference between coronary sinus and arterial blood concentration was noted. The median value of IL-8 concentration in coronary sinus blood was 1.85 pg/ml before ischemia and 15.4, 20.3, and 29.3 pg/ml in 5, 10 and 15 min after aortic declamping, respectively. Our additional finding was that there was a negative correlation between IL-8 level and hemoglobin saturation with oxygen in coronary sinus blood 10 min after coronary reperfusion. CONCLUSIONS: We conclude that the heart is not the main source of IL-8 in early coronary reperfusion, although coronary reperfusion induces its release.     

Cardiac surgery and distribution of the leukocyte L1 protein-calprotectin

Activated polymorphonuclear leukocytes (PMN) secrete lysosomal enzymes, eicosanoids and toxic oxygen metabolites. In cardiac surgery patients, we measured arterial plasma levels of PMN and L1 (calprotectin), a prominent granulocyte protein, during cardiopulmonary bypass (CPB). The myocardial arterio-venous gradients were evaluated during reperfusion after cold cardioplegic arrest (n = 10). The arterial plasma concentration of L1 increased during CPB from 344 +/- 71 micrograms/l (mean +/- SD) preoperatively to 5221 +/- 1267 micrograms/l at the end of CPB (P less than 0.001). Simultaneously, the number of circulating PMN also increased (from 4.4 +/- 0.4 x 10(9)/l to 9.1 +/- 1.2 x 10(9)/l (P less than 0.05)). There was a positive correlation between the mean number of circulating PMN and the plasma level of L1 at all sampling times during CPB (r = 0.93, P less than 0.05). A coronary sequestration of both L1 (P less than 0.006) and PMN (P less than 0.002) was found after 5 min reperfusion. This was not present at 15 and 30 min reperfusion. The coronary entrapment of L1 and PMN did not covary significantly, and was unrelated to both the time of cardioplegic arrest and the arterial levels of L1 and PMN. In conclusion, the increased plasma concentrations of PMN and L1 during CPB and the coronary sequestration of both PMN and L1 may be factors in the pathogenesis of reperfusion injury of the myocardium.     

Myocardial outflow of prostacyclin in relation to metabolic stress during off-pump coronary artery bypass grafting

BACKGROUND: The metabolic changes, possible myocardial damage, and influence on the vascular endothelium during off-pump coronary artery bypass grafting have been investigated. METHODS: Coronary sinus and arterial blood samples were obtained before coronary arterial occlusion, after 10 minutes of ischemia, and after 1 and 10 minutes of reperfusion in 9 patients who had an anastomosis performed to the left anterior descending coronary artery off-pump bypass RESULTS: The mean ischemic time was 14 +/- 1 minutes. The arteriovenous difference in lactate decreased during ischemia to reach a minimum at 1 minute of reperfusion (-0.15 +/- 0.06 micromol/L compared to 0.21 +/- 10 micromol/L before ischemia; p < 0.01). Myocardial lactate extraction decreased from 14.2 +/- 6.8 micromol/min before ischemia to -10.9 +/- 6.5 micromol/min after 1 minute of reperfusion (p < 0.01). Simultaneously, the arteriovenous difference in 6-keto-PGF(1alpha), the stable metabolite of prostacyclin, decreased from -30 +/- 26 pg/mL to -258 +/- 80 pg/mL at 1 minute of reperfusion (p < 0.05), and the 6-keto-PGF(1alpha) extraction over the heart decreased -556 +/- 466 pg/min to -18,560 +/- 5,683 pg/min (p < 0.01). CONCLUSIONS: The localized myocardial ischemia associated with these procedures causes changes in the myocardium and endothelial influence. Coronary bypass surgery performed on the beating heart may not be superior in preventing cardiac ischemia and endothelial disturbance, compared with conventional bypass surgery.     

