Pathological supply dependence of systemic and intestinal O2 uptake during endotoxemia

When systemic delivery of oxygen (QO2 = blood flow X arterial O2 content) is reduced, the systemic O2 extraction ratio [(CaO2 - CVO2)/CaO2; where CaO2 is arterial O2 content and CVO2 is venous O2 content] increases until a critical limit is reached below which O2 uptake (VO2) becomes limited by delivery. Patients with adult respiratory distress syndrome and sepsis exhibit supply dependence of VO2 even at high levels of QO2, which suggests that a peripheral O2 extraction defect may be present. We tested the hypothesis that endotoxemia might produce a similar defect in the efficacy of tissue O2 extraction by determining the whole-body critical systemic QO2 (QO2 c) and critical extraction ratio in a control group of dogs and a group receiving a 5-mg/kg dose of Escherichia coli endotoxin. QO2 c was determined in each group by measuring VO2 as QO2 was gradually reduced by bleeding. The VO2 and QO2 of an isolated segment of small intestine were also measured to determine whether O2 extraction was impaired within a local region of tissue. The dogs were anesthetized, paralyzed, and ventilated with room air. Systemic QO2 was reduced in stages by hemorrhage as hematocrit was maintained. The systemic and intestinal critical points were determined from a plot of VO2 vs. QO2. The mean systemic QO2 c and critical O2 extraction ratio of the endotoxemic group (12.8 +/- 2.0 and 0.54 +/- 0.11 ml.min-1.kg-1) were significantly different from control (6.8 +/- 1.2 and 0.78 +/- 0.04) (P less than 0.001), indicating that endotoxin administration impaired systemic extraction of O2. Endotoxin also increased base-line systemic VO2 [6.1 +/- 0.7 (before) to 7.4 +/- 0.1 (after)] (P less than 0.001). The critical and maximal intestinal O2 extraction ratios of the endotoxemic group (0.47 +/- 0.10 and 0.71 +/- 0.04) were significantly less than control (0.69 +/- 0.06 and 0.83 +/- 0.05) (P less than 0.001). In addition, intestinal reactive hyperemia disappeared in six of seven endotoxemic dogs, whereas it remained intact in all control dogs. Thus endotoxin reduced the ability of tissues to extract O2 from a limited supply at the whole body level as well as within a 40- to 50-g segment of small intestine. These results could be explained by a defect in microvascular regulation of blood flow that interfered with the optimal distribution of a limited QO2 in accordance with tissue O2 needs.     

Systemic and intestinal limits of O2 extraction in the dog

When systemic delivery of O2 (QO2 = QT X CaO2, where QT is cardiac output and CaO2 is arterial O2 content) is reduced by bleeding, the systemic O2 extraction ratio [ER = (CaO2 - CVO2)/CaO2, where CVO2 is venous O2 content] increases until a critical limit is reached below which O2 uptake (VO2) becomes limited by O2 delivery. During hypovolemia, reflex increases in mesenteric arterial tone may preferentially reduce gut blood flow so that the onset of O2 supply dependence occurs in the gut before other regions. We compared the critical O2 delivery (QO2c) and critical extraction ratio (ERc) of whole body and an isolated segment (30-50 g) of small bowel in seven anesthetized paralyzed dogs ventilated with room air. Systemic QO2 was reduced in stages by controlled hemorrhage as arterial O2 content was maintained, and systemic and gut VO2 and QO2 were measured at each stage. Body QO2c was 7.9 +/- 1.9 ml X kg-1 X min-1 (ERc = 0.69 +/- 0.12), whereas gut O2 supply dependency occurred when gut QO2 was 34.3 +/- 11.3 ml X min-1 X kg gut wt-1 (ERc = 0.63 +/- 0.09). O2 supply dependency in the gut occurred at a higher systemic QO2 (9.7 +/- 2.7) than whole-body QO2c (P less than 0.05). The extraction ratio at the final stage (maximal ER) was less in the gut (0.80 +/- 0.05) than whole body (0.87 +/- 0.06). Thus during reductions in systemic QO2, gut VO2 was maintained by increases in gut extraction of O2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathological supply dependence of O2 uptake during bacteremia in dogs

