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G D Buckberg

Publications and source records attributed to G D Buckberg.

At least 19 recordsLinked to original sources
PubMed1996

Pulmonary vasoconstriction due to impaired nitric oxide production after cardiopulmonary bypass.

BACKGROUND: Pulmonary hypertension is a serious complication after cardiopulmonary bypass (CPB). This study tests the hypothesis that CPB provokes oxidant-mediated pulmonary endothelial dysfunction, leading to reduced nitric oxide (NO) production and pulmonary vasoconstriction. METHODS: Twelve piglets underwent 2 hours of CPB. In 6 of them, CPB prime was supplemented with N-mercaptopropionylglycine and catalase, whereas the others were not treated. Left and right ventricular function were evaluated from end-systolic elastance and Starling analysis. Pulmonary vascular resistance and transpulmonary NO production (measuring NO2-, NO3-) were determined to assess pulmonary endothelial function. RESULTS: Cardiopulmonary bypass caused a significant increase in pulmonary vascular resistance (83 +/- 12 to 212 +/- 30 dynes.cm-5.s kg-1, p < 0.05), associated with a reduction of NO production (8.8 +/- 1.4 to 2.5 +/- 0.5 mumol/min, p < 0.05) and depressed right ventricular function (56 +/- 12% of control), whereas N-mercaptopropionylglycine and catalase added to the CPB allowed a substantial improvement of these deleterious effects of CPB. CONCLUSIONS: Cardiopulmonary bypass impairs pulmonary NO production, resulting in pulmonary vasoconstriction and right ventricular dysfunction, which can be reduced by antioxidants. These findings imply the validity of NO inhalation therapy for postoperative pulmonary hypertension as a supplementation of endogenous endothelium-derived relaxing factor.

Animals↗
PubMed1996

Controlled limb reperfusion in patients having cardiac operations.

HYPOTHESIS: Severe limb ischemia in patients having cardiac operations may occur after intraaortic balloon pump insertion, prolonged femoral vessel cannulation, percutaneous cardiopulmonary bypass, dissecting aneurysms, or emboli. Normal blood reperfusion can cause a postischemic syndrome that increases morbidity and mortality. This clinical study is based on an experimental infrastructure patterned after controlled cardiac reperfusion. (1) It tests the hypothesis that controlled limb reperfusion (i.e., modifying the composition of the initial reperfusate and the conditions of reperfusion) reduces the local and systemic complications seen after normal blood reperfusion. (2) It reports initial clinical application of this strategy in three cardiac surgery centers. METHODS: Controlled limb reperfusion was applied to 19 patients with signs of severe prolonged unilateral or bilateral ischemia (including paralysis, anesthesia, and muscle contracture); six patients (32%) were in cardiogenic shock. The mean ischemic duration was 26 +/- 6 hours. The reperfusion method includes a 30-minute infusion into the distal vessels of a normothermic reperfusate solution mixed with the patient's arterial blood (obtained proximal to the obstruction) in a 6:1 blood/reperfusate ratio. Data are mean +/- standard error of the mean. RESULTS: Sixteen patients (84%) survived with salvaged and functional limbs at the time of discharge. No renal, cardiac, pulmonary, cerebral, or hemodynamic complications developed in the survivors. The three deaths occurred in patients undergoing controlled limb reperfusion while in profound postoperative cardiogenic shock; neither postischemic edema nor contracture developed in any of them. CONCLUSIONS: These findings show that controlled limb reperfusion can be applied readily with standard equipment that is used for cardiac surgery and may salvage limbs while reducing postreperfusion morbidity and mortality.

Adult↗
PubMed1996

Oxidative insult associated with hyperoxic cardiopulmonary bypass in the infantile heart and lung.