CD11b may be a less satisfactory indicator for cardiac ischemia-reperfusion injury in coronary artery bypass graft surgery with cardiopulmonary bypass than cardiac troponin I

STUDY OBJECTIVE: To investigate whether CD11b on neutrophils can be used as a marker to predict myocardial ischemia-reperfusion injury for patients undergoing coronary artery bypass graft (CABG) surgery on cardiopulmonary bypass (CPB). DESIGN: Prospective, observational study. SETTING: University teaching hospital and university hospital laboratories. PATIENTS: Twelve adults, physical status II and III (American Society of Anesthesiologists) patients scheduled for elective CABG surgery on CPB. INTERVENTIONS: Anesthesia and surgical interventions were performed according to standard procedures. Coronary sinus was cannulated for retrograde cardioplegia perfusion and for coronary sinus blood sampling. The blood samples were collected from systemic and coronary venous sinus blood respectively at several time points before CPB, during CPB, and after declamping of the ascending aorta. MEASUREMENTS AND MAIN RESULTS: CD11b expressions in systemic circulation blood increased significantly during CPB and maintained higher levels after cardiac reperfusion (P < .05); on the other hand, CD11b expressions in coronary sinus blood declined gradually and reached their lowest level at 5 minutes after aortic declamping. The differences in CD11b expressions between systemic circulatory blood and coronary sinus blood after cardiac reperfusion were significant (P < .05). Cardiac troponin I (cTnI) concentrations in both systemic circulatory blood and coronary sinus blood increased significantly after cardiac reperfusion (P < .05), and the concentrations of cTnI in coronary sinus blood increased much higher than the corresponding concentrations of cTnI at each time point (P < .05). CONCLUSION: CD11b expression on neutrophils may not be a reliable predictor for myocardial ischemia-reperfusion injury in CABG surgery on CPB because of the possible sequestration of neutrophils in myocardium.     

Myocardial outflow of calcitonin gene-related peptide in relation to metabolic stress during coronary artery bypass grafting without cardiopulmonary bypass

OBJECTIVE: Because of adverse effects of cardiopulmonary bypass and the prospect of shortening intensive care and hospital stay, coronary artery bypass grafting without cardiopulmonary bypass is gaining increased attention. The impact of the localized myocardial ischemia that is inherent in these procedures has not been thoroughly investigated in human beings. We have investigated metabolic changes, possible myocardial damage, and myocardial outflow of the vasodilator calcitonin gene-related peptide during coronary artery bypass grafting without cardiopulmonary bypass. METHODS: Coronary sinus and arterial blood was sampled before coronary arterial occlusion, after 10 minutes of ischemia, and after 1 and 10 minutes of reperfusion in 9 consecutive patients (mean age 70 +/- 5 years) who had an anastomosis performed to the left anterior descending artery without cardiopulmonary bypass. RESULTS: No perioperative myocardial infarctions occurred. The arteriovenous difference in lactate decreased during ischemia, to reach a minimum after 1 minute of reperfusion (-0.17 +/- 0.25 vs 0.15 +/- 0.25 mmol/L before ischemia; P =.008). Myocardial lactate extraction decreased (from 11.2 +/- 13.6 micromol/min before ischemia to -3.0 +/- 7.0 micromol/min after 1 minute of reperfusion; P =.012), that is, a net production of lactate. The arteriovenous difference in calcitonin gene-related peptide decreased from -0.1 +/- 2.6 pmol/L before ischemia to -30.5 +/- 26.5 pmol/L (P =.008) after 1 minute of reperfusion. CONCLUSIONS: The localized myocardial ischemia associated with these procedures causes metabolic changes in the myocardium, but no myocardial damage. The ischemia-related outflow of calcitonin gene-related peptide indicates that the vasodilating and cardioprotective properties of this peptide that are known from animal studies may be of importance in myocardial ischemia in human beings.     