When systemic delivery of O2 [QO2 = cardiac output X arterial O2 content (CaO2)] is reduced, the systemic O2 extraction ratio [(CaO2-concentration of O2 in venous blood/CaO2] increases until a critical limit is reached below which O2 uptake (VO2) becomes limited by delivery. Many patients with adult respiratory distress syndrome exhibit supply dependence of VO2 even at high levels of QO2, which suggests that a peripheral O2 extraction defect may be present. Since many of these patients also suffer from serious bacterial infection, we tested the hypothesis that bacteremia might produce a similar defect in the ability of tissues to maintain VO2 independent of QO2, as QO2 reduced. The critical O2 delivery (QO2crit) and critical extraction ratio (ERcrit) were compared in a control group of dogs and a group receiving a continuous infusion of Pseudomonas aeruginosa (5 x 10(7) organisms/min). Dogs were anesthetized, paralyzed, and ventilated with room air. Systemic QO2 was reduced in stages by hemorrhage as hematocrit was maintained. At each stage, systemic VO2 and QO2 were measured, and the critical point was determined from a plot of VO2 vs. QO2. The mean QO2crit and ERcrit of the bacteremic group (11.4 +/- 2.2 ml.min-1.kg-1 and 0.51 +/- 0.09) were significantly different from control (7.4 +/- 1.2 and 0.71 +/- 0.10) (P less than 0.05). These results suggest that bacterial infection can reduce the ability of peripheral tissues to extract O2 from a limited supply, causing VO2 to become limited by O2 delivery at a stage when a smaller fraction of the delivered O2 has been extracted.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of hyperthermia and hypothermia on oxygen extraction by tissues during hypovolemia

As systemic delivery of O2 (QO2 = QT X CaO2) is reduced during progressive hemorrhage, the O2 extraction ratio [(CaO2 - CVO2)/CaO2] increases until a critical delivery is reached below which O2 uptake (VO2) becomes limited by delivery (O2 supply dependence). When tissue metabolic activity and O2 demand are increased or reduced, the critical QO2 required to maintain VO2 should rise or fall accordingly, unless other changes in the distribution of a limited QO2 precipitate the onset of O2 supply dependence at a different critical extraction ratio. We compared the critical QO2 and critical extraction ratio in 23 normothermic (38 degrees C), hyperthermic (41 degrees C), or hypothermic (34 decrees C) dogs during stepwise reduction in delivery produced by bleeding, as arterial O2 content was maintained. Dogs were anesthetized, paralyzed, and mechanically ventilated. Hypothermia reduced whole-body VO2 by 31%, whereas hyperthermia increased VO2 by 20%. The critical QO2 was significantly reduced during hypothermia (5.6 +/- 0.95 ml.min-1.kg-1) (P less than 0.05) and increased during hyperthermia (8.9 +/- 1.1) (P approximately equal to 0.06) compared with normothermic controls (7.4 +/- 1.2). The extraction ratio at the onset of supply dependency was significantly increased in hyperthermia (0.76 +/- 0.05) compared with hypothermia (0.65 +/- 0.10) (P less than 0.05), and the normothermic critical extraction was 0.71 +/- 0.1. These results suggest that higher body temperatures are associated with an improved ability to maintain a VO2 independent of QO2, since a higher fraction of the delivered O2 can be extracted before the onset of O2 supply dependence, relative to lower body temperatures.     

Tissue oxygen extraction during hypovolemia: role of hemoglobin P50

When the delivery of O2 to tissues (QO2 = blood flow X O2 content) falls below a critical threshold, tissue O2 uptake (VO2) becomes limited by QO2. The mechanism responsible for this extraction limitation is not understood but may involve molecular diffusion limitation as mean capillary PO2 drops below a critical minimum level in some capillaries. We tested this hypothesis by measuring the critical QO2 necessary to maintain VO2 independent of QO2 in anesthetized, paralyzed normal dogs (n = 7) and in a second group in which PO2 at 50% saturation of hemoglobin (P50) was reduced by exchange transfusion with low-P50 erythrocytes (n = 7). QO2 was reduced in stages by removing blood volume to reduce blood flow while VO2 was measured by spirometry at each step. To the extent that O2 extraction was limited by a critical capillary PO2, we reasoned that the onset of diffusion limitation should occur at a higher QO2 with low P50, since a lower end-capillary PO2 is required to achieve the same O2 extraction. The critical QO2 (7.8 +/- 1.2 ml X min-1 X kg-1) and extraction ratio (0.63 +/- 0.06) in dogs with reduced P50 were not different from controls. At the critical delivery, mixed venous PO2 was lower in low P50 (16.1 +/- 2.9 Torr) than controls (29.9 +/- 2.3 Torr). We concluded that diffusion limitation does not initiate the early fall in VO2 below the critical QO2 and offer an alternative model to explain the onset of supply dependency.(ABSTRACT TRUNCATED AT 250 WORDS)     

