Systemic hemorrhage augments local O2 extraction in canine intestine.

When O2 delivery (QO2) to a tissue is reduced, microvascular adjustments facilitate increases in O2 extraction, thereby delaying the onset of O2 supply-limited metabolism until a critically low QO2 is reached. The present study investigated the contribution of the autonomic nervous system to these adjustments by measuring O2 extraction in isolated intestine. In anesthetized dogs, a 30- to 50-g segment of intestine was vascularly isolated and its QO2 was decreased in stages by reducing the speed of an occlusive pump. In a normovolemic group (n = 11), blood volume was maintained to minimize sympathetic tone while flow to the intestine was reduced. In a hypovolemic group (n = 7), blood volume was removed in stages to augment sympathetic tone as flow to the intestinal segment was simultaneously reduced. A hypovolemic alpha-adrenergic-blocked (alpha-blocked) group (n = 6) was identical to the corresponding alpha-adrenergic intact (alpha-intact) group except that alpha-adrenergic effects were inhibited with phenoxybenzamine (3 mg/kg). The systemic critical O2 extraction ratio in the alpha-blocked group (69 +/- 6%) was less than that in the alpha-intact group (77 +/- 7%; P = 0.05). In the intestine, the critical O2 extraction ratio was significantly poorer in the normovolemic (45 +/- 11%) group than in either hypovolemic group (alpha-intact: 69 +/- 3%, P < 0.00005; alpha-blocked: 62 +/- 9%, P < 0.005). These findings demonstrate that systemic hemorrhage significantly augments critical O2 extraction in intestine during progressive local stagnant hypoxia and suggest that nonadrenergic vasoconstrictor mechanisms may play an important role.

Determination of the critical O2 delivery from experimental data: sensitivity to error.

Normally, metabolic need determines tissue O2 consumption (VO2). In states of reduced supply, VO2 declines sharply below a critical level of O2 delivery (QO2 = blood flow X arterial O2 content). Although several investigators have measured a critical O2 delivery in whole animals or in isolated tissues, there is no general agreement over how to determine the critical point from a collection of real data. In this study, we compare three algorithms for finding the critical O2 delivery from a set of experimental data. We also present a technique for estimating the effect of experimental error on the precision of these algorithms. Using 16 data sets collected in normal dogs, we compare single-line, dual-line, and polynomial regression algorithms for identifying the critical O2 delivery. The dual-line and polynomial regression techniques fit the data better (mean residual square deviation 0.024 and 0.031, respectively) than the single-regression line approach (0.110). To investigate the influence of experimental error on the derived critical QO2, we used a Monte Carlo technique, repeatedly perturbing the experimental data to simulate experimental error. We then calculated the variance of the critical QO2 frequency distribution obtained when the three algorithms were applied to the perturbed data. By this analysis, the dual-line regression technique was less sensitive to experimental error than the polynomial technique.

Analysis of oxygen delivery and uptake relationships in the Krogh tissue model.

Normally, tissue O2 uptake (VO2) is set by metabolic activity rather than O2 delivery (QO2 = blood flow X arterial O2 content). However, when QO2 is reduced below a critical level, VO2 becomes limited by O2 supply. Experiments have shown that a similar critical QO2 exists, regardless of whether O2 supply is reduced by progressive anemia, hypoxemia, or reduction in blood flow. This appears inconsistent with the hypothesis that O2 supply limitation must occur by diffusion limitation, since very different mixed venous PO2 values have been seen at the critical point with hypoxic vs. anemic hypoxia. The present study sought to begin clarifying this paradox by studying the theoretical relationship between tissue O2 supply and uptake in the Krogh tissue cylinder model. Steady-state O2 uptake was computed as O2 delivery to tissue representative of whole body was gradually lowered by anemic, hypoxic, or stagnant hypoxia. As diffusion began to limit uptake, the fall in VO2 was computed numerically, yielding a relationship between QO2 and VO2 in both supply-independent and O2 supply-dependent regions. This analysis predicted a similar biphasic relationship between QO2 and VO2 and a linear fall in VO2 at O2 deliveries below a critical point for all three forms of hypoxia, as long as intercapillary distances were less than or equal to 80 microns. However, the analysis also predicted that O2 extraction at the critical point should exceed 90%, whereas real tissues typically extract only 65-75% at that point. When intercapillary distances were larger than approximately 80 microns, critical O2 extraction ratios in the range of 65-75% could be predicted, but the critical point became highly sensitive to the type of hypoxia imposed, contrary to experimental findings. Predicted gas exchange in accord with real data could only be simulated when a postulated 30% functional peripheral O2 shunt (arterial admixture) was combined with a tissue composed of Krogh cylinders with intercapillary distances of less than or equal to 80 microns. The unrealistic efficacy of tissue O2 extraction predicted by the Krogh model (in the absence of postulated shunt) may be a consequence of the assumed homogeneity of tissues, because real tissues exhibit many forms of heterogeneity among capillary units. Alternatively, the failure of the original Krogh model to fully predict tissue O2 supply dependency may arise from basic limitations in the assumptions of that model.