Reperfusion after cardioplegic cardiac arrest - effects on intracoronary leucocyte elastase release and oxygen free radical mediated lipid peroxidation

In experimental animal models reperfusion of ischaemic myocardium causes sequestration of leucocytes within the coronary circulation. Leucocytes contribute to postischaemic myocardial injury by releasing proteolytic enzymes and by generating oxygen free radicals. The aim of this study was to investigate whether leucocytes also contribute to myocardial injury following ischaemia and reperfusion associated with cardioplegic cardiac arrest. Therefore, we studied the release of the proteolytic enzyme elastase and oxygen free radical initiated myocardial lipid peroxidation in coronary sinus blood during reperfusion after cardioplegic cardiac arrest. The elastase-alpha-1-proteinase inhibitor complex and malondialdehyde (a byproduct of myocardial lipid peroxidation) were measured in arterial, central venous and coronary sinus blood samples in 19 patients undergoing elective coronary artery bypass grafting before aortic crossclamping and 1,5, 10 and 20 min after aortic declamping. Malondialdehyde concentrations did not increase significantly during the study period, whereas elastase concentrations showed a significant increase during cardiopulmonary bypass in arterial, central venous as well as coronary sinus blood. Neither elastase nor malondialhyde concentrations in coronary sinus blood differed significantly from arterial or central venous blood at any time point measured. Our data demonstrated increased elastase concentrations during cardiopulmonary bypass, but we did not find enhanced intracoronary elastase release or myocardial lipid peroxidation. Our data suggest that patients are sufficiently protected from leucocyte mediated ischaemia reperfusion injury during uncomplicated coronary artery bypass grafting with cardioplegic arrest.     

Simultaneous antegrade and retrograde reperfusion after cardioplegic arrest for coronary artery bypass

Retrograde coronary sinus reperfusion with warm blood during proximal anastomoses permits completion of myocardial revascularization under a single cross-clamp application. Reperfusion with both antegrade (via arterial and vein grafts) and retrograde (via coronary sinus catheter) warm blood has raised concerns about maldistribution of perfusate or overpressurization of capillary beds. This prospective, randomized design compares postcardioplegic myocardial recovery among patients receiving retrograde reperfusion only and patients receiving simultaneous antegrade/retrograde reperfusion. Twenty-four patients were selected among all presenting as outpatients for elective coronary artery bypass (CAB). Each patient underwent CAB with cardioplegic arrest and single cross-clamp technique. During proximal anastomoses the heart was reperfused with warm blood from the cardiopulmonary bypass (CPB) circuit. Twelve received retrograde reperfusion only, and 12 received simultaneous antegrade/retrograde reperfusion via an internal mammary artery (IMA) graft, all vein grafts, and the coronary sinus catheter. Vein graft perfusion was interrupted in each vein as the proximal anastomosis was performed. Myocardial recovery time (interval from initiating reperfusion until electrical and mechanical activity), cardioversion incidence, requirement for inotropic support, and Swan-Ganz hemodynamic parameters measured immediately 6 and 24 hours postoperatively were compared between groups. There were no differences between groups in age, ventricular function, number of grafts, or CPB time. Also, there were no differences in cardioversion, inotropic need, or postoperative hemodynamic performance. Myocardial recovery time was reduced in patients receiving simultaneous antegrade/retrograde reperfusion (13.9+/-7.0 vs 2.6+/-2.1 minutes). Simultaneous reperfusion of warm blood antegrade and retrograde is not deleterious to the myocardium. More rapid recovery of myocardial function may represent a shorter period of warm ischemia but does not appear to translate to improved postoperative myocardial performance.     

