Neurotrauma Department, Naval Medical Research Center, Silver Spring, MD 20910-7500, United States.
Injury. 2012 May;43(5):638-47. doi: 10.1016/j.injury.2010.10.013. Epub 2010 Nov 20.
Development of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N(2)O(3); harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO(2)) with HBOC-201 were investigated.
Swine underwent uncontrolled liver haemorrhage before receiving up to three 10min 10ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO(2) (5.4μmol/kg [LD NaNO(2)] or 10.8μmol/kg [HD NaNO(2)]) or 6% Hetastarch (HEX) with or without HD NaNO(2) during "prehospital" resuscitation (15, 30 and 45min after injury). Definitive surgical care occurred at 75min; anaesthetic recovery at 120min. Animals were euthanised at 72h.
NaNO(2) temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC+HD NaNO(2) (3 of 4 pigs) and HBOC+LD NaNO(2) (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO(2) combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX+NaNO(2). Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC+HD NaNO(2) pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder.
A significant interaction between NaNO(2) and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO(2) was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO(2) in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO(2) and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components.
血红蛋白基氧载体（HBOCs）作为血液替代品的发展已经陷入僵局，因为临床不良反应归因于一氧化氮（NO）清除引起的血管收缩。研究表明血红蛋白具有亚硝酸盐还原酶活性，可产生 NO 和 N(2)O(3)；利用这种特性可能会抵消 NO 的清除。因此，研究了同时输注亚硝酸钠（NaNO(2)）与 HBOC-201 的效果。
猪在接受多达三次 10 分钟 10ml/kg 的 HBOC-201（HBOC）输注之前经历不受控制的肝出血，同时输注亚硝酸钠（5.4μmol/kg[LD NaNO(2)]或 10.8μmol/kg[HD NaNO(2)])或 6%羟乙基淀粉（HEX）与或不与 HD NaNO(2)同时输注，进行“院前”复苏（损伤后 15、30 和 45 分钟）。确定性手术护理在 75 分钟进行；麻醉恢复在 120 分钟。动物在 72 小时时安乐死。
亚硝酸钠（NaNO(2)）以剂量依赖的方式暂时降低了来自 HBOC 的全身和肺血压升高。在组织氧合或存活率方面，各组之间没有显著差异。需要人道安乐死的不良临床体征发生频率最高的是 HBOC+HD NaNO(2)（4 只猪中的 3 只）和 HBOC+LD NaNO(2)（4 只猪中的 2 只）。与单独接受 HBOC、HEX 或 HEX+NaNO(2)的 16 只猪中的 1 只相比，接受 HBOC 和亚硝酸钠组合的 8 只猪中有 5 只出现明显的肺充血迹象。在 4 只 HBOC+HD NaNO(2)猪中发现了 2 只猪的肺纤维蛋白血栓，没有其他猪有类似的血栓证据。不对称的预复苏心指数是一个潜在的混杂因素。
亚硝酸钠（NaNO(2)）与 HBOC-201 之间的显著相互作用减轻了 HBOC-201 的血管收缩作用，这与 HBOC 具有产生血管扩张性 NO 等价物的亚硝酸盐还原酶活性一致。在存活率和组织氧合标志物方面，结果相对相当。最高剂量的亚硝酸钠（NaNO(2)）在降低 HBOC 相关的肺和全身血管活性方面最有效，但不良事件发生率也最高。在该模型中，亚硝酸钠（NaNO(2)）的短暂性使其在抵消 HBOC-201 血管收缩方面的临床前景不如预期，并且亚硝酸钠（NaNO(2)）和 HBOC 的组合似乎以剂量依赖的方式增加了肺并发症的风险，而不考虑对止血成分的血液稀释作用。
