Hepatic glycolytic intermediates and glucoregulatory enzymes in septic shock due to peritonitis: experimental study in rats

The hypoglycemia in septic shock due to peritonitis indicates deranged carbohydrate metabolism. To determine if this metabolic failure could be attributed to changes of glucoregulatory enzymes and glycolytic intermediates, activities and changes of these substances in septic shock have been studied in rats. Liver tissue was sampled 5 hours after induction of peritonitis by cecal incision in fasted male rats. Hepatic glycolytic intermediates were assayed by UV-spectrophotometry. Peritonitis caused 33% decrease in glucose-6-phosphate (G6P), a 2.5 fold increase in fructose-1,6-diphosphate (FDP) and a 3.5 fold increase in lactate. Phosphoenolpyruvate (PEP) levels did not show a significant increase in peritonitis. We investigated activities of glucose-6-phosphatase (G6Pase), fructose-1,6-diphosphatase (FDPase), phosphofructokinase ( PFKase ) and pyruvate kinase ( PKase ) in mitochondria-free supernatants from rat liver homogenates. Tissue was sampled 5 hours after induction of peritonitis by cecal incision. Assays were conducted at optimal substrate levels at pH 7.4; NADH charges produced by coupled reactions were determined by UV-spectrophotometry. A significant increase of PFKase and PKase specific activity was observed. These changes were consistent with stimulated glycolysis. For gluconeogenesis to achieve maximum efficiency it would be necessary to inhibit PFKase and PKase completely.     

Effects of fructose-1,6-diphosphate on endo- and myocardial purine metabolism during coronary artery bypass grafting surgery

AIM: During ischemia, the glycolytic pathway is up-regulated to anaerobically produce adenosine triphosphate (ATP). However, this is short-lived, due to negative feedback on phosphofructokinase from accumulating lactate. Since fructose-1,6-diphosphate (FDP) enters glycolysis distal to this inhibitory site, exogenously administered FDP may yield ATP-independent lactate accumulation and thus ameliorate ischemic injury. The aim of this prospective randomized study was to investigate whether the improved myocardial preservation by FDP could be attributed to improved intermediary metabolism in patients who underwent coronary artery bypass grafting surgery (CABG). METHODS: Thirty-eight patients scheduled for elective CABG were studied. During operation, aortic and coronary sinus blood were collected at different timepoints and analysed by chromatography. Ten patients received 250 mg/kg FDP and 10 received 5% dextrose (control) as intravenous pretreatment prior to cardiopulmonary bypass. In the second stage, 9 patients received 2.5 mM (1.4 g/L) FDP and 9 patients 5% dextrose with the cardioplegic solution. Myocardial metabolism was quantified by measuring nucleotide catabolites including inosine and hypoxanthine. RESULTS: The release of inosine-hypoxantine was increased in both the FDP and the control groups; however, compared to baseline, inosine-hypoxantine levels were significantly elevated at 0, 1, 5 and 10 minutes following reperfusion in the control group. This was in contrast to the earlier recovery to baseline levels (after 5 minutes following reperfusion) in the FDP group. CONCLUSION: These data suggest that FDP may contribute to myocardial cytoprotection during cardiopulmonary bypass. Moreover, myocardial nucleotide metabolite levels showed no evidence for a protective effect of FDP on nucleotide degradation between the treated and the control groups.     

1，6二磷酸果糖后处理对心脏瓣膜置换术患者围术期心肌酶谱的影响

目的观察1,6二磷酸果糖（FDP）后处理对心脏瓣膜置换术患者围术期心肌酶谱的影响。方法30例择期心脏瓣膜置换术患者随机分为1,6二磷酸果糖后处理组（F组）和对照组（C组）,每组15例。于主动脉开放即刻从体外循环机内F组加入250mg／kg的FDP,C组加入等容积的生理盐水。于切皮即刻（T1）,主动脉开放后0．5h（T2）,主动脉开放后3h（T3）,主动脉开放后24h（T4）时取颈内静脉血测定肌酸激酶（CK）、肌酸激酶-同功酶（CK-MB）、乳酸脱氢酶（LDH）的浓度变化。结果与T1比较,两组CK、CK—MB和LDH含量在,T2、T3、T4时均升高（P〈0．05）,且在T3时达到峰值（P〈0．05）;与C组比较,F组在他、仍、T4时CK、CK．MB和LDH含量均降低（P〈0．05）。结论FDP后处理对瓣膜置换术病人的缺血再灌注心肌有保护作用。     

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.     