The effect of leukocyte-depleted blood cardioplegia in patients with severe left ventricular dysfunction: a randomized, double-blind study

BACKGROUND: The propensity for leukocytes to cause reperfusion injury in patients undergoing heart surgery is widely accepted. Reperfusion injury may result in myocardial damage and unfavorable operative outcome, especially in patients with severely reduced ejection fractions. This study was performed to evaluate the impact of leukocyte filtration on the postoperative course of patients undergoing coronary bypass surgery. METHODS: Thirty-two patients with coronary artery disease and left ventricular ejection fraction less than 35% were included in this double-blind, randomized study. Two serial leukocyte removal filters (Pall BC1B filter [Pall Biomedical, Portsmouth, England], group F, 15 patients) or two dummy filters (group C, 17 patients) were connected to the blood cardioplegia line. Leukocyte count, hemodynamic measurement, and transesophageal echocardiography were performed before and after cardiopulmonary bypass. Cardiac-specific enzymes were analyzed from arterial blood during the first 72 hours and from coronary sinus blood 30 and 60 minutes after aortic unclamping. RESULTS: Patient characteristics were similar in the two groups (ejection fraction 20.9% +/- 4.3% in group C and 21.1% +/- 4.8% in group F; P =.773). No early death or perioperative myocardial infarction occurred. Leukocyte count, hemodynamic parameters, cardiac troponin T, cardiac troponin I, and creatine kinase MB mass levels in arterial blood were similar in the two groups. Group F showed lower release of cardiac troponin T from the coronary sinus 30 minutes after unclamping of the aorta (group F, 0.263 +/- 0.12 ng/mL; group C, 0.6 +/- 0.32 ng/mL; P =.005). Lower doses of dopamine were necessary after cardiopulmonary bypass (group F, 0.36 +/- 0.11 mg x kg(-1) x min(-1); group C, 0.49 +/- 0.14 mg x kg(-1) x min(-1); P =.003). A moderate increase in ejection fraction was observed at 30 minutes in both groups (group F, 30.3% +/- 6.2%; group C, 28.0% +/- 6.3%; P =.239) and a significant increase at 60 minutes in group F (group F, 32.5% +/- 6.0%; group C, 27.4% +/- 7.5%; P =.012). CONCLUSIONS: These results indicate that serial leukocyte filters connected to the blood cardioplegia line decrease myocardial cell injury and may therefore help to improve outcome of patients with severely depressed ejection fractions undergoing coronary artery bypass grafting.     

Disadvantages of prostacyclin infusion during cardiopulmonary bypass: a double-blind study of 50 patients having coronary revascularization

Prostacyclin (PGI2) has been suggested for use in cardiopulmonary bypass (CPB) because of its positive effects on platelet number and function. Fifty patients who underwent coronary artery bypass grafting using a bubble oxygenator received heparin, 3 mg per kilogram of body weight, and then were randomly assigned to receive PGI2, 25 ng/kg/min, beginning 5 minutes before and until the end of CPB (26 patients) or a placebo (24 patients). Both groups were similar in sex, age, heparin dose, protamine dose, and CPB time. During CPB, mean arterial pressure fell significantly with PGI2 (76 +/- 2 mm Hg to 53 +/- 2 mm Hg; p less than 0.05) and necessitated pressor substances. Platelet counts fell significantly in both groups with the start of CPB, but after 60 minutes were similar in both groups (118 +/- 9 X 10(3) versus 130 +/- 8 X 10(3); not significant [NS]) and were unchanged 3 hours after CPB. Total chest tube output was 647 +/- 51 ml (placebo group) versus 576 +/- 34 ml (PGI2 group) (NS); 18 of the patients given PGI2 required 26 transfusions compared with 16 transfusions in 8 of the patients given a placebo (p less than 0.05). In PGI2 patients, arterial oxygen tension on 100% oxygen fell from 281 +/- 18 mm Hg before CPB to 223 +/- 17 mm Hg immediately after CPB (p less than 0.05). The placebo patients did not show a change in this variable.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in Platelet, Granulocyte, and Complement Activation During Cardiopulmonary Bypass Using Heparin-coated Equipment

