TREATMENT OF ACUTE HYPOXEMIC RESPIRATORY FAILURE

成人呼吸窘迫综合征（ARDS）是急性呼吸窘迫综合征的一种， 低氧性呼吸衰竭（AHRF），其中急性肺损伤导致 肺血管将血浆泄漏到肺泡腔中， 肺内分流（Qs/Qt）和动脉低氧血症， 氧气疗法 由于没有有效的预防或特异性治疗， 肺毛细血管泄漏尚未出现，该提案旨在改善 支持治疗的原则，通过定义三个机制， AHRF犬模型中相互关联且知之甚少的问题：1） 肺血管压力、流量、分流和水肿之间的关系。 体外膜肺氧合（ECMO）将用于减少肺 静脉注射油酸致急性肺损伤后的压力和流量 和支气管内盐酸。 类似的实验方法将确定 红细胞压积增加对肺水肿蓄积的影响。 如果 ECMO和红细胞压积增加不会增加水肿，但会改善 外周O2输送（QO 2），均代表新的治疗干预措施 在AHRF。 为了确定急性肺损伤减少 在水肿区域的肺血流量，ECMO也将用于 提供肺的部分旁路以限定肺血管 急性肺损伤前后的压力-流量关系 2)到 探索解释病理性氧供应依赖的机制 高F1 O2在狗中诱导的消耗，我们将扩展我们先前的研究 通过研究局部血管床， 特别是在用室内空气或O2通气期间的肠道和后肢。 这些研究应该阐明高氧是否以及如何重新分布 外周平行器官系统中的有限QO 2， 方式 将使用相同的方法来比较有氧运动的极限。 当QO 2因进行性缺氧、贫血或 血流逐渐减少。 3)为了测试 在AHRF中，由于缺氧，酸血症， 或两者，我们将测量左心室压力维度关系， 冠状动脉血流量和心肌氧摄取 缺氧 我们将使用这种方法来确定 血管活性药物对菌血症、高氧和酸中毒的影响 心肌有氧代谢，并确定如何降低阻力 后负荷改善戊巴比妥钠抑制的心肌泵功能 麻醉犬 这些犬类实验的结果应该 阐明影响病理生理学的重要机制， 肺毛细血管渗漏的治疗及其对全身的影响 肠道，后肢和心脏，并促进临床试验，以改善 AHRF的支持治疗。

The adult respiratory distress syndrome (ARDS) is one form of acute acute hypoxemic respiratory failure (AHRF) in which acute lung injury causes pulmonary vessels to leak plasma into alveolar spaces causing intrapulmonary shunt (Qs/Qt) and arterial hypoxemia which is refractory to O2 therapy. Since no effective prevention or specific therapy of the pulmonary capillary leak is yet available, this proposal seeks to improve the principles of supportive therapy by defining the mechanisms of three interrelated and poorly understood problems in canine models of AHRF: 1) Relationships among pulmonary vascular pressures, flow, shunt, and edema. Extracorporeal membrane oxygenation (ECMO) will be used to reduce pulmonary pressure and flow after acute lung injury induced by intravenous oleic acid and by intrabronchial HCl. A similar experimental approach will determine the effect of increased hematocrit on pulmonary edema accumulation. If ECMO and increased hematocrit do not increase edema but do improve peripheral O2 delivery (QO2), both represent new therapeutic interventions in AHRF. To determine the mechanism whereby acute lung injury reduces pulmonary blood flow in edematous areas, ECMO will also be utilized to provide partial bypass of the lung to define the pulmonary vascular pressure flow relationships before and after acute lung injury. 2) To explore mechanisms accounting for pathologic supply dependency of oxygen consumption induced in dogs by high F1O2, we will extend our prior studies of the limits of aerobic metabolism by studying regional vascular beds, specifically the gut and hind limb during ventilation with room air or O2. These studies should elucidate whether and how hyperoxia redistributes limited QO2 among peripheral parallel organ systems in an inefficient manner. The same methodology will be used to compare the limits of aerobic metabolism when QO2 is reduced by progressive hypoxia, by anemia, or by progressive reductions in blood flow. 3) To test the possibility that ventricular pumping function is depressed in AHRF due to hypoxia, acidemia, or both, we will measure left ventricular pressure dimension relationships, coronary blood flow, and myocardial oxygen extraction during progressive hypoxia. We will use this methodology to determine the effects of vasoactive drugs on bacteremia, hyperoxia, and acidosis on these limits of myocardial aerobic metabolism and to determine how a reduced resistive afterload improves depressed myocardial pumping function in pentobarbitol anesthetized dogs. The results of these canine experiments should elucidate important mechanisms influencing the pathophysiology and treatment of pulmonary capillary leak and its systemic consequences on the gut, hind limb and heart, and facilitate clinical trials to improve supportive therapy of AHRF.