Glucose-induced accumulation of fructose-2,6-bisphosphate in pancreatic islets

Rat islets contain the acid-labile activator of phosphofructokinase, fructose-2,6-bisphosphate. The islet content in activator is higher in islets exposed to glucose (16.7 mM) than in islets deprived of glucose. The islets display fructose-6-phosphate, 2-kinase activity with a Km for fructose-6-phosphate close to 0.08 mM. Glucose fails to affect the activity of this enzyme. It is proposed that the effect of glucose to increase the islet content of fructose-2,6-bisphosphate is attributable, in part at least, to the glucose-induced increase in the concentration of fructose-6-phosphate in the islet cells.     

Effect of sialyl Lewis(x) oligosaccharide on myocardial and cerebral injury in the pig

BACKGROUND: Although administration of the sialyl Lewis(x) oligosaccharide may reduce myocardial injury after ischemia-reperfusion, its effect on coronary and cerebral microvascular regulation and its clinical application during cardiac operation have not been examined. METHODS: Pigs were placed on normothermic cardiopulmonary bypass after 30 minutes of left anterior descending coronary artery occlusion. The hearts were then arrested with cold high potassium cardioplegia. After 1 hour the cross-clamp was removed and the pigs were weaned from cardiopulmonary bypass and perfused for an additional 1 hour. CY-1503 (a sodium salt of the sialyl Lewis(x) oligosaccharide, n = 6) was administered before reperfusion. Six other pigs received saline vehicle. Endothelium-dependent relaxation of precontracted coronary and brain arterioles (70 to 180 microm) to adenosine 5'-diphosphate and endothelium-independent relaxation to sodium nitroprusside were studied in vitro with videomicroscopy. Control values were obtained from uninstrumented pigs. Myeloperoxidase activity in the myocardium and brain was measured to quantify neutrophil infiltration. Cardiac function and perfusion were assessed by left ventricular systolic pressure, maximum rate of increase of left ventricular pressure, left anterior descending coronary artery blood flow and percent segmental shortening, and cerebral vascular resistance, internal carotid artery blood flow, and the constitutively expressed and inducible isoform of nitric oxide synthase mRNA were measured. RESULTS: The impaired myocardial contractile function after ischemia and cardioplegia was not improved by administration of CY-1503. The reduced endothelium-dependent relaxation responses of coronary and brain arterioles during ischemia followed by cardioplegia and cardiopulmonary bypass were improved with CY-1503, but the altered pattern of organ perfusion was not improved. Myeloperoxidase activity was increased in the heart after ischemia-cardioplegia and in the brain after cardiopulmonary bypass. CY-1503 reduced myeloperoxidase activity in both the myocardium and in the brain. Expressions of myocardial inducible isoform or constitutively expressed nitric oxide synthase were not altered in the heart. CONCLUSIONS: Although the sialyl Lewis(x) oligosaccharide does reduce neutrophil infiltration and endothelial injury in the coronary and cerebral microcirculation after cardiopulmonary bypass, it does not have significant beneficial acute effects on organ perfusion or function in the myocardium or brain.     

