Loeb A L, McIntosh L J, Raj N R, Longnecker D E
Department of Anesthesia, University of Pennsylvania, Philadelphia 19104-4283, USA.
Crit Care Med. 1998 Jun;26(6):1071-80. doi: 10.1097/00003246-199806000-00030.
Hemoglobin-based oxygen carriers are designed to replace blood volume and to increase oxygen delivery to tissues after blood loss. The goals of the present study were two-fold: a) to determine the systemic and regional vascular effects of resuscitation with recombinant human hemoglobin (rHb1.1) in rats during controlled hemorrhage; and b) to determine whether nitric oxide (NO) or prostaglandins were involved in the observed responses.
Paralyzed, ventilated rats were hemorrhaged (18 mL blood/kg body weight) during halothane anesthesia and allowed to stabilize for 30 mins. Systemic and regional hemodynamics and oxygen delivery were monitored at three time points, using the radioactive microsphere method. Microspheres were first infused at the end of the hemorrhage stabilization period (t=0 min). rHb1.1 (1 g/kg body weight) or rHb1.1 diluent (phosphate buffered saline, 36 mL/kg body weight) were infused over 20 mins and microspheres were administered again, 30 mins later (t=50 mins). Saline (0.5 mL), indomethacin (5 mg/kg to inhibit cyclooxygenase), or NG-monomethyl-L-arginine (L-NMMA, 100 mg/kg, to inhibit NO synthase) were then infused in rHb1.1-treated rats and microspheres injected once more (t=80 mins).
Research laboratory.
Male Wistar rats (n=37).
Recombinant human hemoglobin (rHb1.1), rHb1.1 diluent (phosphate buffered saline) resuscitation of hemorrhaged rats. Saline, L-NMMA, or indomethacin treatment after resuscitation.
Resuscitation with rHb1.1 increased mean arterial pressure (MAP), cardiac output, and systemic oxygen delivery significantly when compared with diluent. After rHb1.1 resuscitation, regional blood flows were significantly increased in skin, kidney, spleen, and heart compared with diluent resuscitation. Compared with saline treatment after rHb1.1 resuscitation, L-NMMA increased MAP and regional resistances in virtually all tissues; indomethacin did not alter MAP, but increased resistance in the brain.
These data indicate that rHb1.1 resuscitation was more effective than diluent in improving systemic and regional hemodynamics and oxygen delivery, suggesting that rHb1.1 may be of benefit in the treatment of acute blood loss. Increased resistance after L-NMMA in the presence of rHb1.1 indicated that rHb1.1 resuscitation did not eliminate NO dependent circulatory control. Increased resistance after indomethacin in brain indicated that vasodilator prostanoids were important in regulating vascular resistance in these tissues after rHb1.1 resuscitation.
基于血红蛋白的氧载体旨在补充血容量，并在失血后增加组织的氧输送。本研究的目标有两个：a）确定在控制性出血期间用重组人血红蛋白（rHb1.1）对大鼠进行复苏的全身和局部血管效应；b）确定一氧化氮（NO）或前列腺素是否参与了观察到的反应。
在氟烷麻醉下，对麻痹、通气的大鼠进行出血（18 mL血液/千克体重），并使其稳定30分钟。使用放射性微球法在三个时间点监测全身和局部血流动力学以及氧输送。在出血稳定期结束时（t = 0分钟）首次注入微球。在20分钟内注入rHb1.1（1克/千克体重）或rHb1.1稀释剂（磷酸盐缓冲盐水，36 mL/千克体重），30分钟后（t = 50分钟）再次注入微球。然后在接受rHb1.1治疗的大鼠中注入生理盐水（0.5 mL）、吲哚美辛（5毫克/千克以抑制环氧化酶）或NG-单甲基-L-精氨酸（L-NMMA，100毫克/千克，以抑制一氧化氮合酶），并再次注射微球（t = 80分钟）。
研究实验室。
雄性Wistar大鼠（n = 37）。
用重组人血红蛋白（rHb1.1）、rHb1.1稀释剂（磷酸盐缓冲盐水）对出血大鼠进行复苏。复苏后用生理盐水、L-NMMA或吲哚美辛治疗。
与稀释剂相比，用rHb1.1复苏可显著提高平均动脉压（MAP）、心输出量和全身氧输送。与稀释剂复苏相比，rHb1.1复苏后皮肤、肾脏、脾脏和心脏的局部血流显著增加。与rHb1.1复苏后用生理盐水治疗相比，L-NMMA可提高几乎所有组织的MAP和局部阻力；吲哚美辛未改变MAP，但增加了脑内阻力。
这些数据表明，在改善全身和局部血流动力学以及氧输送方面，rHb1.1复苏比稀释剂更有效，这表明rHb1.1可能对急性失血的治疗有益。在存在rHb1.1的情况下，L-NMMA后阻力增加表明rHb1.1复苏并未消除NO依赖性循环控制。吲哚美辛后脑内阻力增加表明血管舒张性前列腺素在rHb1.1复苏后调节这些组织的血管阻力方面很重要。