Critical O2 delivery to skeletal muscle at high and low PO2 in endotoxemic dogs

An ischemic canine limb model was used to determine whether endotoxin reduces the ability of resting skeletal muscle to extract O2 and whether increasing the arterial PO2 would increase its O2 extraction. Isolated limbs were pump perfused via an extracorporeal circuit with membrane oxygenator at three progressively lower flows and PO2 of both 60 and 200 Torr, whereas the rest of the body remained normoxic and normotensive. Six anesthetized, paralyzed dogs were injected with endotoxin (4 mg/kg, ENDO), and another six were controls (CONT). Limb critical O2 delivery was higher (P less than 0.05) in ENDO than CONT (8.3 vs. 6.1 ml.kg-1.min-1). Critical venous PO2 was also higher (P less than 0.05) in ENDO than CONT (38 vs. 30 Torr). Critical O2 extraction ratio was lower (P less than 0.05) in ENDO than CONT (0.60 vs. 0.73). There were no differences in these variables between low and high arterial PO2. We concluded that 1) endotoxin can cause a small but significant O2 extraction defect in skeletal muscle, 2) increasing arterial PO2 did not correct such a defect, nor did it improve O2 uptake in ischemic, but otherwise healthy, muscle, and 3) skeletal muscle may contribute to the peripheral O2 extraction defect in adult respiratory distress syndrome insofar as endotoxin effects model those found in adult respiratory distress syndrome.     

Continued divergence in VO2max of rats artificially selected for running endurance is mediated by greater convective blood O2 delivery.

We previously showed that after seven generations of artificial selection of rats for running capacity, maximal O2 uptake (VO2max) was 12% greater in high-capacity (HCR) than in low-capacity runners (LCR). This difference was due exclusively to a greater O2 uptake and utilization by skeletal muscle of HCR, without differences between lines in convective O2 delivery to muscle by the cardiopulmonary system (QO2max). The present study in generation 15 (G15) female rats tested the hypothesis that continuing improvement in skeletal muscle O2 transfer must be accompanied by augmentation in QO2max to support VO2max of HCR. Systemic O2 transport was studied during maximal normoxic and hypoxic exercise (inspired PO2 approximately 70 Torr). VO2max divergence between lines increased because of both improvement in HCR and deterioration in LCR: normoxic VO2max was 50% higher in HCR than LCR. The greater VO2max in HCR was accompanied by a 41% increase in QO2max: 96.1 +/- 4.0 in HCR vs. 68.1 +/- 2.5 ml stpd O2 x min(-1) x kg(-1) in LCR (P < 0.01) during normoxia. The greater G15 QO2max of HCR was due to a 48% greater stroke volume than LCR. Although tissue O2 diffusive conductance continued to increase in HCR, tissue O2 extraction was not significantly different from LCR at G15, because of the offsetting effect of greater HCR blood flow on tissue O2 extraction. These results indicate that continuing divergence in VO2max between lines occurs largely as a consequence of changes in the capacity to deliver O2 to the exercising muscle.     

Effect of respiratory alkalosis on skeletal muscle metabolism in the dog

These experiments were conducted to determine whether changes in skeletal muscle metabolism contribute to the previously reported increase in whole-body O2 uptake (VO2) during respiratory alkalosis. The hind-limb and gastrocnemius-plantaris preparations in anesthetized and paralyzed dogs were used. VO2 of the hindlimb and gastrocnemius muscle was calculated from measurements of venous blood flow and arterial and venous O2 concentrations (Van Slyke analysis). Whole-body VO2 was measured by the open-circuit method. Minute ventilation (hence blood gases and pH) was controlled by a mechanical respirator. Whole-body, hind-limb, and gastrocnemius muscle VO2 increased 14, 19, and 20%, respectively, during alkalosis (P less than 0.05). In all experiments, arterial lactate concentration increased significantly (P less than 0.05) during alkalosis. A positive venoarterial lactate difference across muscle during alkalosis indicated that skeletal muscle is a source of the elevated blood lactate. We concluded that VO2 of resting skeletal muscle is increased during states of respiratory alkalosis and that this increase can account for much of the increase in whole-body VO2.     

