Reoxygenation Injury in Hypoxemic Immature Hearts

利用低氧未成熟仔猪进行了一系列体内实验，以验证以下假说：在常规高PO2状态下开始体外循环(CPB)时，发紫未成熟猪心脏失控复氧会产生复氧损伤，即a)由氧化剂引发的心肌脂质过氧化反应介导，b)通过控制CPB中的PO2和在CPB初期添加添加剂(受控复氧)可以避免。将3周龄未成熟仔猪置于体外循环120分钟，并将5只仔猪作为生化对照。5只仔猪在无低氧血症的情况下接受体外循环(CPB对照组)。另28例在体外循环中低氧60分钟，氧分压降至20-30毫米汞柱，然后在氧分压-400毫米汞柱(高氧组)或氧分压2100毫米汞柱(常氧组)下复氧60分钟。其他人被分配到处理组，在处理组中，体外循环中加入以下添加剂：去铁胺(…总剂量>50 mg/kg)、一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯(L-NAME，4 mg/kg)、L-精氨酸(20 mg/kg)、抗氧化剂(MPG过氧化氢酶辅酶Q10)、谷氨酸/天冬氨酸(13mMol)。心肌共轭二烯(CD)的产生(脂质过氧化的标志物)肌酸磷酸激酶(CPK)漏出作为损伤的生化指标，通过测定在氧化剂叔丁基氢过氧化氢(t-BHP)中孵育的CPB后心肌的丙二醛(MDA)含量来确定抗氧化储备能力。相反，复氧(高氧)增加了心肌共轭双烯和CPK的产生，降低了抗氧化储备能力，并产生了严重的体外循环后功能障碍。相比之下，去铁胺、L-NAME抑制NO生成、MPG过氧化氢酶减少抗氧化剂、辅酶Q10同样避免了共轭双烯的产生和CPK的释放，恢复了正常的抗氧化储备，功能恢复明显改善。我们认为，通过启动传统的高氧体外循环，低氧未成熟心脏复氧导致以脂质过氧化和抗氧化剂减少为特征的氧化损伤，导致功能抑制，外科手术后心肌的复氧损伤。通过在生理氧分压下启动CPB或在CPB中添加抗氧化剂，可以减少这些有害影响。较少

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