Abstract: The effects of heparin-coated cardiopulmonary bypass (CPB) systems on platelet, granulocyte, and complement activation were investigated during cardiopulmonary bypass. Thirty patients underwent coronary artery bypass surgery with a heparin-coated (Carmeda Bio-Active Surface, CBAS, Medtronic, U.S.A.) CPB system (HC group, n = 10), a heparin-coated oxygenator and uncoated CPB circuit (HO group, n = 10), or an uncoated system (UC group, n = 10). In the HO group, plasma C3a (1667 ± 632 ng/ml) and C4a (1088 ± 319 ng/ml) concentrations were significantly (p < 0.05) lower than in the UC group (2846 ± 1045 ng/ml and 1494 ± 480 ng/ml, respectively) 10 min after the administration of protamine, but there were no significant differences in the platelet or granulocyte counts. In the HC group, granulocyte elastase concentrations 120 min after the onset of CPB (365 ± 177 μg/L) and 10 min after the administration of protamine (676 ± 314 μg/L) were significantly (p < 0.05) lower than in the other 2 groups (820 ± 341 and 893 ± 303 μg/L and 1365 ± 595 and 1,258 ± 622 μg/L). In addition, the increase in the plasma C3a concentration in the HC group 60 (p < 0.05) and 120 min after the onset of CPB (p < 0.05) was significantly less than in the other 2 groups. The C3a and C4a concentrations 10 min after the administration of protamine were significantly (p < 0.005 and p < 0.05) less in the HC group than in the UC group. Platelet counts 10 min after the administration of protamine were significantly higher (p < 0.05) and plasma β-throm-boglobulin concentrations during CPB were significantly lower in the HC group than in the other 2 groups 5 (p < 0.05), 60, and 120 min (p < 0.005) after the onset of CPB. Postoperative blood loss during the first 12 h in the HC group was significantly (p < 0.05) less than that in the UC group. The heparin-coated oxygenator and uncoated CPB circuit reduced complement activation but demonstrated no significant effects on the platelet and granulocyte systems. However, the heparin-coated CPB circuit (with all components making blood contact) reduced platelet, granulocyte, and complement activation and significantly reduced postoperative blood loss. Therefore, heparin coating of CPB systems improves biocompatibility.     

Elevated troponin I level with hemoglobin based oxygen carrying solutions (HBOCs) as a priming solution despite improved left ventricular function

Stroma free hemoglobin based oxygen-carrying solutions (HBOCs) have been shown to have the capability to transport oxygen, suggesting their use as a temporary blood substitute to maintain oxygenation of tissue. HBOCs might be the proper priming solution; however, elevated troponin associated with their application might be a major concern, particularly in patients with damaged myocardium. This study was performed in mongrel dogs (n=14). The animals underwent cardiac arrest with cardioplegic solution and aortic clamping using cardiopulmonary bypass (CPB). HBOC was used as a priming solution for CPB in the study group, and Lactated Ringer's in the control group. The extreme hemodilution in the study group was achieved by replacing more than 80% of the animal's blood with HBOC. A right heart bypass was performed to control the cardiac output. The hemodynamic parameters were measured with increasing cardiac output before and after CPB. At a cardiac output of 2500 ml/min, LAP (19+/-9 mmHg vs. 8.7+/-1.3 mmHg in the HBOCs group) and LVEDP (22+/-16 mmHg in the control group vs. 11+/-2.8 mmHg in the HBOC group) were significantly higher in control animals. The overall coronary sinus flow did not show any significant difference between both groups. The PO2 in the HBOCs group was slightly higher (534+/-10 mmHg vs. 494+/-71 mmHg) at 30 min after removal of aortic clamp compared to PO2 in control group. Post-ischemic troponin I level was increased in both groups, however, it was significantly higher in HBOCs group (49.64+/-48.58 ng/ml) compared to its level in control group (28.33+/-17.2 ng/ml). After the priming was completed and CPB was initiated, the hematocrit in the study group was 5.37+/-3.7% compared to 15+/-3.3% in the control group. However, the hemoglobin (Hb) in the study group remained higher throughout the experiment compared to control group, 8.34+/-1.55 g/dl vs. 5.37+/-1.04 g/dl, respectively. HBOC based priming permits cardiopulmonary bypass at a very low hematocrit with a better preservation of myocardium and adequate oxygen supply. However, elevated troponin I at the postischemic phase is a serious concern and its significance needs to be addressed before broad clinical application of HBOC.     