Temporal endothelin dynamics of the myocardial interstitium and systemic circulation in cardiopulmonary bypass

OBJECTIVE: Increased systemic levels of the bioactive peptide endothelin 1 during and after cardioplegic arrest and cardiopulmonary bypass have been well documented. However, endothelin 1 is synthesized locally, and therefore myocardial endothelin 1 production during and after cardiopulmonary bypass remains unknown. METHODS: Pigs (n = 11) were instrumented for cardiopulmonary bypass, and cardioplegic arrest was initiated. Myocardial interstitial and systemic arterial levels of endothelin 1 were measured before cardiopulmonary bypass, throughout bypass and cardioplegic arrest (90 minutes), and up to 90 minutes after separation from bypass. Myocardial interstitial endothelin 1 was determined by microdialysis and radioimmunoassay. RESULTS: Baseline myocardial endothelin 1 levels were higher than systemic endothelin 1 levels (25.6 +/- 6.7 vs 8.3 +/- 1.1 fmol/mL, P <.05). With the onset of bypass, myocardial endothelin 1 increased by 327% +/- 92% from baseline (P <.05), which preceded the increase in systemic endothelin 1 levels. CONCLUSION: Myocardial compartmentalization of endothelin 1 exists in vivo. Cardiopulmonary bypass and cardioplegic arrest induce temporal differences in endothelin 1 levels within the myocardial interstitium and systemic circulation, which, in turn, may influence left ventricular function in the postbypass period.     

Dynamic and differential changes in myocardial and plasma endothelin in patients undergoing cardiopulmonary bypass

OBJECTIVE: The bioactive peptide endothelin modulates left ventricular function by changing afterload, coronary vascular tone, and myocardial contractility. However, whether increased plasma endothelin levels observed in patients during and after coronary revascularization and cardiopulmonary bypass reflect actual myocardial interstitial levels are unknown. METHODS: A microdialysis probe (outer diameter: 0.77 mm; length: 4 mm) was placed in the left ventricular apical midmyocardium in 20 patients and myocardial interstitial fluid was collected (2.5 microL/min) at baseline and up to 30 minutes after cardiopulmonary bypass. Myocardial interstitial and systemic arterial endothelin were measured by radioimmunoassay. RESULTS: Baseline myocardial interstitial endothelin was over 6-fold higher than plasma (20.11 +/- 2.07 vs 3.19 +/- 0.25 fmol/mL, P < .05). Plasma endothelin increased by 23% +/- 12% at 60 minutes of cardiopulmonary bypass whereas myocardial interstitial endothelin increased by 105% +/- 24%, P < .05), and this change was higher than in the plasma ( P < .05). Although no further change in plasma endothelin occurred during cardiopulmonary bypass, myocardial interstitial levels increased further after crossclamp removal (400% +/- 75%) and remained significantly higher than plasma at separation from cardiopulmonary bypass. CONCLUSION: The unique findings of this study were 2-fold: First, significant compartmentalization of endothelin exists within the human myocardium. Second, a significantly higher and temporally disparate change in myocardial interstitial endothelin occurs during and after cardiopulmonary bypass when compared with systemic levels. These dynamic changes in myocardial endothelin likely influence coronary vascular tone and contractility.     

1,6-二磷酸果糖对心肺转流期间氧代谢的影响

目的研究1,6-二磷酸果糖(FDP)对心肺转流(CPB)手术期间氧代谢的影响。方法随机将24例CPB手术病人均分成研究组(A组)和对照组(B组)。A组于转机前静滴FDP200mg/kg,B组于转机前滴入等量生理盐水,观察麻醉后(T1)、CPB前(T2)、升主动脉开放后10min(T3)、停CPB后10min(T4)、停CPB后60min(T5)的氧供(DO2)、氧耗(VO2)、氧摄取率(ERO2)及动脉血乳酸(ABL)的变化。结果两组T3时DO2明显降低(P<0.05),T3时A组ERO2和B组VO2、ERO2及两组T4、T5时VO2、ERO2明显增加(P<0.05或P<0.01),T3、T4和T5时ABL明显增加(P<0.01);B组T3、T4和T5时VO2、ERO2、ABL明显高于A组(P<0.05)。结论FDP对改善CPB手术期间氧供需平衡障碍有明显作用。     