Effects of surface tension and viscosity on airway reopening.

We studied airway opening in a benchtop model intended to mimic bronchial walls held in apposition by airway lining fluid. We measured the relationship between the airway opening velocity (U) and the applied airway opening pressure in thin-walled polyethylene tubes of different radii (R) using lining fluids of different surface tensions (gamma) and viscosities (mu). Axial wall tension (T) was applied to modify the apparent wall compliance characteristics, and the lining film thickness (H) was varied. Increasing mu or gamma or decreasing R or T led to an increase in the airway opening pressures. The effect of H depended on T: when T was small, opening pressures increased slightly as H was decreased; when T was large, opening pressure was independent of H. Using dimensional analysis, we found that the relative importance of viscous and surface tension forces depends on the capillary number (Ca = microU/gamma). When Ca is small, the opening pressure is approximately 8 gamma/R and acts as an apparent "yield pressure" that must be exceeded before airway opening can begin. When Ca is large (Ca greater than 0.5), viscous forces add appreciably to the overall opening pressures. Based on these results, predictions of airway opening times suggest that airway closure can persist through a considerable portion of inspiration when lining fluid viscosity or surface tension are elevated.

Adrenergic vasoconstriction augments tissue O2 extraction during reductions in O2 delivery.

When systemic O2 delivery is reduced, increases in systemic O2 extraction are facilitated by sympathetically mediated increases in vascular resistance that limit blood flow to regions with low metabolic demand. Local metabolic vasodilation competes with this vasoconstriction, thereby effecting a balance between tissue O2 supply and demand. This study examined the role of sympathetically mediated vasoconstriction on the critical level of O2 extraction in hindlimb and whole body during progressive reductions in O2 delivery. In anesthetized dogs, the left hindlimb was vascularly isolated and its O2 delivery was decreased in stages by reducing the speed of an occlusive pump. In a normovolemic group (n = 6), blood volume was maintained to minimize sympathetic tone while flow to the hindlimb was reduced. In a hypovolemic group (n = 6), blood volume was removed in stages to augment sympathetic tone progressively while flow to the limb was reduced simultaneously. A phenoxybenzamine group (n = 6) was identical to the hypovolemic group, except that alpha-adrenergic effects were inhibited with phenoxybenzamine (3 mg/kg). The systemic critical O2 extraction ratio in the phenoxybenzamine group (0.60 +/- 0.06) was less than for the hypovolemic group (0.71 +/- 0.04; P = 0.004). In the hindlimb, critical O2 extractions were significantly less in the normovolemic (0.46 +/- 0.17) and phenoxybenzamine (0.49 +/- 0.10) groups compared with the hypovolemic group (0.72 +/- 0.10; P < or = 0.008).(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.

Effect of endotoxin on systemic and skeletal muscle O2 extraction.