Cardiac interleukin-6 release and myocardial recovery after aortic crossclamping. Crystalloid versus blood cardioplegia

BACKGROUND: Pro-inflammatory cytokines may play an important role in patient response to cardiopulmonary bypass (CPB). Since the myocardium is proposed to be a major source of cytokines, we studied the influence of the cardiolpegia type on interleukin-6 release and early myocardial recovery. METHODS: Experimental design: prospective, randomized study. Setting: university hospital, operative and intensive care. Patients: 20 consecutive patients (3 females) scheduled for elective coronary artery bypass grafting (CABG), mean age 62.8+/-5 years, history of myocardial infarction 11/20, left ventricular ejection fraction 62.9+/-15%. Interventions: patients were operated on using randomly either cold blood cardioplegia (B, n = 10) or cold crystalloid cardioplegia (C, n = 10). Measures: plasma levels of interleukin-6 (IL-6) were measured prior to CPB, after aortic declamping, after CPB, 1 hour, 6 hours and 12 hours postoperatively. RESULTS: Groups were comparable with respect to demographic data, left ventricular function, number of grafts, CPB and aortic crossclamp time. Group B patients demonstrated significant lower IL-6 levels after 1 hour (210+/-108 vs. 578+/-443 pg/ml), 6 hours (204+/-91 vs. 1210+/-671 pg/ml) and 12 hours (174+/-97 vs. 971+/-623 pg/ml). Post-CPB cardiac index was superior in group B (3.9+/-0.3 vs. 3.2+/-0.3 l/min/m2, p<0.05) with similar doses of inotropes. Group B patients could earlier be weaned off respirator (10+/-4 vs. 13+/-4 hours, p<0.05) and showed minor blood loss (635+/-211 vs. 918+/-347 ml, p<0.05). CONCLUSIONS: Inflammatory response to CPB is associated with delayed myocardial recovery. The use of blood cardioplegia may attenuate inflammatory reactions.     

Does warm antegrade intermittent blood cardioplegia really protect the heart during coronary surgery?