Cardiopulmonary bypass (CPB) per se alters many factors simultaneously, including free radical generation, which suggests that conventional hyperoxic CPB may produce oxidative injury in the infantile heart and lung. This study tests the hypothesis that CPB provokes oxidative cardiopulmonary changes and pulmonary endothelial dysfunction in immature piglets that can be prevented by free radical scavengers. We studied 15 2- to 3-week-old piglets. Five served as a control without CPB. Ten piglets underwent 60 min of CPB with a membrane oxygenator (Sarns). In 5 of these 10, the bypass prime was supplemented with N-mercaptopropionylglycine (MPG: 80 mg/kg) plus catalase (50,000 U/kg), whereas the others were not treated. Pre- and post-bypass cardiopulmonary function was measured in terms of left ventricular end-systolic elastance [Ees] by a conductance catheter, the arterial/alveolar pO2 ratio (a/A ratio) and static lung compliance. Conjugated dienes (A233 nm/mg lipid) were measured to detect lipid peroxidation in heart and lung tissue, and myocardial antioxidant reserve capacity [malondialdehyde (MDA) production in cardiac tissue incubated with the oxidant t-butyl hydroperoxide (t-BHP)] was assessed to detect oxidative changes. Pulmonary vascular resistance (PVR) and transpulmonary nitric oxide (NO) production were measured to assess pulmonary endothelial injury. Myocardial antioxidant reserve capacity was significantly reduced after 60 min of CPB, compared to control animals (MDA 779 +/- 100 vs 470 +/- 30 nmol/g protein, p < 0.05 at t-BHP 2.0 mmol/L), without evidence of lipid peroxidation or myocardial dysfunction. Pulmonary vascular resistance after CPB was dramatically increased (83 +/- 12 to 212 +/- 30, p < 0.05) without any change in lung function. In parallel to pulmonary vasoconstriction, NO production was significantly decreased after CPB (from 8.8 +/- 1.4 to 2.5 +/- 0.5 mmol/min/kg, p < 0.05). The addition of antioxidants (MPG+catalase) to the prime significantly improved myocardial antioxidant status (MDA: 604 +/- 30 vs 779 +/- 100 nmol/g protein, p < 0.05) and pulmonary vascular resistance (114 +/- 29 vs 212 +/- 30, p < 0.05 vs no-treatment group). In conclusion, the present study confirms that 1) Cardiopulmonary bypass produces substantial oxidative stress in normal immature myocardium, as assessed by reduced antioxidant reserve capacity; 2) CPB impairs pulmonary endothelial function, characterized by NO production, resulting in pulmonary vasoconstriction; and 3) These deleterious effects can be prevented by the addition of antioxidants (MPG/catalase) to the pump prime.

Animals↗
PubMed1995

Update on current techniques of myocardial protection.

The spectrum of strategies for myocardial protection has led to the artificial creation of adversarial positions in regard to warm versus cold blood cardioplegia, antegrade versus retrograde delivery, and intermittent versus continuous perfusion. This report reviews the background for the aforementioned methods, that has led to the evolution of an integrated myocardial management technique that combines the advantages of the aforementioned methods to compensate for their individual shortcomings. This approach coordinates the myocardial protective strategies with the continuity of the operation so that the surgical procedure is never interrupted. It provides unimpaired vision, avoids unnecessary ischemia and cardioplegic overdose, allows aortic clamping as soon as cardiopulmonary bypass is started, permits aortic unclamping and discontinuation of bypass shortly after the technical procedure is completed, and minimizes the ration of ischemia and cardiopulmonary bypass. The preliminary results in 1,474 patients from four centers with surgeons participating in the infrastructure of this method are presented.

Aorta↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. II. Evidence for reoxygenation damage.

