In patients with acute lung injury of diverse etiologies, diffuse alveolar damage leads to pulmonary edema and acute hypoxemic respiratory failure. Because no specific prevention or treatment of the primary lung injury is available, supportive therapy consists of positive pressure ventilation with high levels of end-expiratory pressure (Peep) and inspired oxygen fraction (FI02) while cardiac output (Qt) is maintined with plasma volume expansion. One adverse outcome of the approach is a non-hypoxic patient with bounding circulation confined to a ventilator awaiting spontaneous clearance of the lung edema while complications of critical illness develop. Conceivably, early aggressive cardiovascular management can reduce extravascular lung liquid (EVLL) without reducing Qt, arterial oxygen transport (QO2) and tissue oxygen utilitization (VO2). This application describes four proposals to evaluate aspects of this approach. 1) In canine models of acid aspiration and lung contusion, pulmonary wedge pressure (Ppw) will be reduced from 10 to 5 torr by plasmapheresis to determine the effect on EVLL, and vasoactive drugs (nitroprusside or dopamine) will be infused to determine whether Qt, QO2, and VO2 can be maintained at low Ppw without adverse effects on lung gas exchange. 2) The effect of reducing Qt by plasmapheresis on the critical value of QO2 needed to maintain aerobic metabolism will be studied before and after acute lung injury is induced in dogs by intravenous oleic acid and again during treatment with Peep or vasoactive drugs. 3) The Starling relationship of the left ventricle is depressed in canine oleic acid pulmonary edema, and this dysfunction is corrected by nitroprusside. To determine whether these effects are due to the acute lung injury, to direct effects of oleic acid on the myocardium, or to effects of altered resistive afterload, we will compare them with corresponding effects on Starling relationships and on isovolemic contractility after left atrial injection of oleic acid which does not cause lung damage. These results will demonstrate whether this cardiovascular management effectively reduces EVLL in diverse canine models of acute lung injury, and how the management is affected by potential cardiovascular depression and by potential changes in the limits of aerobic metabolism. 4) Then we will test whether plasmapheresis (to lower Ppw) and dopamine (to maintain cardiac output) reduce EVLL and the duration and complications of intensive care in patients with acute hypoxemic respiratory failure.
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