Patients with the adult respiratory distress syndrome (ARDS) show a pathological dependence of O2 consumption (VO2) on O2 delivery (QO2, blood flow X arterial O2 content). In these patients, a defect in tissues' ability to extract O2 from blood can leave tissue O2 needs unmet, even at a normal QO2. Endotoxin administration produces a similar state in dogs, and we used this model to study mechanisms that may contribute to human pathology. We measured systemic and hindlimb VO2 and QO2 while reducing cardiac output by blood withdrawal. At the onset of supply dependence, the systemic QO2 was 11.4 +/- 2.7 ml.kg-1.min-1 in the endotoxin group vs. 8.0 +/- 0.7 in controls (P less than 0.05). At this point, the endotoxin-treated animals extracted only 61 +/- 11% of the arterial O2, whereas control animals extracted 70 +/- 7% (P less than 0.05). Systemic VO2 rose by 15% after endotoxin (P less than 0.05) but did not change in controls. Despite this poorer systemic ability to extract O2 by the endotoxin-treated dogs, isolated hindlimb O2 extraction at the onset of supply dependence was the same in endotoxin-treated and control dogs. At normal levels of QO2, hindlimb VO2 in endotoxin-treated dogs was 23% higher than in controls (P less than 0.05). Fractional blood flow to skeletal muscle did not differ between control and endotoxin-treated dogs. Thus skeletal muscle was not overperfused in endotoxemia and did not contribute to a systemic extraction defect by stealing blood flow from other tissues. Skeletal muscle in endotoxin-treated dogs demonstrated an increase in VO2 but no defect in O2 extraction, differing in both respects from the intestine.

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)

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.

Gas density dependence of regional VA/V and VA/Q inequality during constant-flow ventilation.

Constant-flow ventilation (CFV) is achieved by delivering a constant stream of inspiratory gas through cannulas aimed down the main stem bronchi at flow rates totaling 1-3 l.kg-1.min-1 in the absence of tidal lung motion. Previous studies have shown that CFV can maintain a normal arterial PCO2, although significant ventilation-perfusion (VA/Q) inequality appears. This VA/Q mismatch could be due to regional differences in lung inflation that occur during CFV secondary to momentum transfer from the inflowing stream to resident gas in the lung. We tested the hypothesis that substitution of a gas with lower density might attenuate regional differences in alveolar pressure and reduce the VA/Q inequality during CFV. Gas exchange was studied in seven anesthetized dogs by the multiple inert gas elimination technique during ventilation with intermittent positive-pressure ventilation, CFV with O2-enriched nitrogen (CFV-N2), or CFV with O2-enriched helium (CFV-He). As an index of VA/Q inequality independent of shunt, the log SD blood flow increased from 0.757 +/- 0.272 during intermittent positive-pressure ventilation to 1.54 +/- 0.36 (P less than 0.001) during CFV-N2. Switching from CFV-N2 to CFV-He at the same flow rate did not improve log SD blood flow (1.45 +/- 0.21) (P greater than 0.05) but tended to increase arterial PCO2. In excised lungs with alveolar capsules attached to the pleural surface, CFV-He significantly reduced alveolar pressure differences among lobes compared with CFV-N2 as predicted. Regional alveolar washout of Ar after a stap change of inspired concentration was slower during CFV--He than during CFV-N2.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Hepatic oxygen and lactate extraction during stagnant hypoxia.

As O2 delivery falls, tissues must extract increasing amounts of O2 from blood to maintain a normal O2 consumption. Below a critical delivery threshold, increases in O2 extraction cannot compensate for the falling delivery, and O2 uptake falls in a supply-dependent fashion. Numerous studies have identified a critical delivery in whole animals, but the regional contributions to the critical O2 delivery are less fully understood. In the present study, we explored the limits of O2 extraction in the isolated liver, seeking to determine 1) the normal relationship between O2 consumption and delivery in the liver and 2) the relationship of hepatic lactate extraction to the drop in hepatic O2 consumption at low O2 deliveries. To answer these questions, using support dogs as a source for oxygenated metabolically stable blood, we studied eight pump-perfused canine livers. By lowering the blood flow in a model of stagnant hypoxia, we explored the relationship between O2 consumption and delivery over the entire physiological range of O2 delivery. The critical O2 delivery was 28 +/- 5 (SD) ml.kg-1.min-1; the livers extracted 68 +/- 9% of the delivered O2 before reaching supply dependence. This suggests that the liver has an O2 extraction capacity quite similar to the body as a whole and not different from other tissues that have been isolated. At high blood flows, the livers extracted approximately 10% of the lactate delivered by the blood, but the arteriovenous lactate differences were small. At low blood flows, however, the livers changed from lactate consumption to production. The O2 delivery coinciding with the dropoff in lactate extraction did not differ significantly from the critical O2 delivery. We conclude that reductions in lactate uptake by the liver do not precede the transition to O2 supply dependence.