OBJECTIVE: Intermittent antegrade blood cardioplegia (IABC) has been standardized as a routine technique for myocardial protection in coronary surgery. However, if the myocardium is known to tolerate short periods of ischemia during hypothermic arrest, it may be less tolerant of warm ischemia, so the optimal cardioplegic temperature of intermittent antegrade blood cardioplegia is still controversial. The aim of this study was to compare the effects of warm intermittent antegrade blood cardioplegia and cold intermittent antegrade blood cardioplegia on myocardial pH and different parameters of the myocardial metabolism. METHODS: Thirty patients undergoing first-time isolated coronary surgery were randomly allocated into two groups: group 1 (15 patients) received warm (37 degrees C) intermittent antegrade blood cardioplegia and group 2 (15 patients) received cold (4 degrees C) intermittent antegrade blood cardioplegia. The two randomization groups had similar demographic and angiographic characteristics. Total duration of cardiopulmonary bypass (108+/-17 and 98+/-21 min) and of aortic cross-clamping (70+/-13 and 65+/-15 min) were similar. The cardioplegic solutions were prepared by mixing blood with potassium and infused at a flow rate of 250 ml/min for a concentration of 20 mEq/l during 2 min after each anastomosis or after 15 min of ischemia. Intramyocardial pH was continuously measured during cardioplegic arrest by a miniature glass electrode and values were corrected by temperature. Myocardial metabolism was assessed before aortic clamping (pre-XCL), 1 min after removal of the clamp (XCL off) and 15 min after reperfusion (Rep) by collecting coronary sinus blood samples. All samples were analyzed for lactate, creatine kinase (MB fraction), myoglobin and troponin I. Creatine kinase and troponin I were also daily evaluated in peripheral blood during 6 days post-operatively. RESULTs: The clinical outcomes and the haemodynamic parameters between the two groups were identical. In group 1, XCL off and Rep were associated with higher coronary sinus release of lactate (5.5 +/- 1.8 and 2.2 +/- 0.5 mmol/l) than in group 2 (2.0 +/- 0.7 and 1.6 +/- 0.3 mmol/l, P < 0.05). Mean intramyocardial pH was lower in group 1 (7.23 +/- 0.08) than in group 2 (7.65 +/- 0.30, P < 0.05). There were no significant differences between the two groups with respect of creatine kinase (MB fraction) either after Rep or during the post-operative period. Lower coronary sinus release of myoglobin was detected at Rep in group 1 (170 +/- 53 microg/l) than in group 2 (240 +/- 95 microg/l, P < 0.05). At day 1, a lower release of troponin I was found in group 1 (0.11 +/- 0.07 g/ml) compared to group 2 (0.17 +/- 0.07 ng/ml, P < 0.05). CONCLUSION: With regards to similar clinical and haemodynamic results, myocardial protection induced by warm IAEX is associated with more acidic conditions (intramyocardial pH and lactate release) and less myocardial injury (myoglobin and troponin I release) than cold intermittent antegrade blood cardioplegia during coronary surgery.     

Addition of dextran sulfate to blood cardioplegia attenuates reperfusion injury in a porcine model of cardiopulmonary bypass

Objective: Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury. Methods: Eighteen pigs (DXS, n=10; phosphate buffered saline [PBS], n=8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60min with BCP containing either DXS (300mg/10ml, equivalent to 5mg/kg) or 10ml of PBS. Following 30min reperfusion, pigs were weaned from CPB. During 2h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed. Results: DXS significantly reduced CK-MB levels (43.4+/-14.8ng/ml PBS, 35.9+/-11.1ng/ml DXS, p=0.042) and significantly diminished cytokine release: TNFalpha (1507.6+/-269.2pg/ml PBS, 222.1+/-125.6pg/ml DXS, p=0.0071), IL1beta (1081.8+/-203.0pg/ml PBS, 110.7+/-79.4pg/ml DXS, p=0.0071), IL-6 (173.0+/-91.5pg/ml PBS, 40.8+/-19.4pg/ml DXS, p=0.002) and IL-8 (304.6+/-81.3pg/ml PBS, 25.4+/-14.2pg/ml DXS, p=0.0071). Tissue endothelin-1 levels were significantly reduced (6.29+/-1.90pg/100mg PBS, 3.55+/-1.15pg/100mg DXS p=0.030) as well as thrombin-anti-thrombin formation (20.7+/-1.0mug/ml PBS, 12.8+/-4.1mug/ml DXS, p=0.043). Also DXS reduced cardiac and pulmonary complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81+/-3% vs 78+/-3%, p=0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dt(min)), pulmonary artery pressure (21+/-3mmHg PBS, 19+/-3mmHg DXS, p=0.002) and right ventricular pressure (21+/-1mmHg PBS, 19+/-3mmHg DXS p=0.021) were significantly improved with the use of DXS. Conclusions: Addition of DXS to the BCP solution ameliorates post-CPB injury and to a certain extent improves cardiopulmonary function. Endothelial protection in addition to myocyte protection may improve post-CPB outcome and recovery.     

Adenine nucleotide catabolism in human myocardium during heart and heart-lung transplantation.