依达拉奉和1,6-二磷酸果糖联合应用对全身抗炎作用的影响

目的探讨氧自由基清除剂依达拉奉和能量代谢调节剂1,6-二磷酸果糖(FDP)联合应用对在心肺转流(CPB)下行心脏瓣膜置换手术患者的全身抗炎作用的影响。方法瓣膜置换术患者40例,随机分为依达拉奉组(A组)、FDP组(B组)、联合用药组(C组)和对照组(D组),每组10例。A组将依达拉奉0.5 mg/kg一次性加入CPB预充液中,B组于主动脉阻断前15 min静脉滴注FDP 200 mg/kg,C组为A、B两组药物的联合使用,D组给予等量生理盐水。分别于切皮前(T1)、主动脉阻断前(T2)、CPB停止2 h(T3)6、h(T4)和术后24 h(T5)采集桡动脉血测定血浆超氧化物歧化酶(SOD)、丙二醛(MDA)、肿瘤坏死因子α(TNF-α)、白细胞介素(IL)-6I、L-8及IL-10水平,记录心脏复跳情况、心血管活性药物的应用情况及术后24 h创面引流量。结果与D组比较,其他三组能显著减少血浆SOD活性降低的幅度,降低血浆MDA、TNF-αI、L-6I、L-8的升高幅度,增加IL-10的升高幅度(P0.05),以C组作用最为明显。结论 CPB主动脉阻断前给予依达拉奉或FDP均可减轻自由基反应,抑制全身炎性反应,且两者联合用药作用更明显。     

Elevated mid-myocardial oxygen tension in the fibrillating heart during cardiopulmonary bypass

Mid-myocardial tissue oxygen tension was measured in the left ventricular wall of the hearts of ten dogs by means of a Silastic tonometer implanted earlier. During cardiopulmonary bypass, myocardial PO2 was significantly higher in a spontaneously fibrillating heart (5.4 +/- 0.9 kPa) than during the initial beating period (3.7 +/- 0.5 kPa) or after defibrillation (4.0 +/- 0.7 kPa). In general, there was a tendency towards increased myocardial blood flow, elevated oxygen uptake and reduced coronary sinus oxygen content during ventricular fibrillation, compared with the situation in the beating heart. Myocardial lactate extraction remained unchanged during the different phases of cardiopulmonary bypass. The increase in mid-myocardial oxygen tension during ventricular fibrillation was probably due to increased total myocardial blood flow and redistribution of regional myocardial circulation. In two additional dogs, ventricular fibrillation resulted in left ventricular distension and a simultaneous fall of myocardial oxygen tension, which indicates the necessity of left ventricular decompression suction in a fibrillating heart during cardiopulmonary bypass.     

Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts

OBJECTIVES: Heart function is variably impaired after cardiopulmonary bypass. We hypothesized that, similar to other myocardial injury states, cardiopulmonary bypass leads to enhanced activity of nitric oxide synthase and matrix metalloproteinases. METHODS: We obtained right atrial biopsy specimens and plasma samples at the onset and termination of cardiopulmonary bypass in 10 patients. Biopsy specimens were analyzed for nitric oxide synthase activity by using a citrulline assay, whereas plasma and tissue were analyzed for matrix metalloproteinase-9 and matrix metalloproteinase-2 activity by using zymography. Tissue inhibitor of metalloproteinase-4 was analyzed by means of Western blotting. The cellular expression of inducible nitric oxide, endothelial nitric oxide synthase, matrix metalloproteinase-2, and matrix metalloproteinase-9 was determined in right atrial biopsy samples from 3 additional patients by using the appropriate conjugated antibodies. RESULTS: Nitric oxide synthase activity increased from the beginning to the end of bypass (4.46 +/- 1.07 vs 16.77 +/- 4.86 pmol citrulline/mg of protein per minute, respectively; P =.018). Pro-matrix metalloproteinase-9 activity increased in hearts (199 +/- 41 vs 660 +/- 177 density units/mg protein; P =.008) and plasma (14.1 +/- 4.6 vs 52.2 +/- 5.9 density units/mg protein; P =.008). Pro-matrix metalloproteinase-2 activity increased in the heart (201 +/- 23 vs 310 +/- 35 density units/mg protein, P <.05) but not in plasma. Tissue inhibitor of metalloproteinase-4 expression in the heart decreased (1574 +/- 280 vs 864 +/- 153 density units, P =.014). CONCLUSIONS: Cardiopulmonary bypass activates enzymes mediating acute inflammation and organ injury (ie, nitric oxide synthase, matrix metalloproteinase-9, and matrix metalloproteinase-2). Decreased tissue inhibitor of metalloproteinase-4 expression allows relatively unopposed increases in matrix metalloproteinase tissue activity. We postulate that these changes play a role in the pathogenesis of heart dysfunction after bypass surgery.     