This study tested the hypothesis that the developing heart is susceptible to oxygen-mediated damage after reintroduction of molecular oxygen and that this "unintended" reoxygenation injury causes lipid peroxidation and functional depression that may contribute to perioperative cardiac dysfunction. Among 49 Duroc-Yorkshire piglets (2 to 3 weeks old, 3 to 5 kg) 15 control studies were done without hypoxemia to test the effects of the surgical preparation (n = 10) and 60 minutes of cardiopulmonary bypass (n = 5). Twenty-nine piglets underwent up to 2 hours of ventilator hypoxemia (with inspired oxygen fraction reduced to 6% to 7%) to lower arterial oxygen tension to approximately 25 mm Hg. Five piglets did not undergo reoxygenation to determine alterations caused by hypoxemia alone. Twenty-four others received reoxygenation by either raising ventilator inspired oxygen fraction to 1.0 (n = 12) or instituting cardiopulmonary bypass at oxygen tension 400 mm Hg (n = 12). Ventilator hypoxemia produced sufficient hemodynamic compromise and metabolic acidosis that 18 piglets required premature reoxygenation (78 +/- 12 minutes). To avoid the influence of acidosis and hemodynamic deterioration during ventilator hypoxemia, five others underwent 30 minutes of hypoxemia during cardiopulmonary bypass (circuit primed with blood at oxygen tension 25 mm Hg) and 30 minutes of reoxygenation (oxygen tension 400 mm Hg) during cardiopulmonary bypass. Biochemical markers of oxidant damage included measurement of coronary sinus and myocardial conjugated dienes to determine lipid peroxidation and antioxidant reserve capacity assessed by incubating myocardial tissue in the oxidant t-butylhydroperoxide. Functional recovery was determined by inscribing pressure volume loops to determine end-systolic elastance and Starling curves by volume infusion. No biochemical or functional changes occurred in control piglets. Hypoxemia without reoxygenation did not change plasma levels of conjugated dienes, but lowered antioxidant reserve capacity 24%. Reoxygenation by ventilator caused refractory ventricular arrhythmias in two piglets (17% mortality), raised levels of conjugated dienes 45%, and reduced antioxidant reserve capacity 40% with recovery of 39% of mechanical function in the survivors. Comparable biochemical and functional changes occurred in piglets undergoing ventilator hypoxemia and/or cardiopulmonary bypass hypoxemia and reoxygenation on cardiopulmonary bypass. We conclude that hypoxemia increases vulnerability to reoxygenation damage by reducing antioxidant reserve capacity and that reoxygenation by either ventilator or cardiopulmonary bypass produces oxidant damage with resultant functional depression that is not a result of cardiopulmonary bypass. These findings suggest that initiation of cardiopulmonary bypass in cyanotic immature subjects causes an unintended reoxygenation injury, which may increase vulnerability to subsequent ischemia during surgical repair.

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. III. Comparison of the magnitude of damage by hypoxemia/reoxygenation versus ischemia/reperfusion.

The immature heart is more tolerant to ischemia than the adult heart, yet infants with cyanosis show myocardial damage after surgical correction of congenital cardiac defects causing hypoxemia. This study tested the hypothesis that the hypoxemic developing heart is susceptible to oxygen-mediated damage when it is reoxygenated during cardiopulmonary bypass and that this hypoxemic/reoxygenation injury is more severe than ischemic/reperfusion stress. Fifteen Duroc-Yorkshire piglets (2 to 3 weeks old, 3 to 5 kg) underwent 60 minutes of 37 degrees C cardiopulmonary bypass. Five piglets (control) were not made ischemic or hypoxemic. Five underwent 30 minutes of normothermic ischemia (aortic clamping) and 25 minutes of reperfusion before cardiopulmonary bypass was discontinued. Five others underwent 30 minutes of hypoxemia (bypass circuit primed with blood with oxygen tension 20 to 30 mm Hg) and 30 minutes of reoxygenation during cardiopulmonary bypass. Functional (left-ventricular contractility) and biochemical (levels of plasma and tissue conjugated dienes and antioxidant reserve capacity) measurements were made before ischemia/hypoxemia and after reperfusion/reoxygenation. Cardiopulmonary bypass (no ischemia or hypoxemia) caused no changes in left-ventricular function or coronary sinus levels of conjugated dienes. The tolerance to normothermic ischemia was confirmed, inasmuch as left-ventricular function returned to 108% of control values and coronary sinus levels of conjugated dienes did not rise after reperfusion. Conversely, reoxygenation raised plasma levels of conjugated dienes in coronary sinus blood in the hypoxic group 57% compared with end-hypoxic levels (p < 0.05 versus end-hypoxic levels and versus ischemia, by analysis of variance). Antioxidant reserve capacity showed the lowest levels (highest production of malondialdehyde) in the hypoxemic group (51% higher than control values; p < 0.05 by analysis of variance). These biochemical changes were associated with a 62% depression of left-ventricular function after bypass because end-systolic elastance recovered only 38% of control levels (p < 0.05 by analysis of variance). These data confirm the tolerance of the immature heart to ischemia and reperfusion and document a hypoxemic/reoxygenation injury that occurs in immature hearts reoxygenated during bypass. Hypoxemia seems to render the developing heart susceptible to reoxygenation damage that depresses postbypass function and is associated with lipid peroxidation. These findings suggest that starting bypass in cyanotic immature subjects causes an unintended reoxygenation injury that may potentially be counteracted by adding antioxidants to the prime of the extracorporeal circuit.