Role of tissue hypoxia as the mechanism of lactic acidosis during E. coli endotoxemia.

We compared the hemodynamic and metabolic alterations produced in rabbits by similar decreases in cardiac output created by inflating a balloon placed in the right ventricle (n = 6) with those produced by an intravenous bolus of Escherichia coli lipopolysaccharide (LPS; SEP group; n = 6). We measured O2 consumption (VO2), O2 transport (TO2), and O2 extraction ratio (ERO2) for the whole animal and also for the left hindlimb. Both groups experienced similar decreases in cardiac output, systemic TO2, and VO2 and similar increases in ERO2. For the hindlimb, TO2 was similar, but VO2 and ERO2 were lower for the SEP group 30 min after LPS administration (P less than 0.05); however, this difference disappeared during the remainder of the experiment. Arterial lactate concentration was greater (P less than 0.05) for the SEP group. There were no differences in skeletal muscle PO2, measured with a multiwire surface electrode, or in cardiac and skeletal muscle concentrations of high-energy phosphates. We hypothesize that a direct effect of LPS on cellular metabolism may have resulted in greater arterial lactate concentration for the SEP group.     

Low-dose dopamine hastens onset of gut ischemia in a porcine model of hemorrhagic shock.

Gut metabolism may become anaerobic before the whole body during progressive phlebotomy in dogs. Because dopamine has selective mesenteric vasodilator effects, we asked whether dopamine could delay onset of bowel ischemia during hemorrhagic shock. We studied whole body and gut O2 consumption (VO2) and O2 delivery (QO2) using progressive phlebotomy in anesthetized pigs. Nine pigs received a dopamine infusion of 2 micrograms.kg-1.min-1, whereas a control group of seven pigs received equivalent saline infusion. Onset of ischemia in whole body and gut was determined as critical O2 delivery (QO2c), the intersection point of biphasic regression on plots of VO2-QO2 relationships. Blood flow and O2 extraction were measured as mechanisms of gut ischemia for entire in situ small and large gut using a superior mesenteric venous fistula. Dopamine hastened onset of gut ischemia relative to onset of whole body ischemia (gut critical point in terms of whole body QO2 9.9 +/- 2.1 ml O2.kg-1.min-1, whole body QO2c 7.8 +/- 0.7 ml O2.kg-1.min-1, P less than 0.01). In contrast, onset of gut ischemia in control animals occurred at same time as onset of whole body ischemia (gut critical point in terms of whole body QO2 7.4 +/- 2.3 ml O2.kg-1.min-1, whole body QO2c 7.1 +/- 2.7 ml O2.kg-1.min-1, P = not significant). Hastening of onset of gut ischemia in dopamine-treated animals was associated with decreased ability of gut to extract O2. Low-dose dopamine was not protective against gut ischemia during shock but rather caused earlier onset of gut ischemia during hemorrhagic shock.     

Effects of transfusion-induced polycythemia on O2 transport during exercise in the dog

An increased hematocrit could enhance peripheral O2 transport during exercise by improving arterial O2 content. Conversely, it could reduce maximal delivery of O2 by limiting cardiac output during exercise or by limiting the distribution of blood flow to peripheral capillaries with high O2 extractions. We studied O2 transport at rest and during graded treadmill exercise in splenectomized tracheostomized dogs at normal hematocrit (38 +/- 3%), and 48 h after transfusion of type-matched donor cells. This procedure increased hematocrit (60 +/- 3%) but also increased blood volume (P less than 0.05). Following transfusion, resting cardiac output (QT) and heart rate were not different. During exercise, QT was significantly lower at each level of O2 consumption (VO2) at high hematocrit (P less than 0.01). A reduction in QT was also seen during polycythemic exercise with hypoxemia produced by breathing 12 or 10% O2 in N2. Despite the reduction in QT, mixed venous PO2 was not lower at high hematocrit, and the increase in base deficit with VO2 was not different from control measurements. O2 delivery (QT X arterial content) was similar at each level of VO2 at both levels of hematocrit, during both normoxic and hypoxic studies. Both systemic and pulmonary arterial pressures were increased at rest after transfusion (P less than 0.05). However, pulmonary and systemic pressures were not higher than control during exercise at high hematocrit. We conclude that a hematocrit of 60% with increased blood volume is not associated with a cardiac limitation of O2 delivery, nor does it interfere with peripheral O2 extraction during exercise in the dog.     