Metabolic indices of pulmonary damage. Changes in angiotensin converting enzyme and alpha 1 anti-trypsin activity after cardiopulmonary bypass

The activity of angiotensin-converting enzyme was measured in patients undergoing cardiopulmonary bypass and in a control group requiring thoracotomy for pulmonary surgery. The activity of the enzyme was higher in patients with cardiac disease, fell during operations involving cardiopulmonary bypass, but did not change during thoracotomy for pulmonary surgery. Possible reasons for these differences are discussed. The activity of another enzyme, alpha 1 anti-trypsin, did not change during cardiopulmonary bypass and no arteriovenous difference could be detected during or after operation.     

Fructose-1,6-bisphosphate for improved outcome after hypothermic circulatory arrest in pigs

Objective: Fructose-1,6-bisphosphate is a high-energy intermediate in the anaerobic metabolism. It enhances glycolysis, preserves cellular adenosine triphosphate, and prevents the increase of intracellular calcium during ischemia. The potential neuroprotective effect of fructose-1,6-bisphosphate during hypothermic circulatory arrest was evaluated in a surviving porcine model.Methods: Twenty-four pigs were randomly assigned to receive two intravenous infusions of either fructose-1,6-bisphosphate (500 mg/kg) or saline solution. The first infusion was given immediately before a 75-minute period of hypothermic circulatory arrest and the second was given immediately after hypothermic circulatory arrest.Results: The 7-day survivals were 83.3% in the fructose-1,6-bisphosphate group and 41.7% in the control group (P = .09). The treated animals had significantly better postoperative behavioral scores. The administration of fructose-1,6-bisphosphate was associated with higher venous phosphate and sodium levels, lower venous ionized calcium levels, higher blood osmolarity, and a better fluid balance. Intracranial pressure and venous creatine kinase isoenzyme MB were significantly lower in the fructose-1,6-bisphosphate group during rewarming (P = .01 and P = .001, respectively). Among the treated animals, brain glucose, pyruvate and lactate levels tended to be higher, brain glycerol levels tended to be lower, and the histopathologic score of the brain was significantly lower (P = .04).Conclusions: Intravenous administration of fructose-1,6-bisphosphate at 500 mg/kg before and after hypothermic circulatory arrest in a surviving porcine model was associated with better survival, behavioral outcome, and histopathologic score. The observed lower blood creatine kinase isoenzyme MB and brain glycerol levels and the higher brain glucose, pyruvate, and lactate levels in the fructose-1,6-bisphosphate group suggest that this drug has supportive effects on myocardial and brain metabolisms.     

Studies on liver cell injury in obstructive jaundice: activities of key enzymes responsible for carbohydrate metabolism in rat after bile duct ligation

Key enzyme activities of carbohydrate metabolism were evaluated as sensitive indicators of liver cell injury of rats. Hexokinase and glucose 6-phosphatase distribution in the acinus of the liver was also studied histochemically with the following results: The activities of liver-specific enzymes, such as glucose 6-phosphatase, fructose 1.6-diphosphatase, glucokinase and pyruvate kinase Type L, were decreased. While the activities of nonspecific enzymes to liver, such as hexokinase, glucose 6 phosphate dehydrogenase, phosphofructokinase and pyruvate kinase Type M2 were increased. The decrease in glucokinase activity was marked and was found as early as one day after bile duct ligation. Isozymes of HK, I, II and III, all increased to the same extents. Increased hexokinase activity was found in the centrolobular area, where the decreased activity of glucose 6-phosphatase was observed. These changes in the key enzyme activities indicated the presence of a hepatocyte injury caused by bile duct ligation.     