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. IV. Role of the iron-catalyzed pathway: deferoxamine.

This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.

Alkadienes↗
PubMed1995

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 NG-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.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. VI. Counteraction of oxidant damage by exogenous antioxidants: N-(2-mercaptopropionyl)-glycine and catalase.

This study tests the hypothesis that antioxidants administered before reoxygenation can reduce oxygen-mediated damage and improve myocardial performance. Of 25 Duroc-Yorkshire piglets (2 to 3 weeks, 3 to 5 kg) five underwent 60 minutes of cardiopulmonary bypass without hypoxemia (control group), and five others underwent 30 minutes of hypoxemia on cardiopulmonary bypass with a circuit primed with oxygen tension about 25 mm Hg blood followed by reoxygenation on cardiopulmonary bypass (no treatment). In vitro studies were performed to obtain the optimal dosage of the antioxidants N-(2-mercaptopropionyl)-glycine and and catalase to be used in subsequent in vivo experimental studies; cardiac homogenates were incubated in 0 to 5 mmol/L concentrations of the oxidant t-butylhydroperoxide and malondialdehyde production was measured. Fifteen piglets were made hypoxemic on cardiopulmonary bypass for 30 minutes, and the antioxidants N-(2-mercaptopropionyl)-glycine at either 30 or 80 mg/kg body weight or N-(2-mercaptopropionyl)-glycine, 30 mg/kg body weight, and catalase, 50,000 U/kg body weight, were added to the cardiopulmonary bypass circuit 15 minutes before reoxygenation. Left ventricular contractility, which was expressed as end-systolic elastance, was measured by conductance catheter before hypoxemia and after reoxygenation. Myocardial antioxidant reserve capacity was determined after reoxygenation by incubating cardiac homogenates in the oxidant t-butylhydroperoxide and measuring subsequent malondialdehyde elution. The in vitro bioassay studies showed a dose-dependent reduction of lipid peroxidation with N-(2-mercaptopropionyl)-glycine, with maximal benefits of a 40% decrease and malondialdehyde elaboration occurring with N-(2-mercaptopropionyl)-glycine and catalase compared with untreated cardiac homogenates. Cardiopulmonary bypass (no hypoxemia) caused no oxidant damage or changes in contractile function after cardiopulmonary bypass. Reoxygenation without treatment raised conjugated diene levels 57%,* lowered antioxidant reserve capacity 51%,* and was associated with only 38%* recovery of contractile function (p < 0.05 vs control). In contrast, treatment with antioxidants avoided lipid peroxidation, maintained antioxidant reserve capacity, and resulted in a dose-dependent improvement in left ventricular contractility with complete recovery occurring in N-(2-mercaptopropionyl)-glycine and catalase-treated piglets (*p < 0.05 vs no treatment). This study confirms the occurrence of hypoxemic/reoxygenation injury in immature hearts placed on cardiopulmonary bypass and shows that biochemical and functional damage can be counteracted by adding antioxidants to the cardiopulmonary bypass priming fluid. Contractile function improved in a dose-dependent manner, and oxygen-mediated damage could be avoided by mercaptopropionyl glycine/catalase treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. VII. Counteraction of oxidant damage by exogenous antioxidants: coenzyme Q10.