Airway reopening pressure in isolated rat lungs.

In a previous modeling study, we predicted that the yield pressure for airway reopening (Pyield) should depend on airway fluid surface tension (gamma) and airway radius (R), according to the relationship Pyield = 8.3 gamma/R. To test this prediction, we studied tantalum bronchograms of isolated perfused rat lungs from three rats by using microfocal X-ray imaging. Thirty-two airways with diameters ranging from 300 to 2,400 microns were recorded as the airways were collapsed and reinflated. Airway pressure was reduced transiently to -40 cmH2O to produce airway closure. Airway pressure was then slowly increased from 0 to 25 cmH2O. In each airway, the observed diameter remained constant until a Pyield was reached; at this pressure, airways were seen to "pop" open, allowing clear identification of airway reopening pressure. When Pyield was plotted against diameter at maximum inflation, the experimental data were in approximate agreement with predictions of Pyield made assuming a gamma of 35 dyn/cm. The close correspondence of the measured values with these predictions suggests that surfactant is present in these airways and facilitates airway reopening.

L-canavanine selectively augments contraction in aortas from endotoxemic rats.

Contractile responses to KCl or phenylephrine were inhibited in endothelium-denuded aorta from endotoxin-treated rats. L-Canavanine, a selective inhibitor of inducible nitric oxide synthase, augmented contractile responses in vessels from endotoxin, but not saline-pretreated animals. In contrast to nitroarginine, L-canavanine did not inhibit endothelium-dependent relaxation induced by acetylcholine. Selective inhibitors of inducible nitric oxide synthase may be useful probes of vascular dysfunction in sepsis.

Oxygen supply and consumption in the adult respiratory distress syndrome.

Our understanding of acute hypoxemic respiratory failure has evolved continually over the past 100 years. Currently, much attention is focused on the peripheral consequences of the adult respiratory distress syndrome, because the systemic sequelae are a significant contributor to morbidity and death from the condition. The unexpected relation between O2 supply and uptake in the periphery of these patients could be a signal of occult tissue hypoxia. If so, this would have important implications for clinical care aimed at minimizing the multiple system organ failure that often develops. Alternatively, the increases in uptake seen when delivery is increased could arise in part from coupling error, uptake by nonmitochondrial oxidase systems, oxygen radical formation, and the normal increases in uptake seen in the range of relative O2 supply independence. Future evolution in our understanding of ARDS will require a careful evaluation of the adequacy of tissue oxygenation and the role of tissue hypoxia in this syndrome. Promising new approaches such as near-infrared spectroscopy and magnetic resonance imaging may help provide indices of tissue O2 supply limitation that complement regional measurements of tissue function.

The effect of adrenergic agonists on the systemic response to hemorrhage.

PURPOSE: Systemic blood loss elicits a variety of reflex cardiovascular responses, which preserve cardiac output as possible and preserve arterial blood pressure when cardiac output decreases. When compensatory venoconstriction is exhausted, hemorrhage reduces oxygen delivery (QO2), and systemic vasoconstriction competes with local metabolic vasodilation to preserve tissue oxygen uptake (VO2). Through their effects on vascular tone and blood flow distribution, adrenergic agents might interfere with the physiological responses to reduced O2 delivery. This study was designed to determine the effects of dobutamine and norepinephrine on oxygen extraction and systemic vascular resistance during progressive hemorrhage. METHODS: We infused dobutamine or norepinephrine into anesthetized, ventilated dogs and measured the systemic vascular resistance, oxygen consumption, and oxygen extraction ratio as oxygen delivery (blood flow) was reduced by blood withdrawal. Four groups were compared: control (saline), dobutamine (10 micrograms/kg/min), high-dose norepinephrine (1.0 microgram/kg/min), and low-dose norepinephrine (0.1 microgram/kg/min). RESULTS: High-dose norepinephrine increased oxygen demand but did not alter extraction significantly at the critical point. Neither low-dose norepinephrine nor dobutamine affected oxygen extraction during hemorrhage. Dobutamine and norepinephrine both ablated the increase in systemic vascular resistance that accompanies hemorrhage. Low-dose norepinephrine was not different from control. CONCLUSIONS: Norepinephrine and dobutamine appear to block reflex vasoconstriction, and mechanistic explanations for this finding remain speculative. Despite inhibition of reflex vasoconstriction, neither dobutamine nor norepinephrine significantly impaired oxygen extraction during hemorrhage.

