Oxygen distribution and utilization after phorbol myristate acetate-induced lung injury

There is considerable evidence suggesting that substrate (e.g., oxygen) distribution and utilization are abnormal in the setting of acute respiratory failure from the adult respiratory distress syndrome (ARDS). The mechanisms that may explain this anomalous relationship include: redistribution of cardiac output resulting in the nonuniform delivery of substrate to regional vascular beds; increases in flow through anatomic precapillary arteriovenous channels; increased organ metabolic demand; and direct injury to the regional microvasculature. To test these hypotheses, we used radiolabeled 15-mu microspheres to measure cardiac output, regional blood flow, total systemic shunt flow, oxygen uptake (VO2), and oxygen delivery (QO2) in dogs after phorbol myristate acetate (PMA: 30 micrograms/kg; n = 5)-induced neutrophil activation and acute lung injury. These studies demonstrated that neutrophil activation and acute lung injury was accompanied by an increase in the level of QO2 (e.g., 19.1 ml/min.kg) necessary to maintain a constant level of VO2. Although PMA-induced acute lung injury did not result in an increase in the fraction of cardiac output comprising total systemic shunt flow or in an increase in whole body metabolic demand compared to control animals (e.g., PMA = 0 micrograms/kg; n = 10), it did result in a significant decrease in cardiac output. In addition, there were significant reductions in blood flow to most organs after PMA-induced acute lung injury that were not reversible with intravascular volume expansion (80 ml isotonic saline/kg; n = 5). The exclusion of reversible volume depletion, anatomic shunts, and increased metabolic demand suggest a role for microvascular injury in the development of the regional blood flow abnormalities and the supply dependence of oxygen uptake observed in this study. In the context of the mechanisms of lung injury known to be operative in this model, these microcirculatory abnormalities may be mediated through the intravascular activation of circulating neutrophils.