Myocardial Reoxygenation Injury Research Articles

Cardiopulmonary bypass-induced myocardial reoxygenation injury in pediatric patients with cyanosis

J Thorac Cardiovasc Surg 2002;124:1035-6

Does normoxemic cardiopulmonary bypass prevent myocardial reoxygenation injury in cyanotic children?

Objective: To evaluate whether the deleterious effect of cardiopulmonary bypass (CPB) can be prevented by controlling PaO2 in cyanotic children. Design: Prospective, randomized, clinical study. Setting: Single university hospital. Participants: Pediatric patients undergoing cardiac surgery for repair of congenital heart disease (n = 24). Interventions: Patients were randomly allocated into 3 groups. Patients in the acyanotic group (group I, n = 10) had CPB initiated at a fraction of inspired oxygen (FIO2) of 1.0 (PO2, 300 to 350 mmHg). Cyanotic patients were subdivided as follows: Group II (n = 7) had CPB initiated at an FIO2 of 1.0, and group III (n = 7) had CPB initiated at an FIO2 of 0.21 (PO2, 90 to 110 mmHg). A biopsy specimen of right atrial tissue was removed during venous cannulation, and another sample was removed after CPB before aortic cross-clamping. The tissue was incubated in 4 mmol/L of t-butylhydroperoxide, and the malondialdehyde (MDA) level was measured to determine the antioxidant reserve capacity. Blood samples for cytokine levels, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 response to CPB were collected after induction of anesthesia and at the end of CPB before protamine administration. Measurements and Main Results: After initiation of CPB, MDA level rose markedly in the cyanotic groups compared with the acyanotic group (210 ± 118% v 52 ± 34%, p < 0.05), which indicated the depletion of antioxidants. After initiation of CPB, TNF-α and IL-6 levels of the cyanotic groups were higher than for the acyanotic group (168 ± 77 v 85 ± 57, p < 0.001; 249 ± 131 v 52 ± 40; p < 0.001). When a comparison between the cyanotic groups was performed, group II (initiating CPB at an FIO2 of 1.0) had significantly increased MDA production compared with group III (initiating CPB at an FIO2 of 0.21) (302 ± 134% v 133 ± 74%, p < 0.05). Group II had higher TNF-α and IL-6 levels than group III (204 ± 81 v 131 ± 52, p < 0.001; 308 ± 147 v 191 ± 81, p < 0.01). Conclusion: Conventional clinical methods of initiating CPB at a hyperoxemic PO2 may increase the possibility of myocardial reoxygenation injury in cyanotic children. This deleterious effect of reoxygenation can be modified by initiating CPB at a lower level of oxygen concentration. Subsequent long-term studies are needed to determine the best method of decreasing the oxygen concentration of the CPB circuit. Copyright 2002, Elsevier Science (USA). All rights reserved.

Myocardial protection in hypoxic immature hearts.

Current myocardial protection techniques in cyanotic immature hearts are not optimal. Despite successful surgical correction of congenital cardiac defects causing hypoxemia, myocardial dysfunction remains the leading cause of postoperative mortality. New studies indicate that the intraoperative reintroduction of molecular oxygen on cardiopulmonary bypass causes a reoxygenation injury leading to postoperative cardiac dysfunction. Biochemical and functional changes of reoxygenation injury can be avoided by several methods aimed at reducing oxygen free radical production and nitric oxide release. The present investigation provides an overview of our current understanding of pathogenesis, implication, and treatment of myocardial reoxygenation injury. New surgical concepts of myocardial protection including normoxic CPB and controlled reoxygenation are introduced.

Effect of halothane on myocardial reoxygenation injury in the isolated rat heart

Several studies have reported a protective effect of halothane on myocardial injury in an ischaemia-reperfusion situation. It is unclear if the protection is a result of the haemodynamic effects of halothane or if halothane has a specific action on ischaemia or reperfusion pathomechanisms. To examine this question, we have used an isolated rat heart model where heart rate (300 beat min-1), ventricular volume and coronary flow are constant. Left ventricular developed pressure (LVDP) and release of creatine kinase (CK) were measured as variables of myocardial performance and cellular injury, respectively. Five control hearts were subjected to 35 min of low-flow (2 ml min-1) anoxic and substrate-free perfusion and were then perfused for 1 h with the oxygenated buffer. In the treatment groups, halothane 0.4 mmol litre-1 was added during the first 30 min of anoxic perfusion (n = 5) or during the first 30 min of reoxygenation (n = 5). In five additional hearts, the effect of halothane 0.4 mmol litre-1 was tested under normoxic conditions. Mean basal CK release was 0.29 (SEM 0.13) iu g-1 min-1 and LVDP was 105.5 (4.0) mm Hg. Under normoxic conditions, halothane reduced LVDP to 52.0 (2.6) mm Hg. In control hearts, the major cell injury occurred at the onset of reoxygenation (CK release increased to 149.1 (9.1) iu g-1 min-1) and functional recovery after 1 h of reoxygenation was poor (control LVDP, 14.2(2.)% of baseline). Halothane during anoxia attenuated myocardial injury only moderately (CK release 50.2(5.7) iu g-1 min-1) and LVDP recovered to 30.8(3.0)% (each P < 0.05 vs control). When halothane was administered at reoxygenation, CK release was reduced to 10.1 (0.9) iu g-1 min-1 and LVDP recovered to 69.4(4.9)% (each P < .05 vs control). We conclude that halothane not only attenuated ischaemic injury but had a specific protective action against reoxygenation injury.