Absence of supply dependence of oxygen consumption in patients with septic shock.

We tested whether oxygen consumption (VO2) was dependent on oxygen delivery (QO2) in 10 patients with septic shock when QO2 was changed by the use of the inotropic agent, dobutamine. The mean acute physiology and chronic health evaluation (APACHE) II score of the patients was 27.3 +/- 8.1 with a mean blood pressure on entry of 66.8 +/- 12.4 mm Hg, and all had been volume resuscitated to a pulmonary artery occlusion pressure of greater than 10 mm Hg. We measured VO2 by analysis of respiratory gases (VO2G) while calculating VO2 by the Fick equation (VO2F) at three different O2 deliveries. When the dobutamine infusion rate was increased from 2.5 +/- 4.0 to 12.3 +/- 6.0 micrograms/kg/min, thermodilution cardiac output increased from 7.7 +/- 2.6 to 10.1 +/- 2.7 L/min (P < .01). Accordingly, dobutamine increased QO2 from 13.5 +/- 3.8 to 18.2 +/- 4.3 mL/min per kg (increase of 36.4% +/- 19.7%; P < .01), but VO2G did not increase (3.2 +/- 0.5 to 3.2 +/- 0.6 mL/min per kg). During these same interventions, the VO2F tended to increase (2.9 +/- 0.7 to 3.4 +/- 0.8 mL/min per kg, P < .06), presumably a spurious correlation because of measurement errors shared by the calculation of VO2F and QO2. Neither lactic acidosis nor acute respiratory distress syndrome (ARDS) conferred supply dependence of VO2G, but the presence of ARDS was predictive of death in this cohort. It is concluded that VO2 is independent of QO2 in patients with septic shock and lactic acidosis. These data confirm that maximizing QO2 beyond values achieved by initial fluid and vasoactive drug resuscitation of septic shock does not improve tissue oxygenation as determined by respiratory gas measurement of VO2.

Oxygen delivery and uptake by peripheral tissues: physiology and pathophysiology.

When oxygen availability to tissues becomes limited, several mechanisms interact to maintain a supply-independent O2 uptake by tissues. Among tissues, adrenergic vasoconstriction prevents a vascular steal of a limited O2 supply by tissues with low metabolic demands. Within tissues, increases in perfused capillary density facilitate an increase in the extraction ratio for oxygen ([CaO2-CvO2]/CaO2). Factors that disrupt the physiologic balance between sympathetic-mediated vasoconstriction and local metabolic vasodilation may impair the ability of the organism to adjust the regional extraction of oxygen in response to changes in O2 delivery, resulting in a pathologic dependence of O2 uptake on supply. Patients with ARDS have demonstrated such an O2 extraction defect, although the mechanism is not fully understood. Although a tissue mitochondrial abnormality could explain these findings, experimental studies of endotoxemia and bacteremia demonstrate a peripheral O2 extraction defect similar to that seen in patients. This defect has been found at the whole body level and within intestine, but not within skeletal muscle. Evidence points to a defect in microvascular control as the mechanism responsible for the defect. Other evidence suggests that damaged peripheral endothelial cells may mediate the loss of vascular control. Hence, in patients with ARDS a damaged endothelium in the pulmonary circulation contributes to the lung edemagenesis, and damaged peripheral endothelium may mediate the defect in microvascular control, leading to the pathologic dependence of oxygen uptake on delivery.