Dissociation of changes in VO2 max, muscle QO2, and performance with training in rats

Before the start and after 4, 8, and 12 wk of a treadmill training program male rats were randomly selected and tested for running performance, maximum O2 consumption (VO2 max), running economy (VO2 submax), and skeletal muscle oxidative capacity (QO2). Data were compared with values from untrained weight-matched control rats. Maximum running time to exhaustion increased significantly (P less than 0.01) by 4 wk and again at 12 wk (P less than 0.01). Submaximal running endurance increased by 120 (4 wk), 320 (8 wk), and 372% (12 wk) (P less than 0.01). VO2 max was increased only at 12 wk (86.0 +/- 2.7 vs. 75.5 +/- 1.9 ml O2.kg-1.min-1); VO2 submax was decreased at 4 and 8 wk but not at 12 wk. Soleus QO2 was unchanged after 4 wk of training and increased by 50% at 8 wk and by 77% at 12 wk. This study is the first to show a dissociation in both the time course and the magnitude of longitudinal changes in VO2 max, VO2 submax, QO2, and maximal and submaximal running performance. We conclude that factors other than those measured explain the improvement in running performance that resulted from endurance training in these rats.     

Impaired muscle oxygen transfer in patients with chronic renal failure

We hypothesized that impaired O2 transport plays a role in limiting exercise in patients with chronic renal failure (CRF). Six CRF patients (25 +/- 6 yr) and six controls (24 +/- 6 yr) were examined twice during incremental single-leg isolated quadriceps exercise. Leg O2 delivery (QO2(leg)) and leg O2 uptake (VO2(leg)) were obtained when subjects breathed gas of three inspired O2 fractions (FI(O2)) (0.13, 0.21, and 1.0). On a different day, myoglobin O2 saturation and muscle bioenergetics were measured by proton and phosphorus magnetic resonance spectroscopy. CRF patients, but not controls, showed O2 supply dependency of peak VO2 (VO2(peak)) by a proportional relationship between peak VO2(leg) at each inspired O2 fraction (0.59 +/- 0.20, 0.47 +/- 0.10, 0.43 +/- 0.10 l/min, respectively) and 1) work rate (933 +/- 372, 733 +/- 163, 667 +/- 207 g), 2) QO(2leg) (0.80 +/- 0.20, 0.64 +/- 0.10, 0.59 +/- 0.10 l/min), and 3) cell PO2 (6.3 +/- 5.4, 1.7 +/- 1.3, 1.2 +/- 0.7 mmHg). CRF patients breathing 100% O2 and controls breathing 21% O2 had similar peak QO2(leg) (0.80 +/- 0.20 vs. 0.79 +/- 0.10 l/min) and similar peak VO2(leg) (0.59 +/- 0.20 vs. 0.57 +/- 0.10 l/min). However, mean capillary PO2 (47.9 +/- 4.0 vs. 38.2 +/- 4.6 mmHg) and the capillary-to-myocite gradient (40.7 +/- 6.2 vs. 34.4 +/- 4.0 mmHg) were both higher in CRF patients than in controls (P < 0.03 each). We conclude that low muscle O2 conductance, but not limited mitochondrial oxidative capacity, plays a role in limiting exercise tolerance in these patients.     