Nitrotyrosine and 8-isoprostane formation indicate free radical-mediated injury in hearts of patients subjected to cardioplegia

OBJECTIVE: Myocardial ischemia and reperfusion induced by cardioplegic arrest subjects the heart to free radical-mediated stress. The purpose of our study was to investigate the effect of cardioplegia-induced ischemia and reperfusion on myocardial formation and distribution of (1) nitrotyrosine as an indicator for peroxynitrite-mediated tissue injury resulting from increased nitric oxide release and (2) 8-isoprostane as an indicator for oxygen-derived free radical-mediated lipid peroxidation. METHODS: In 10 patients undergoing coronary artery operations (64 +/- 6 [mean +/- SD] years, 3 women and 7 men) subjected to cardiopulmonary bypass and intermittent cold blood cardioplegia, we collected transmural left ventricular biopsy specimens before and at the end of cardiopulmonary bypass. Specimens were cut at 10 micro m and subjected to immunocytochemical staining against the nitric oxide-producing enzyme constitutive nitric oxide synthase, cyclic guanosine monophosphate (intracellular second messenger of nitric oxide), nitrotyrosine, and 8-isoprostane by using polyclonal antibodies. For global left ventricular function determination, we measured the fractional area of contraction using transesophageal echocardiography. RESULTS: Nitric oxide synthase activity in cardiac myocytes increased from 34 +/- 10 gray units before cardiopulmonary bypass to 47 +/- 12 gray units at the end of bypass (P =.015), and all hearts showed increased cyclic guanosine monophosphate content in both myocytes and endothelial cells at the end of bypass. The number of nitrotyrosine-positive capillaries increased from 36 +/- 29/mm(2) before bypass to 82 +/- 47/mm(2) at the end of bypass (P =.012), and 8-isoprostane-positive capillaries increased from 92 +/- 72/mm(2) before bypass to 209 +/- 108/mm(2) at the end of bypass (P =.005). The fractional area of contraction was 53% +/- 12% before bypass and 56% +/- 12% after bypass (P =.47) but was slightly decreased to 45% +/- 14% at 4 hours after bypass (P =.121). CONCLUSIONS: Our data show that cardioplegia-induced myocardial ischemia and reperfusion is associated with nitrotyrosine and 8-isoprostane formation mainly in the coronary endothelium, indicating injury mediated by both peroxynitrite and oxygen-derived free radicals. Because nitric oxide synthase activation was accompanied with increased cyclic guanosine monophosphate, these data suggest that direct effects of nitric oxide on cardiac myocytes, as well as nitric oxide-mediated coronary endothelial injury, might contribute to injury associated with cardioplegia and cardiopulmonary bypass.     

Metabolic changes and myocardial injury during cardioplegia: a pilot study.

BACKGROUND: The timing, nature, and severity of both increased cardiac troponin I (cTn-I) levels and myocardial injury during ischemic arrest with cardioplegia are unknown. To define them more accurately, we studied myocardial metabolic activity and the release of markers of myocardial cell injury into the coronary sinus before, during, and after cardioplegia. METHODS: We simultaneously measured creatine kinase, creatine kinase-MB, cTn-I, lactate, phosphate, and blood gases in coronary sinus and systemic arterial blood from 12 patients before cardiopulmonary bypass, after removal of the aortic cross-clamp, and after discontinuation of cardiopulmonary bypass. We also measured coronary sinus flow and transmyocardial fluxes of all analytes and calculated myocardial oxygen consumption, myocardial carbon dioxide production, and myocardial energy expenditure. RESULTS: Myocardial lactate release increased 10-fold after removal of the aortic cross-clamp (p = 0.012) and was accompanied by a surge in myocardial phosphate uptake (p = 0.056). These events were associated with only partial cardioplegia-induced suppression of myocardial oxygen consumption (p = 0.0047), myocardial carbon dioxide production (p = 0.0022), and myocardial energy expenditure (p = 0.0029). Simultaneously, coronary sinus cTn-I levels increased from a mean of 0.76 to 2.43 ng/mL after removal of the aortic cross-clamp, and 2.51 ng/mL after cardiopulmonary bypass (p = 0.014), leading to an increase in arterial cTn-I concentration from 0.18 to 0.98 and 3.01 ng/mL (p = 0.0002). Thus, cTn-I release across the myocardium was absent at baseline, became detectable (p = 0.012) after removal of the aortic cross-clamp, and correlated with cross-clamp and pump times. Similar changes occurred with creatine kinase-MB. CONCLUSIONS: Metabolic myocardial stress occurs during ischemic arrest with cardioplegia and is associated with inadequate suppression of metabolism and with a surge in cTn-I and creatine kinase-MB release, which is maximal after removal of the aortic cross-clamp. These changes are likely to represent structural myocardial cell injury.     