Coenzyme Q10 (CoQ10) is a natural mitochondrial respiratory chain constituent with antioxidant properties. This study tests the hypothesis that CoQ10 administered before the onset of reoxygenation on cardiopulmonary bypass, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass. The antioxidant properties of CoQ10 were confirmed by an in vitro study in which normal myocardial homogenates were incubated with the oxidant, t-butylhydroperoxide. Fifteen immature piglets (< 3 weeks old) were placed on 60 minutes of cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (oxygen tension about 400 mm Hg). Ten others became hypoxemic on cardiopulmonary bypass for 30 minutes by lowering oxygen tension to approximately 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 30 minutes. In five piglets, CoQ10 (45 mg/kg) was added to the cardiopulmonary bypass circuit 15 minutes before reoxygenation, and five others were not treated (no treatment). Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance (conductance catheter), oxidant damage (lipid peroxidation) was assessed by measuring conjugated diene levels in coronary sinus blood, and antioxidant reserve capacity was determined by measuring malondialdehyde in myocardium after cardiopulmonary bypass incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant damage and allowed complete functional recovery. Reoxygenated hearts (no treatment) showed a progressive increase in conjugated diene levels in coronary sinus blood after reoxygenation (2.3 +/- 0.6 A233 nm/0.5 ml plasma at 30 minutes after reoxygenation) and reduced antioxidant reserve capacity (malondialdehyde: 1219 +/- 157 nmol/g protein at 4.0 mmol/L t-butylhydroperoxide), resulting in severe postbypass dysfunction (percent end-systolic elastance = 38 +/- 6). Conversely, CoQ10 treatment avoided the increase in conjugated diene levels (2.1 +/- 0.6 vs 1.1 +/- 0.3, p < 0.05 vs no treatment), retained normal antioxidant reserve (896 +/- 76 nmol/g protein, p < 0.05 vs no treatment), and allowed nearly complete recovery of function (94% +/- 7%, p < 0.05 vs no treatment). We conclude that reoxygenation of the hypoxemic immature heart on cardiopulmonary bypass causes oxygen-mediated myocardial injury, which can be limited by CoQ10 treatment before reoxygenation. These findings imply that coenzyme Q10 can be used to surgical advantage in cyanotic patients, because therapeutic blood levels can be achieved by preoperative oral administration of this approved drug.

Animals↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. VIII. Counteraction of oxidant damage by exogenous glutamate and aspartate.