Oxygen delivery and utilization in hypothermic dogs

Hypothermia produces a decrease in metabolic rate that may be beneficial under conditions of reduced O2 delivery (Do2). Another effect of hypothermia is to increase the affinity of hemoglobin for O2, which can adversely affect the release of O2 to the tissues. To determine the overall effect of hypothermia on the ability of the peripheral tissues to extract O2 from blood, we compared the response to hypoxemia of hypothermic dogs (n = 8) and of normothermic controls (n = 8). The animals were anesthetized, mechanically ventilated, and paralyzed to prevent shivering. The inspired concentration of O2 was progressively reduced until the dogs died. The core temperatures of the control and hypothermic dogs were 37.7 +/- 0.3 and 30.5 +/- 0.1 degree C, respectively (P less than 0.01). The O2 consumption (VO2) of the control dogs was significantly greater than that of the hypothermic dogs (P less than 0.05), being 4.7 +/- 0.4 and 3.2 +/- 0.3 ml X min-1 X kg-1, respectively. Hypothermia produced a left shift of the oxyhemoglobin dissociation curve (ODC) to a PO2 at which hemoglobin is half-saturated with O2 of 19.8 +/- 0.7 Torr (control = 32.4 +/- 0.7 Torr, P less than 0.01). The O2 delivery at which the VO2 becomes supply dependent (DO2crit) was 8.5 ml X min-1 X kg-1 for control and 6.2 ml X min-1 X kg-1 for hypothermia. The hypothermic dogs maintained their base-line VO2's at lower arterial PO2's than control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional hemodynamic responses to hypoxia in polycythemic dogs

Polycythemia increases blood viscosity so that systemic O2 delivery (QO2) decreases and its regional distribution changes. We examined whether hypoxia, by promoting local vasodilation, further modified these effects in resting skeletal muscle and gut in anesthetized dogs after hematocrit had been raised to 65%. One group (CON, n = 7) served as normoxic controls while another (HH, n = 6) was ventilated with 9% O2--91% N2 for 30 min between periods of normoxia. Polycythemia decreased cardiac output so that QO2 to both regions decreased approximately 50% in both groups. In compensation, O2 extraction fraction increased to 65% in muscle and to 50% in gut. When QO2 was reduced further during hypoxia, blood flow increased in muscle but not in gut. Unlike previously published normocythemic studies, there was no initial hypoxic vasoconstriction in muscle. Metabolic vasodilation during hypoxia was enhanced in muscle when blood O2 reserves were first lowered by increased extraction with polycythemia alone. The increase in resting muscle blood flow during hypoxia with no change in cardiac output may have decreased O2 availability to other more vital tissues. In that sense and under these experimental conditions, polycythemia caused a maladaptive response during hypoxic hypoxia.     

Treatment of canine aspiration pneumonitis: fluid volume reduction vs. fluid volume expansion

The aspiration of gastric acid causes pulmonary edema and hypoxemia. One approach to the management of this syndrome is to raise cardiac output (Qt) and O2 delivery (QO2) to ensure tissue oxygenation (VO2) at the risk of increasing the edema. Another approach reduces the edema by reducing pulmonary microvascular pressure (Pmv) at the risk of reducing QO2 and VO2. We compared these approaches in 24 anesthetized, ventilated dogs with pulmonary wedge pressure (Ppw), a clinical approximation of Pmv, of 12.5 mmHg. Before and again 1 h after endobronchial instillation of 0.1 N HCl, we measured Qt, QO2, VO2, venous admixture, and in vivo extravascular lung liquid. The dogs were then randomly divided into four equal groups: 1) 12.5 mmHg Ppw, high Qt; 2) 7.5 mmHg Ppw, intermediate Qt; 3) 4.5 mmHg Ppw, low Qt; and 4) 4.5 mmHg Ppw plus dopamine, intermediate Qt. Measured values were followed for 4 more h, after which the lungs were excised to compare wet weight-to-body weight ratios (W/B). When plasmapheresis reduced Ppw at 1 h, edema did not increase further and W/B of groups 2 (21 +/- 3), 3 (18 +/- 3), and 4 (22 +/- 3) were significantly less than in group 1 (27 +/- 3) (P less than 0.001). Although Qt decreased with Ppw, increased hematocrit and reduced venous admixture maintained QO2 in group 2 but not in group 3. In group 4 an intermediate Qt maintained QO2 even at 4.5 mmHg Ppw but edema increased to the group 2 level presumably because Pmv rose with Qt on dopamine. VO2 remained constant over time in each group. These data demonstrate that canine HCl-induced pulmonary edema, measured in vivo or gravimetrically, is very sensitive to reductions in Pmv. Moreover, the lowest Pmv (and QO2) was well tolerated because an O2 supply dependency of VO2 was not observed.     

Subcutaneous PO2 as an index of the physiological limits for hemodilution in the rat.