Studies of hypoxemic/reoxygenation injury: Without aortic clamping:: V. Role of the l-arginine–nitric oxide pathway: The nitric oxide paradox

This study tests the hypothesis that nitric oxide, which is endothelial-derived relaxing factor, produces reoxygenation injury via the L-arginine–nitric oxide pathway in hypoxemic immature hearts when they are placed on cardiopulmonary bypass. Twenty 3-week-old piglets undergoing 2 hours of hypoxemia (oxygen tension about 25 mm Hg) on a ventilator were reoxygenated by initiating cardiopulmonary bypass (oxygen tension about 400 mm Hg). Five animals were not treated, whereas the pump circuit was primed with the nitric oxide–synthase inhibitor N G -nitro- L-arginine methyl ester( L-NAME, 4 mg/kg) in five piglets. L-Arginine, the substrate for nitric oxide, was administered in a fivefold excess (20 mg/kg), together with L-NAME in five piglets ( L-NAME and L-arginine), and given alone in five other piglets ( L-arginine). Five normoxemic, instrumented piglets served as a control group, and five others underwent 30 minutes of cardiopulmonary bypass without preceding hypoxemia. Left ventricular contractility was determined as end-systolic elastance by pressure-dimension loops. Myocardial conjugated dienes were measured as a marker of lipid peroxidation, and the antioxidant reserve capacity (malondialdehyde production in tissue incubated with t-butylhydroperoxide) was measured. Nitric oxide level was determined in coronary sinus plasma as its spontaneous oxidation product, nitrite. Cardiopulmonary bypass per se did not alter left ventricular contractility, cause lipid peroxidation, or lower antioxidant capacity. Reoxygenation without treatment depressed cardiac contractility (end-systolic elastance 38% ± 12% of control*), raised nitric oxide (127% above hypoxemic values), increased conjugated dienes (1.3 ± 0.2 vs 0.7 ± 0.1, control*), and reduced antioxidant reserve capacity (910 ± 59 vs 471 ± 30, control*). Inhibition of nitric oxide production by L-NAME improved end-systolic elastance to 84% ±12%,** limited conjugated diene elution (0.8 ± 0.1 vs 1.3 ± 0.2, no treatment**), and improved antioxidant reserve capacity (679 ± 69 vs 910 ± 59, no treatment**). Conversely, L-arginine counteracted these beneficial effects of L-NAME, because left ventricular function recovered only 24% ± 6%,* conjugated dienes were 1.2 ± 0.1,* and antioxidant reserve capacity was 826 ± 70.* L-Arginine alone caused the same deleterious biochemical changes as L-NAME/ L-arginine and resulted in 60% mortality. The close relationship between postbypass left ventricular dysfunction (percent end-systolic elastance) and myocardial conjugated diene production ( r = 0.752) provides in vivo evidence that lipid peroxidation contributes to myocardial dysfunction after reoxygenation. These results suggest the L-arginine–nitric oxide pathway, which is normally of physiologic benefit by producing endothelial-derived relaxing factor, is involved in the pathogenesis of myocardial reoxygenation injury (* p < 0.05 vs control; ** p < 0.05 vs no treatment, analysis of variance). (J T HORAC C ARDIOVASC S URG 1995;110:1200-11)

Role of L-arginine-nitric oxide pathway in myocardial reoxygenation injury

In view of the recent findings that NO reacts with superoxide anion to generate hydroxyl radical, the present study was conducted to ascertain the role of endogenous NO in mediating myocardial reoxygenation injury in the hypoxic piglet on cardiopulmonary bypass. Anesthetized piglets were made hypoxic (PaO2 = 20-30 mmHg) for up to 120 min, followed by reoxygenation on cardiopulmonary bypass for 30 min. Reoxygenation caused rapidly developing myocardial injury characterized by decreased contractility (expressed as end-systolic elastance) and increased lipid peroxidation (measured as conjugated dienes). Systemic venous and coronary sinus blood content of NO decreased significantly during hypoxia and increased substantially above prehypoxic levels during reoxygenation on cardiopulmonary bypass. Administration of either the antioxidants mercaptopropionyl glycine and catalase or the NO synthase inhibitor, NG-nitro-L-arginine methyl ester, to the extracorporeal circuit afforded similar and nearly complete protection against myocardial reoxygenation injury. The protective effects of NG-nitro-L-arginine methyl ester were nullified by adding an excess of L-arginine to the pump circuit, suggesting that the L-arginine-NO pathway is involved in myocardial reoxygenation injury.

Formation of hydroxyl radicals in biological systems. Does myoglobin stimulate hydroxyl radical formation from hydrogen peroxide?

Incubation of horse-heart oxymyoglobin or metmyoglobin with excess H2O2 causes formation of myoglobin(IV), followed by haem degradation. At the time when haem degradation is observed, hydroxyl radicals (.OH) can be detected in the reaction mixture by their ability to degrade the sugar deoxyribose. Detection of hydroxyl radicals can be decreased by transferrin or by .OH scavengers (mannitol, arginine, phenylalanine) but not by urea. Neither transferrin nor any of these scavengers inhibit the haem degradation. It is concluded that intact oxymyoglobin or metmyoglobin molecules do not react with H2O2 to form .OH detectable by deoxyribose, but that H2O2 eventually leads to release of iron ions from the proteins. These released iron ions can react to form .OH outside the protein or close to its surface. Salicylate and the iron chelator desferrioxamine stabilize myoglobin and prevent haem degradation. The biological importance of .OH generated using iron ions released from myoglobin by H2O2 is discussed in relation to myocardial reoxygenation injury.