Previous studies show that (1) hypoxemia depletes immature myocardium of amino acid substrates and their replenishment improves ischemic tolerance, (2) reoxygenation on cardiopulmonary bypass causes oxygen-mediated damage without added ischemia, and (3) this damage may be related to the nitric oxide-L-arginine pathway that is affected by amino acid metabolism. This study tests the hypothesis that priming the cardiopulmonary bypass circuit with glutamate and aspartate limits reoxygenation damage. Of 22 immature Duroc-Yorkshire piglets (< 3 weeks old), five were observed over a 5-hour period (control), and five others underwent 30 minutes of CPB without hypoxemia (cardiopulmonary bypass control). Twelve others became hypoxemic by reducing ventilator inspired oxygen fraction to 6% to 7% (oxygen tension about 25 mm Hg) before reoxygenation on cardiopulmonary bypass for 30 minutes. Of these five were untreated (no treatment), and the cardiopulmonary bypass circuit was primed with 5 mmol/L glutamate and aspartate in seven others (treatment). Left ventricular function before and after bypass was measured by inscribing pressure-volume loops (end-systolic elastance). Myocardial conjugated diene levels were measured to detect lipid peroxidation, and antioxidant reserve capacity was tested by incubating cardiac muscle with the oxidant t-butylhydroperoxide to determine the susceptibility to subsequent oxidant injury. CPB (no hypoxemia) allowed complete functional recovery without changing conjugated dienes and antioxidant reserve capacity, whereas reoxygenation injury developed in untreated hearts. This was characterized by reduced contractility (elastance end-systolic recovered only 37% +/- 8%*), increased conjugated diene levels (1.3 +/- 0.1 vs 0.7 +/- 0.1*), and decreased antioxidant reserve capacity (910 +/- 59 vs 471 +/- 30 malondialdehyde nmol/g protein at 2 mmol/L t-butylhydroperoxide*). In contrast, priming the cardiopulmonary bypass circuit with glutamate and aspartate resulted in significantly better left ventricular functional recovery (75% +/- 8% vs 37% +/- 8%*), minimal conjugated diene production (0.8 +/- 0.1 vs 1.3 +/- 0.1*), and improved antioxidant reserve capacity (726 +/- 27 vs 910 +/- 59 malondialdehyde nmol/g protein*) (*p < 0.05 vs cardiopulmonary bypass control). We conclude that reoxygenation of immature hypoxemic piglets by the initiation of cardiopulmonary bypass causes myocardial dysfunction, lipid peroxidation, and reduced tolerance to oxidant stress, which may increase vulnerability to subsequent ischemia (i.e., aortic crossclamping). These data suggest that supplementing the prime of cardiopulmonary bypass circuit with glutamate and aspartate may reduce these deleterious consequences of reoxygenation.

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. IX. Importance of avoiding perioperative hyperoxemia in the setting of previous cyanosis.

This study of an in vivo infantile piglet model of compensated hypoxemia tests the hypothesis that reoxygenation on hyperoxemic cardiopulmonary bypass produces oxygen-mediated myocardial injury that can be limited by normoxemic management of cardiopulmonary bypass and the interval after cardiopulmonary bypass. Twenty-five immature piglets (< 3 weeks old) were placed on 120 minutes of cardiopulmonary bypass and five piglets served as a biochemical control group without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Twenty others became hypoxemic on cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg. The study was terminated in five piglets at the end of hypoxemia, whereas 15 others were reoxygenated at an oxygen tension about 400 mm Hg or about 100 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level to avoid metabolic acidosis and lactate production. Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde after cardiopulmonary bypass in myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation at an oxygen tension about 400 mm Hg raised myocardial conjugated diene level and creatine kinase production (CD: 3.5 +/- 0.7 A233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g, p < 0.05 vs cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4.0 mmol t-butylhydroperoxide, p < 0.05 vs control), and produced severe postbypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 vs cardiopulmonary bypass control). Lowering oxygen tension to about 100 mm Hg during reoxygenation avoided conjugated diene production and creatine kinase release, retained normal antioxidant reserve, and improved functional recovery (80% +/- 11%, p < 0.05 vs oxygen tension about 400 mm Hg). These findings show that conventional hyperoxemic cardiopulmonary bypass causes unintended reoxygenation injury in hypoxemic immature hearts that may contribute to myocardial dysfunction after cardiopulmonary bypass and that normoxemic management may be used to surgical advantage.

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: with aortic clamping. X. Exogenous antioxidants to avoid nullification of the cardioprotective effects of blood cardioplegia.