This study was designed to test the hypothesis that changes in subcutaneous PO2 (PscO2) during progressive hemodilution will reliably predict a "critical point" at which tissue O2 consumption (VO2) becomes dependent on O2 delivery (QO2). Twelve pentobarbital-anesthetized male Sprague-Dawley rats (315-375 g) underwent stepwise exchange of plasma for blood (1.5 ml of plasma for each 1 ml of blood lost). The initial exchange was equal to 25% of the estimated circulatory blood volume, and each subsequent exchange was equal to 10% of the estimated circulatory blood volume. After nine exchanges, the hematocrit (Hct) fell from 42 +/- 1 to 6 +/- 1%. Cardiac output and O2 extraction rose significantly. PscO2 became significantly reduced (P < 0.05) after exchange of 45% of the blood volume (Hct = 16 +/- 1%). VO2 became delivery dependent when QO2 fell below 21 ml x min(-1) x kg body wt(-1) (mean Hct = 13 +/- 1%). Eight control rats undergoing 1:1 blood-blood exchange showed no change in PscO2, pH, HCO3(-), or hemodynamics. Measurement of PscO2 may be a useful guide to monitor the adequacy of QO2 during hemodilution.     

Regulation of perfused capillary density in canine intestinal mucosa during endotoxemia.

When O2 delivery (blood flow X arterial O2 content) is reduced, many tissues respond by increasing perfused capillary density. This facilitates the increase in O2 extraction required to maintain tissue O2 consumption in the face of limited O2 supply. In a previous study of isolated canine small intestine (J. Appl. Physiol. 64: 2410-2419, 1988), endotoxin administration was associated with an impaired ability to increase O2 extraction in response to progressive reductions in O2 delivery. The aim of the present study was to determine whether reductions in perfused capillary density occur after endotoxin administration. Fourteen male dogs were anesthetized with chloralose (150 mg/kg iv) and urethan (750 mg/kg iv), and a segment of small intestine was exteriorized through a midline laparotomy. The segment was isolated vascularly, autoperfused, and maintained at body temperature. Escherichia coli endotoxin (5 mg/kg) or sham challenge was administered, and the animals were allowed to stabilize. Blood flow and arterial and gut venous blood O2 contents were measured after 3 h. Perfused vessels were then labeled by injecting colloidal carbon (less than 0.8 microns) through the arterial cannula and clamping the artery and vein as the bolus passed through the tissue. In some of the experiments a second gut segment was successfully obtained within 1 h of the first, yielding a total of 14 gut segments in nine endotoxin animals and nine segments in five control animals. Morphological analysis of capillary surface density in mucosal villi and crypts showed a significantly higher perfused capillary density in control tissue blocks (77.8 +/- 9.2%) than in blocks from endotoxin-treated animals (68.8 +/- 8.0%, P less than 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of increased Hb-O2 affinity on VO2max at constant O2 delivery in dog muscle in situ

We investigated the effect of increasing hemoglobin- (Hb) O2 affinity on muscle maximal O2 uptake (VO2max) while muscle blood flow, [Hb], HbO2 saturation, and thus O2 delivery (muscle blood flow X arterial O2 content) to the working muscle were kept unchanged from control. VO2max was measured in isolated in situ canine gastrocnemius working maximally (isometric tetanic contractions). The muscles were pump perfused, in alternating order, with either normal blood [O2 half-saturation pressure of hemoglobin (P50) = 32.1 +/- 0.5 (SE) Torr] or blood from dogs that had been fed sodium cyanate (150 mg.kg-1.day-1) for 3-4 wk (P50 = 23.2 +/- 0.9). In both conditions (n = 8) arterial PO2 was set at approximately 200 Torr to fully saturate arterial blood, which thereby produced the same arterial O2 contents, and muscle blood flow was set at 106 ml.100 g-1.min-1, so that O2 delivery in both conditions was the same. VO2max was 11.8 +/- 1.0 ml.min-1.100 g-1 when perfused with the normal blood (control) and was reduced by 17% to 9.8 +/- 0.7 ml.min-1.100 g-1 when perfused with the low-P50 blood (P less than 0.01). Mean muscle effluent venous PO2 was also significantly less (26 +/- 3 vs. 30 +/- 2 Torr; P less than 0.01) in the low-P50 condition, as was an estimate of the capillary driving pressure for O2 diffusion, the mean capillary PO2 (45 +/- 3 vs. 51 +/- 2 Torr). However, the estimated muscle O2 diffusing capacity was not different between conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of ATP-induced leg vasodilation on VO2 peak and leg O2 extraction during maximal exercise in humans

During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.