Patients with acute hypoxemic respiratory failure (ARDS) associated with severe noncardiogenic pulmonary edema exhibit a depressed ability to extract oxygen in the periphery. In these patients, an increase in O2 delivery (QO2 = cardiac output x arterial O2 content) caused by a change in cardiac output (Qt) is associated with an increase in O2 uptake (VO2). Published studies of patients with ARDS suggest that systemic O2 delivery of 21 ml/min/kg is necessary to maintain VO2 independent of QO2. By contrast, patients without respiratory failure show no dependence of VO2 on QO2 unless delivery fails below 8.2 ml/min/kg. Hence, patients with ARDS exhibit supply dependence of VO2 at an extraction ratio ((CaO2-CVO2)/CaO2) of .3 - .4,; patients without respiratory failure can achieve extraction rations of .6 - .7 without introducing QO2 dependence. An inability of peripheral tissues to extract sufficient O2 to maintain aerobic metabolism may be caused by a maldistribution of VO2/QO2 at a regional tissue level, or within tissue beds. Alternatively, increased diffusion distance between capillary and mitochondria may limit O2 unloading by diffusion. It is also possible that a pathologic supply dependence of VO2 on QO2 may occur if hypoxic tissue damage causes O2 uptake to increase via superoxide radical formation. Experimental studies are proposed to test regional tissue O2 extraction in anesthetized canine isolated hind limb, isolated small bowel segment, and isolated kidney preparations relative to whole body. This approach will clarify relative contributions of interregional vs intraregional blood flow maldistribution as mechanisms contributing to a pathologic supply dependence. I propose to compare the extraction limit in normal animals with that in two experimental models demonstrating whole body abnormal dependence of VO2 on QO2. Specifically, mechanisms responsible for a disordered extraction capacity during Pseudomonas aeruginosa bacterial infusions or ventilation with high inspired O2 fractions will be explored. Additionally, I propose to explore the value of multiple indicator dilution assessment of permeability surface area products in our isolated tissue models to clarify the contribution of changes in the recruitable capillary surface area as a mechanism for altered extraction capacity. These studies will help to clarify the pathophysiological mechanisms responsible for a dependence of VO2 on QO2, and will help to uncover potentially therapeutic interventions for the maintenance of peripheral O2 extraction in patients with acute hypoxemic respiratory failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Physician Scientist Award (K11)
Project #
1K11HL001857-01
Application #
3087421
Study Section
(SRC)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Samsel, R W; Lewis, T H; Sanders, W M et al. (1994) The effect of adrenergic agonists on the systemic response to hemorrhage. J Crit Care 9:25-33
Umans, J G; Samsel, R W (1992) L-canavanine selectively augments contraction in aortas from endotoxemic rats. Eur J Pharmacol 210:343-6
Drazenovic, R; Samsel, R W; Wylam, M E et al. (1992) Regulation of perfused capillary density in canine intestinal mucosa during endotoxemia. J Appl Physiol 72:259-65
Samsel, R W; Schumacker, P T (1991) Oxygen delivery to tissues. Eur Respir J 4:1258-67
Samsel, R W; Cherqui, D; Pietrabissa, A et al. (1991) Hepatic oxygen and lactate extraction during stagnant hypoxia. J Appl Physiol 70:186-93
Wylam, M E; Samsel, R W; Umans, J G et al. (1990) Endotoxin in vivo impairs endothelium-dependent relaxation of canine arteries in vitro. Am Rev Respir Dis 142:1263-7
Schumacker, P T; Samsel, R W (1989) Analysis of oxygen delivery and uptake relationships in the Krogh tissue model. J Appl Physiol 67:1234-44
Schumacker, P T; Samsel, R W; Sznajder, J I et al. (1989) Gas density dependence of regional VA/V and VA/Q inequality during constant-flow ventilation. J Appl Physiol 66:1722-9
Samsel, R W; Schumacker, P T (1988) Determination of the critical O2 delivery from experimental data: sensitivity to error. J Appl Physiol 64:2074-82
Nelson, D P; Samsel, R W; Wood, L D et al. (1988) Pathological supply dependence of systemic and intestinal O2 uptake during endotoxemia. J Appl Physiol 64:2410-9

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