This study tests the hypothesis that reoxygenation of cyanotic immature hearts when starting cardiopulmonary bypass produces an "unintended" reoxygenation injury that (1) nullifies the cardioprotective effects of blood cardioplegia and (2) is avoidable by adding antioxidants N-(2-mercaptopropionyl)-glycine plus catalase to the cardiopulmonary bypass prime. Twenty immature piglets (2 to 3 weeks) underwent 30 minutes of aortic clamping with a blood cardioplegic solution that was hypocalcemic, alkalotic, hyperosmolar, and enriched with glutamate and aspartate during 1 hour of cardiopulmonary bypass. Of these, six piglets did not undergo hypoxemia (blood cardioplegic control) and 14 others remained hypoxemic (oxygen tension about 25 mm Hg) for up to 2 hours by lowering ventilator fraction of inspired oxygen before reoxygenation on cardiopulmonary bypass. The primary solution of the cardiopulmonary bypass circuit was unchanged in eight piglets (no treatment) and supplemented with the antioxidants N-(2-mercaptopropionyl)-glycine (80 mg/kg) and catalase (5 mg/kg) in six others (N-(2-mercaptopropionyl)-glycine and catalase). Myocardial function (end-systolic elastance), lipid peroxidation (myocardial conjugated diene production), and antioxidant reserve capacity were evaluated. Blood cardioplegic arrest produced no biochemical or functional changes in nonhypoxemic control piglets. Reoxygenation caused an approximate 10-fold increase in conjugated production that persisted throughout cardiopulmonary bypass, lowered antioxidant reserve capacity 86% +/- 12%, and produced profound myocardial dysfunction, because end-systolic elastance recovered only 21% +/- 2%. Supplementation of the cardiopulmonary bypass prime with N-(2-mercaptopropionyl)-glycine and catalase reduced lipid peroxidation, restored antioxidant reserve capacity, and allowed near complete functional recovery (80% +/- 8%).** Lipid peroxidation (conjugated diene) production was lower during warm blood cardioplegic reperfusion than during induction in all reoxygenated hearts, which suggests that blood cardioplegia did not injure reoxygenated myocardium. We conclude that reoxygenation of the hypoxemic immature heart causes cardiac functional and antioxidant damage that nullifies the cardioprotective effects of blood cardioplegia that can be avoided by supplementation of the cardiopulmonary bypass prime with antioxidants (*p < 0.05 vs blood cardioplegic control; **p < 0.05 vs reoxygenation).

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury with aortic clamping: XI. Cardiac advantages of normoxemic versus hyperoxemic management during qardiopulmonary bypass.

The conventional way to start cardiopulmonary bypass is to prime the cardiopulmonary bypass circuit with hyperoxemic blood (oxygen tension about 400 mm Hg) and deliver cardioplegic solutions at similar oxygen tension levels. This study tests the hypothesis that an initial normoxemic oxygen tension strategy to decrease the oxygen tension-dependent rate of oxygen free radical production will, in concert with normoxemic blood cardioplegia, limit reoxygenation damage and make subsequent hyperoxemia (oxygen tension about 400 mm Hg) safer. Thirty-five immature (3 to 5 kg, 2 to 3 week old) piglets underwent 60 minutes of cardiopulmonary bypass. Eleven control studies at conventional hyperoxemic oxygen tension (about 400 mm Hg) included six piglets that also underwent 30 minutes of blood cardioplegic arrest. Of 25 studies in which piglets were subjected to up to 120 minutes of ventilator hypoxemia (reducing fraction of inspired oxygen to 5% to 7%; oxygen tension about 25 mm Hg), 11 underwent either abrupt (oxygen tension about 400 mm Hg, n = 6) or gradual (increasing oxygen tension from 100 to 400 mm Hg over a 1-hour period, n = 5) reoxygenation without blood cardioplegia. Fourteen others underwent 30 minutes of blood cardioplegic arrest during cardiopulmonary bypass. Of these, nine were reoxygenated at oxygen tension about 400 mm Hg, and five others underwent normoxemic cardiopulmonary bypass and blood cardioplegia (oxygen tension about 100 mm Hg) with systemic oxygen tension raised to 400 mm Hg after aortic unclamping. Measurements of lipid peroxidation (conjugated dienes and antioxidant reserve capacity) and contractile function (pressure-volume loops, conductance catheter, end-systolic elastance) were made before and during hypoxemia and 30 minutes after reoxygenation. Hyperoxemic cardiopulmonary bypass did not produce oxidant damage or reduce functional recovery after cardiopulmonary bypass in nonhypoxemic controls. In contrast, abrupt and gradual reoxygenation without blood cardioplegia produced significant lipid peroxidation (84% increase in conjungated dienes), lowered antioxidant reserve capacity 68% +/- 5%, 44% +/- 8%, respectively, and decreased functional recovery 75% +/- 6% (p < 0.05), 66% +/- 4% (p < 0.05). Similar impairment followed abrupt reoxygenation before blood cardioplegic myocardial management, because conjungated diene production increased 13-fold, antioxidant reserve capacity fell 40%, and contractility recovered only 21% +/- 2% (p < 0.05). Conversely, normoxemic induction of cardiopulmonary bypass and blood cardioplegic myocardial management reduced conjungated diene production 73%, avoided impairment of antioxidant reserve capacity, and resulted in 58% +/- 11% recovery of contractile function.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkadienes↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: with aortic clamping. XII. Delay of cardiac reoxygenation damage in the presence of cyanosis: a new concept of controlled cardiac reoxygenation.

