Kentner Rainer, Safar Peter, Behringer Wilhelm, Wu Xianren, Kagan Valerian E, Tyurina Yulia Y, Henchir Jeremy, Ma Li, Hsia Carleton J C, Tisherman Samuel A
Department of Anesthesiology/Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pennsylvania 15260, USA.
J Trauma. 2002 Nov;53(5):968-77. doi: 10.1097/00005373-200211000-00025.
Hemorrhagic shock (HS) is associated with the generation of reactive oxygen species, which may contribute to delayed multiple organ system failure and death. Previous studies have shown that the antioxidant Tempol improved physiologic variables, although not necessarily outcome, in septic shock and HS. We hypothesized that the combination of free Tempol with polynitroxylated albumin (PNA)-bound Tempol (which prolongs half-life and decreases toxicity) improves outcome after HS in rats.
In study 1, HS was induced by blood withdrawal of 3 mL/100 g over 15 minutes. Mean arterial pressure was maintained at 40 mm Hg with either infusion of normal saline or withdrawal of blood from 20 to 90 minutes. Resuscitation (90-270 minutes) was with infusion of shed blood. Observation was to 72 hours. At HS 45 min, albumin (ALB) (n = 10) or PNA + Tempol (n = 10) was infused slowly (1 mL/100 g/h) until 120 minutes. Study 2 was the same as study 1 (n = 6 per group), but terminated at 150 minutes. Study 3 was the same as study 1, but started with ALB or PNA + Tempol (n = 7 per group) at 20 minutes. The primary outcome variable in studies 1 and 3 was survival, whereas the primary outcome variables in study 2 were antioxidant reserve (ability of the serum or tissue homogenate to scavenge peroxyl radicals produced by 2,2'-azobis [2-aminodipropane]-dihydrochloride) in serum and small intestine, and low-molecular-weight thiols in tissues (liver, small intestine, and kidney).
In study 1, 72-hour survival was 1 of 10 (ALB group) versus 2 of 10 (PNA + Tempol group). At 90 minutes, pH was lower in the ALB group versus the PNA + Tempol group (p = 0.02) and remained low. Arterial lactate increased to 8.9 +/- 3.2 (mean +/- SD) versus 6.5 +/- 1.8 mmol/L (p = 0.04) and base excess was -9.6 +/- 4.3 versus -5.2 +/- 3.2 mmol/L (p = 0.01) (ALB vs. PNA + Tempol groups, respectively). In study 2, antioxidant reserve in serum was lower in the ALB group versus the PNA + Tempol group (p = 0.002). There were no differences between groups in antioxidant reserve in the small intestine or low-molecular-weight thiols in liver, kidney, and small intestine. In study 3, 72-hour survival was zero of seven (ALB group) versus five of seven (PNA + Tempol group) (p = 0.02). Heart rate and systolic blood pressure during late HS were higher in the ALB group in studies 1 and 3 (p < 0.05).
When infused early in HS, PNA + Tempol can increase survival. When given late, it significantly improves acid-base and serum antioxidant status, without an effect on survival. Additional studies will be required to determine whether early resuscitation with PNA + Tempol attenuates reactive oxygen species-mediated injury as the mechanism for preventing the progression toward multiple organ failure and death after HS. The results suggest that antioxidant therapy with Tempol deserves further study as a potential adjunct in the initial resuscitation from HS.
失血性休克（HS）与活性氧的产生有关，这可能导致延迟性多器官系统衰竭和死亡。先前的研究表明，抗氧化剂Tempol可改善脓毒症休克和HS中的生理变量，尽管不一定能改善预后。我们假设游离Tempol与多硝基化白蛋白（PNA）结合的Tempol（可延长半衰期并降低毒性）联合使用可改善大鼠HS后的预后。
在研究1中，通过在15分钟内抽取3 mL/100 g血液诱导HS。通过输注生理盐水或在20至90分钟内抽血将平均动脉压维持在40 mmHg。复苏（90 - 270分钟）采用回输失血。观察至72小时。在HS 45分钟时，缓慢输注白蛋白（ALB）（n = 10）或PNA + Tempol（n = 10）（1 mL/100 g/h）直至120分钟。研究2与研究1相同（每组n = 6），但在150分钟时终止。研究3与研究1相同，但在20分钟时开始给予ALB或PNA + Tempol（每组n = 7）。研究1和3的主要结局变量是生存率，而研究2的主要结局变量是血清和小肠中的抗氧化储备（血清或组织匀浆清除2,2'-偶氮二[2-氨基丙烷]-二盐酸盐产生的过氧自由基的能力）以及组织（肝脏、小肠和肾脏）中的低分子量硫醇。
在研究1中，72小时生存率在ALB组（10只中的1只）与PNA + Tempol组（10只中的2只）之间。在90分钟时，ALB组的pH低于PNA + Tempol组（p = 0.02）且持续较低。动脉乳酸分别升至8.9±3.2（均值±标准差）与6.5±1.8 mmol/L（p = 0.04），碱剩余为 -9.6±4.3与 -5.2±3.2 mmol/L（p = 0.01）（分别为ALB组与PNA + Tempol组）。在研究2中，ALB组血清中的抗氧化储备低于PNA + Tempol组（p = 0.002）。小肠中的抗氧化储备或肝脏、肾脏和小肠中的低分子量硫醇在组间无差异。在研究3中，72小时生存率在ALB组（7只中的0只）与PNA + Tempol组（7只中的5只）之间（p = 0.02）。在研究1和3中，HS后期ALB组的心率和收缩压较高（p < 0.05）。
在HS早期输注时，PNA + Tempol可提高生存率。在后期给予时，它可显著改善酸碱和血清抗氧化状态，但对生存率无影响。需要进一步研究以确定早期用PNA + Tempol进行复苏是否可减轻活性氧介导的损伤，作为预防HS后向多器官衰竭和死亡进展的机制。结果表明，用Tempol进行抗氧化治疗作为HS初始复苏的潜在辅助手段值得进一步研究。