The influence of ischemia and reperfusion on nucleotide concentration in human myocardium was investigated during heart and heart-lung transplantation. Myocardial preservation during heart transplantation was achieved by infusion of cold St. Thomas' Hospital cardioplegic solution followed by storage in Ringer's solution at 4 degrees C during transport. In contrast, the hearts of heart and lung donors were preserved by core cooling using cardiopulmonary bypass and infusion of cold blood cardioplegia containing 26 mM potassium. The heart-lung block was transported in cold donor blood. Nucleotides and their catabolite concentrations were measured in donor tissue specimens taken before organ collection, before commencement of implantation and 30 min after aortic clamp removal. During reperfusion, samples of coronary sinus and arterial blood were collected and analysed for nucleotide catabolite concentration. Myocardial ATP and total nucleotide pool remained almost unchanged during the ischemic transport of the donor organs with only very small increases in myocardial inosine and hypoxanthine concentrations. However, a significant decrease of total adenine nucleotide pool by 10%-20% was demonstrated between the start of implantation and 30 min post-reperfusion. A release of inosine + hypoxanthine was greatest in the 1st minute (15-25 microM), but was still substantial after 10 min of reperfusion (5-15 microM). Metabolic changes tended to be more pronounced during heart-lung transplantation than during heart transplantation.     

Biochemical indicators of myocardial ischaemia during coronary artery bypass grafting

Metabolic indicators of myocardial ischaemia were measured in coronary sinus blood in six patients undergoing coronary artery bypass grafting (CABG). Five arterial and coronary sinus blood samples were taken in each case--one before cardiopulmonary bypass (CPB), and three during and one after CPB. Moderate hypothermia with topical cardiac cooling and cold cardioplegia were used. Myocardial infarction occurred perioperatively in two patients. Myocardial lactate production was not found before CPB in any patient, but it was common during CPB. Adenosine, inosine and hypoxanthine were released into the coronary sinus blood, but their release did not correlate significantly with lactate production. Myocardial noradrenaline production showed positive correlation with lactate levels (p less than 0.05). Release of adrenaline from the myocardium during CABG was also demonstrated. Myocardial catecholamine production was especially seen in the patients with myocardial infarction. Myocardial catecholamine release seemed to be the most sensitive of the studied biochemical indicators of myocardial ischaemia during CABG.     

Leukocyte-depleted blood cardioplegia reduces cardiac troponin T release in patients undergoing coronary artery bypass grafting.

OBJECTIVE: Activated neutrophils have been implicated in reperfusion injury of the myocardium. Leukocyte depletion at reperfusion may contribute to better myocardial protection during cardiac surgery. We tested the efficacy of leukocyte-depleted blood cardioplegia in reducing myocardial injury during coronary artery bypass grafting. METHODS: Subjects were 27 patients undergoing elective coronary artery bypass grafting divided into controls (perfused with nonfiltered blood cardioplegia, n = 12) and those undergoing leukocyte-depleted blood cardioplegia (n = 15). Oxygenated blood mixed with a potassium crystalloid cardioplegic solution was delivered through the aortic root at every 30 minutes during cardiac arrest and terminal warm blood was administered before aortic declamping in both groups. In leukocyte depletion, blood was filtered prior to the mixture with crystalloid solution in the cardioplegic reservoir. RESULTS: Patient profiles did not differ significantly between groups, nor did systemic leukocyte count during or after surgery despite more than 81% removal of leukocytes in cardioplegic delivery. No consistent differences between groups in creatine kinase or creatine kinase-MB were seen up to 18 hours after surgery. Peak troponin T levels were significantly lower in the leukocyte-depleted blood cardioplegia group (0.52 +/- 0.13 ng/ml), however, than in controls (3.85 +/- 0.85 ng/ml). CONCLUSION: We concluded that leukocyte-depleted blood cardioplegia reduces the release of cardiac troponin T in patients undergoing elective coronary artery bypass grafting and may produce better myocardial protection in patients with impaired cardiac function or a damaged myocardium.