Dipyridamole reduced myocardial platelet and leukocyte deposition following ischemia and cardioplegia

Urgent coronary revascularization for acute myocardial ischemia results in an increased mortality and morbidity. Deposition of activated platelets and leukocytes into the ischemic myocardium during reperfusion may augment perioperative ischemic injury. Dipyridamole reduces platelet activation and may reduce myocardial deposition and prevent ischemic injury during reperfusion. The effects of dipyridamole on myocardial platelet and leukocyte deposition were evaluated in a canine model of acute regional myocardial ischemia with reperfusion during cardioplegia on cardiopulmonary bypass. Eight dogs underwent left anterior descending (LAD) coronary artery ligation for 45 min followed by cardiopulmonary bypass and release of the ligature during 60 min of cold crystalloid cardioplegic arrest to simulate urgent revascularization. Four dogs were randomized to receive an infusion of dipyridamole perioperatively (50 mg/hr) and 4 dogs served as controls. Autologous platelets were labeled with 111In, leukocytes with 99mTc, and erythrocytes with 51Cr. The labeled cells were infused immediately after cross-clamp release and myocardial biopsies were obtained at 10, 20, 30, and 60 min of reperfusion. Platelets were deposited in the myocardium during reperfusion and four times more platelets were found in the LAD region than the circumflex region. Leukocyte deposition was similar in the LAD and circumflex regions. Dipyridamole reduced both platelet and leukocyte deposition and the reduction was greater in the LAD than in the circumflex region. Myocardial platelet and leukocyte deposition was found after regional ischemia, cardioplegia, and cardiopulmonary bypass. Dipyridamole reduced myocardial platelet and leukocyte deposition and may reduce perioperative ischemic injury.     

Effect of triiodothyronine (T3) on myocardial high energy phosphates and lactate after ischemia and cardiopulmonary bypass. An experimental study in baboons

Cardiopulmonary bypass is associated with a reduction in plasma free triiodothyronine in patients undergoing cardiac operations. A previous experimental study in pigs demonstrated a marked inotropic effect when triiodothyronine was administered after a period of myocardial ischemia and cardiopulmonary bypass; this was associated with a significant reduction in mortality compared with the mortality in control pigs. To clarify the effect of triiodothyronine on myocardial high energy phosphate stores and lactate, a series of experiments was done in baboons undergoing 3 hours of myocardial ischemia while supported by cardiopulmonary bypass. Seven baboons received no triiodothyronine and six received 6 micrograms of triiodothyronine at the end of the ischemic period. Seventy minutes after cardiopulmonary bypass, the myocardial adenosine triphosphate level was significantly higher (p less than 0.01) in the treated animals. In untreated animals, a steady increase in myocardial lactate occurred after cardiopulmonary bypass; by 120 minutes after ischemia (70 minutes after cardiopulmonary bypass) there was a significant difference in lactate levels between the two groups (p less than 0.01). We postulate that a combination of global ischemia and depletion of triiodothyronine results in reduced mitochondrial function, inhibition of the tricarboxylic acid cycle, and increased anaerobic metabolism and depletion of myocardial phosphates. Triiodothyronine replacement therapy leads to improved mitochondrial function and increased aerobic metabolism, which results in increased synthesis of myocardial phosphates. We suggest that there may be a place for the administration of triiodothyronine in patients undergoing cardiac operations with a prolonged myocardial ischemic period or in whom there is any evidence of low cardiac output after discontinuation of cardiopulmonary bypass.