Reoxygenation Injury in Hypoxemic Immature Hearts

采用低氧血症的未成熟仔猪进行了一系列体内实验，以验证在常规高pO2条件下启动体外循环（CPB）时，青紫未成熟心脏不受控制的再氧会导致再氧损伤的假设：A)是由氧化剂引起的心肌脂质过氧化介导的，b)是通过控制CPB的pO2和CPB的添加剂（受控再氧）来避免的。未成熟仔猪（<3周龄）体外循环120分钟，5头仔猪作为不加CPB的生化对照组（生化对照组）。5头仔猪进行CPB，无低氧血症（CPB对照组）。另外28人在CPB上低氧60分钟，将p02降至20-30mmHg，然后在pO2-400mmHg（高氧REOX组）或pO2100mmHg（常氧REOX组）下再氧60分钟。另一部分被分配到治疗组，在治疗组中给CPB添加以下添加剂：去铁胺（…超过50mg/kg总剂量）；no合成酶抑制剂N -硝基- l -精氨酸甲酯（L-NAME, 4mg/kg）；l -精氨酸（20 mg/kg）；抗氧化剂（过氧化氢酶辅酶Q10）；谷氨酸/天冬氨酸（13mMol）。CPB后心肌功能通过收缩末期弹性（Ees，导尿管）和Starling曲线分析进行评价。心肌偶联二烯（CD）生成（脂质过氧化的标志物）肌酸磷酸激酶（CPK）泄漏作为损伤的生化标志物进行评估，并通过测定过氧化叔丁基（t-BHP）氧化剂培养的CPB后心肌的丙二醛（MDA）来确定抗氧化储备能力。无缺氧的CPB未引起氧化损伤或功能损伤。相反，再氧化（高氧）会增加心肌共轭二烯和CPK的产生，降低抗氧化储备能力，并产生严重的旁路功能障碍。相反，去铁胺、L-NAME抑制NO生成、MPG过氧化氢酶、辅酶Q10减少抗氧化剂均可避免偶联二烯的产生和CPK的释放，保持正常的抗氧化储备，并显著改善Rx组的功能恢复。我们认为，通过启动常规高氧CPB对低氧未成熟心脏进行再氧化，可引起以脂质过氧化和抗氧化剂减少为特征的氧化损伤，导致心肌手术再氧化损伤的功能抑制。这些有害影响可以通过在生理pO2启动CPB或在CPB中添加抗氧化剂来减少。少

A series of in vivo experiments using hypoxemic immature piglets was performed to test the hypotheses that uncontrolled reoxygenation of cyanotic immature hearts when starting cardiopulmonary bypass (CPB) with the conventional high pO2 pmduces a reoxygenation injury that a) is mediated by oxidants derived myocardial lipidperoxidation , and b) is avoidable by controlling pO2 at CPB and additives to the CPB prime (Controlled Reoxygenation).Immature piglets (<3 weeks old) were placed on 120 minutes of cardiopulmonary bypass, and 5 piglets served as biochemical control without CPB (biochemical Control Group). Five piglets underwent CPB without hypoxemia (CPB control). Twenty eight others were made hypoxic on CPB for 60 minutes by lowering p02 to 20-30mmHg, followed by reoxygenation for 60 minutes at pO2-400mmHg (Hyperoxic REOX Group) or pO2100mmHg (Normoxemic REOX Group). Others were allocated to the treatment groups in which following additives were administered to the CPB: deferoxamine ( … More 50mg/kg total dose); the NO-synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME, 4mg/kg); L-arginine (20 mg/kg); antioxidants (MPG Catalase Coenzyme Q10); Glutamate/ Asparatate (13mMol).Post CPB myocardial function was evaluated from endsystolic elastance (Ees, conductance catheter) and Starling curv analysis. Myocardial conjugated diene (CD) production, ( a marker of lipidperoxidation) creatine phosphokinase (CPK) leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity determined by measuring malondialdehyde (MDA) in post CPB myocardium incubated in the oxidant, t-butyl hydroperoxide(t-BHP).CPB without hypoxia caused no oxidant or functional damage. Conversely, reoxygenation (Hyperoxic) raised myocardial conjugated dienes and CPK production, reduced antioxidant reserve capacity, and produced severe postbypass dysfunction. In contrast, deferoxamine, inhibition of NO production by L-NAME, reduction of antioxidants by MPG catalase, coenzyme Q10 equally avoided conjugated dienes production and CPK release, retaine normal antioxidant reserve, and functional recovery was significantly improved in all Rx groups.We conclude that reoxygenation of the hypoxemic immature heart by initiating the conventional hyperoxic CPB causes oxidant damage characterized by lipid peroxidation and reduced antioxidants, leading to functional depression surgical reoxygenation injury of myocardium . These detrimental effects can be reduced by starting CPB at the physiological pO2 or addition of anti-oxidants agents to the CPB. Less