Kiyozo Morita

Pulmonary vasoconstriction due to impaired nitric oxide production after cardiopulmonary bypass

BACKGROUNDnPulmonary 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.nnnMETHODSnTwelve 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.nnnRESULTSnCardiopulmonary 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.nnnCONCLUSIONSnCardiopulmonary 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.

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.

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.

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.

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.

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)

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.

Reduced oxygen tension during cardiopulmonary bypass limits myocardial damage in acute hypoxic immature piglet hearts

OBJECTIVESnCardiopulmonary bypass (CPB) is usually instituted in a hyperoxic fashion (oxygen tension (pO2) 300-500 mm Hg), which may expose cyanotic infants to potential reoxygenation damage. Oxygen free radicals play an important role in this injury. The rate of production of this highly reactive toxic oxygen species is dependent on the oxygen level during reoxygenation. This study tested the hypothesis that reduction of the oxygen in the bypass prime and in blood cardioplegia (BCP) to normoxic levels can reduce reoxygenation injury and will result in improved contractility.nnnMETHODSnWe operated on 19 Duroc-Yorkshire piglets (2-3 weeks, 3-5 kg). Five underwent 30 min of BCP arrest during 1 h of CPB without hypoxia (control). Fourteen underwent 120 min of hypoxia (arterial pO2 20-30 mmHg) on ventilator before reoxygenation on CPB. Reflecting the clinical routine procedure, nine of them were reoxygenated on CPB for 5 min with high pO2 (350-450 mm Hg) followed by 30 min of BCP arrest (high pO2) and 25 min of reoxygenation/reperfusion on CPB with high pO2 levels (NoRx). Five others were put on CPB with pO2 reduced to normoxic levels (pO2 100 mm Hg) in CPB and BCP (Rx). Functional and biochemical measurements were made before hypoxia, as well as during and after reoxygenation.nnnRESULTSnIn contrast to controls, NoRx resulted in a 40% decrease in antioxidant reserve capacity (P<0.01) at 4 mM t-butyl hydroperoxide (t-BHP), a 1212% increase in myocardial conjugated diene production during BCP induction (P<0.0003), a 1000% during reperfusion (P<0.002), a 36.1% and a 37.0% increase in coronary sinus blood conjugated dienes at 35 min (P<0.05) and 60 min (P<0.05) of reoxygenation. These biochemical changes were accompanied by a 79% reduction of left ventricular contractility (P<0.0003). Conversely, Rx led to an improvement in antioxidant reserve capacity (939+/-212 vs. 1342+/-177 nmol/g protein; P<0.003), less conjugated diene production during BCP induction (15.5+/-6.1 vs. 42.1+/-8.8 A233 nm/min per 100 g; P<0.003) and reperfusion (1.8+/-3.9 vs 22.0+/-5.5 A233 nm/min per 100 g; P<0.005), and to a significantly improved post bypass LV contractility (58+/-25 vs. 21+/-5; P<0.0003).nnnCONCLUSIONSnThese data document that hypoxemic/reoxygenation injury occurs in acute hypoxic immature piglet hearts when reoxygenated on CPB with hyperoxic pO2 (normal clinical practice). By lowering the antioxidant reserve capacity, hypoxemia seems to render the developing heart susceptible to reoxygenation damage, which occurs with the reintroduction of molecular oxygen, and is associated with free radical production, subsequent lipid peroxida tion, and depressed post bypass LV function. Reduction of pO2 during the initial reoxygenation period and during BCP arrest to normoxic levels resulted in a significant reduction of this oxygen-related damage and in much improved myocardial performance.

Delayed cardioplegic reoxygenation reduces reoxygenation injury in cyanotic immature hearts

BACKGROUNDnHypoxemic developing hearts are susceptible to oxygen-mediated damage that occurs after reintroduction of molecular oxygen. This unintended hypoxemic/reoxygenation injury leads to lipid peroxidation and membrane damage and may contribute to postoperative cardiac dysfunction. Biochemical and functional status are improved by delaying reoxygenation on cardiopulmonary bypass (CPB) until cardioplegic arrest.nnnMETHODSnSix immature piglets (3 to 5 kg) without hypoxemia underwent 30 minutes of cardioplegic arrest during 1 hour of CPB. Fourteen others underwent 2 hours of hypoxemia on ventilator before reoxygenation on CPB. Reflecting our clinical routine, 9 were reoxygenated on CPB for 5 minutes followed by 30 minutes of cardioplegic arrest and 25 minutes of reperfusion. The other 5 were put on hypoxemic CPB for 5 minutes, before being reoxygenated during cardioplegic arrest for 30 minutes followed by 25 minutes of reperfusion.nnnRESULTSnCardioplegic arrest (no hypoxemia group) caused no functional or biochemical changes. In contrast, by preceding hypoxemia with subsequent reoxygenation on CPB (no treatment group) we found 39.5% decrease in antioxidant reserve capacity, 1,212% increase in myocardial conjugated diene production, significant increase in coronary sinus blood conjugated dienes, and an 81% reduction of left ventricular contractility, all of which were statistically significant (p < 0.05) when compared with the no hypoxemia group. Conversely, delaying reoxygenation until cardioplegic arrest (treatment group) resulted in 33.1% improvement in antioxidant reserve capacity, 91.7% less conjugated diene production, lower coronary sinus blood conjugated diene levels, and a 95% improved contractility, all of which were significant (p < 0.05) when compared with the no treatment group.nnnCONCLUSIONSnA reoxygenation injury associated with lipid peroxidation and decreased postbypass contractility occurs in cyanotic immature hearts when reoxygenated on CPB. Delaying reoxygenation until cardioplegic arrest by starting CPB with ambient partial pressure of oxygen results in significantly improved myocardial status.

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)