Twenty-one immature piglets (< 3 weeks old) underwent 30 minutes of aortic clamping with hypocalcemic glutamate/aspartate blood cardioplegia. Six piglets underwent hyperoxemic cardiopulmonary bypass and blood cardioplegia without preceding hypoxemia (control). Fifteen piglets became hypoxemic (oxygen tension about 25 mm Hg) for up to 2 hours by decreasing ventilator fraction of inspired oxygen to 6% to 7% before cardiopulmonary bypass. Of these, six piglets underwent 5 minutes of abrupt hyperoxemic uncontrolled reoxygenation by starting cardiopulmonary bypass at oxygen tension of about 400 mm Hg before they received oxygen tension of about 400 mm Hg blood cardioplegia. Nine others underwent controlled cardiac reoxygenation by starting cardiopulmonary bypass at ambient oxygen tension (about 25 mm Hg) followed 5 minutes later by 30 minutes of cardiopulmonary bypass at normoxemic oxygen tension (about 100 mm Hg) before raising oxygen tension to about 400 mm Hg. Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance by conductance catheter, oxidant damage was estimated by measuring transcoronary conjugated diene levels to detect lipid peroxidation, and antioxidant reserve capacity was determined by measuring malondialdehyde produced from myocardium incubated with the oxidant t-butylhydroperoxide. Hyperoxemic cardiopulmonary bypass and blood cardioplegia preserved myocardial function and produced no oxidant damage in nonhypoxemic piglets. In contrast, uncontrolled reoxygenation at oxygen tension about 400 mm Hg, followed by blood cardioplegia, resulted in marked conjugated dienes production (42 +/- 4* vs 3 +/- 1) A233 nm/min/100 g during blood cardioplegic induction, reduced antioxidant reserve capacity malondialdehyde at 4 mmol/L t-butylhydroperoxide; 1342 +/- 59* vs 958 +/- 50 nmol/g protein) and caused profound myocardial dysfunction; end-systolic elastance recovered only 21% +/- 2%* despite a blood cardioplegic regimen that was cardioprotective in nonhypoxemic piglets. Conversely, controlled cardiac reoxygenation reduced lipid peroxidation (conjugated dienes production was 2 +/- 1**), restored antioxidant reserve capacity (malondialdehyde at 4 mmol/L t-butylhydroperoxide; 982 +/- 88**), and allowed near-complete (83 +/- 8%**) functional recovery. We conclude that reoxygenation of the hypoxemic immature heart by initiating conventional hyperoxemic cardiopulmonary bypass causes oxidant damage characterized by lipid peroxidation, reduced antioxidant reserve capacity, and results in functional depression that nullifies the cardioprotective effects of blood cardioplegia. These changes can be reduced by starting cardiopulmonary bypass at the ambient oxygen tension of the hypoxemic subject and delaying subsequent reoxygenation until blood cardioplegic induction by controlled cardiac reoxygenation (*p < 0.05 vs control; **p < 0.05 vs uncontrol reoxygenation) and analysis of variance.

Alkadienes↗