Metabolic component of intestinal PCO(2) during dysoxia.

The adequacy of intestinal perfusion during shock and resuscitation might be estimated from intestinal tissue acid-base balance. We examined this idea from the perspective of conventional blood acid-base physicochemistry. As the O(2) supply diminishes with failing blood flow, tissue acid-base changes are first "respiratory, " with CO(2) coming from combustion of fuel and stagnating in the decreasing blood flow. When the O(2) supply decreases to critical, the changes become "metabolic" due to lactic acid. In blood, the respiratory vs. metabolic distinction is conventionally made using the buffer base principle, in which buffer base is the sum of HCO(3)(-) and noncarbonate buffer anion (A(-)). During purely respiratory acidosis, buffer base stays constant because HCO(3)(-) cannot buffer its own progenitor, carbonic acid, so that the rise of HCO(3)(-) equals the fall of A(-). During anaerobic "metabolism," however, lactate's H(+) is buffered by both A(-) and HCO(3)(-), causing buffer base to decrease. We quantified the partitioning of lactate's H(+) between HCO(3)(-) and A(-) buffer in anoxic intestine by compressing intestinal segments of anesthetized swine into a steel pipe and measuring PCO(2) and lactate at 5- to 10-min intervals. Their rises followed first-order kinetics, yielding k = 0. 031 min(-1) and half time = approximately 22 min. PCO(2) vs. lactate relations were linear. Over 3 h, lactate increased by 31 +/- 3 mmol/l tissue fluid (mM) and PCO(2) by approximately 17 mM, meaning that one-half of lactate's H(+) was buffered by tissue HCO(3)(-) and one-half by A(-). The data were consistent with a lumped pK(a) value near 6.1 and total A(-) concentration of approximately 30 mmol/kg. We conclude that the respiratory vs. metabolic distinction could be made in tissue by estimating tissue buffer base from measured pH and PCO(2).

Human PaCO2 and standard base excess compensation for acid-base imbalance.

OBJECTIVES: Renal and respiratory acid-base regulation systems interact with each other, one compensating (partially) for a primary defect of the other. Most investigators striving to typify compensations for abnormal acid-base balance have reported their findings in terms of arterial pH, PaCO2, and/or HCO3-. However, pH and HCO3- are both altered by both respiratory and metabolic changes. We sought to simplify these relations by expressing them in terms of standard base excess (SBE in mM), which quantifies the metabolic balance and is independent of PaCO2. DESIGN: Meta-analysis. SETTING: Historical synthesis developed via the Internet. PATIENTS: Arterial pH, PaCO2, and/or HCO3- data sets were obtained from 21 published reports of patients considered to have purely acute or chronic metabolic or respiratory acid-base problems. INTERVENTIONS: We used the same data to compute the typical compensatory responses to imbalances of SBE and PaCO2. Relations were expressed as difference (delta) from normal values for PaCO2 (40 torr [5.3 kPa]) and SBE (0 mM). MEASUREMENTS AND MAIN RESULTS: The data of patient compensatory changes conformed to the following equations, as well as to the traditional PaCO2 vs. HCO3- or H+ vs. PaCO2 equations: Metabolic change responding to change in PaCO2: Acute deltaSBE = 0 x deltaPaCO2, hence: SBE = 0, Chronic deltaSBE = 0.4 x deltaPaCO2. Respiratory change responding to change in SBE: Acidosis deltaPaCO2 = 1.0 x deltaSBE, Alkalosis deltaPaCO2 = 0.6 x deltaSBE. CONCLUSION: Data reported by many investigators over the past 35 yrs on typical, expected, or "normal" human compensation for acid-base imbalance may be expressed in terms of the independent variables: PaCO2 (respiratory) and SBE (metabolic).

Mitochondrial redox state as a potential detector of liver dysoxia in vivo.

Dysoxia can be defined as ATP flux decreasing in proportion to O2 availability with preserved ATP demand. Hepatic venous beta-hydroxybutyrate-to-acetoacetate ratio (beta-OHB/AcAc) estimates liver mitochondrial NADH/NAD and may detect the onset of dysoxia. During partial dysoxia (as opposed to anoxia), however, flow may be adequate in some liver regions, diluting effluent from dysoxic regions, thereby rendering venous beta-OHB/AcAc unreliable. To address this concern, we estimated tissue ATP while gradually reducing liver blood flow of swine to zero in a nuclear magnetic resonance spectrometer. ATP flux decreasing with O2 availability was taken as O2 uptake (VO2) decreasing in proportion to O2 delivery (QO2); and preserved ATP demand was taken as increasing Pi/ATP. VO2, tissue Pi/ATP, and venous beta-OHB/AcAc were plotted against QO2 to identify critical inflection points. Tissue dysoxia required mean QO2 for the group to be critical for both VO2 and for Pi/ATP. Critical QO2 values for VO2 and Pi/ATP of 4.07 +/- 1.07 and 2.39 +/- 1.18 (SE) ml . 100 g-1 . min-1, respectively, were not statistically significantly different but not clearly the same, suggesting the possibility that dysoxia might have commenced after VO2 began decreasing, i.e., that there could have been "O2 conformity." Critical QO2 for venous beta-OHB/AcAc was 2.44 +/- 0.46 ml . 100 g-1 . min-1 (P = NS), nearly the same as that for Pi/ATP, supporting venous beta-OHB/AcAc as a detector of dysoxia. All issues considered, tissue mitochondrial redox state seems to be an appropriate detector of dysoxia in liver.

[Base excess] vs [strong ion difference]. Which is more helpful?

Blood [base excess] ([BE]) is defined as the change in [strong acid] or [strong base] needed to restore pH to normal at normal PCO2. Some believe that [BE] is unhelpful because [BE] may be elevated with a "normal" [strong ion difference] ([SID]), where a strong ion is one that is always dissociated in physiological solution, and where [SID] = [strong cations]-[strong anions]. Using a computer simulation, the hypothesis was tested that [SID] = [SID Excess] ([SIDEx]), where [SIDEx] is the change in [SID] needed to restore pH to normal at normal PCO2. The most current version of the plasma [SID] ([SID]p) equation was used as a template, and an [SIDEx] formula, of the Siggaard-Andersen form, derived: [SIDEx]p = [HCO3-]p -24.72 + (pHp - 7.4) x (1.159 x [alb]p + 0.423 x [Pi]p). [SID] was compared to [SIDEx] over the physiologic range of plasma buffering, and it was found that [SIDEx] varied by approximately 15 mM at any given [SID], thereby faulting the hypothesis. It is concluded that [SID] can be "normal" with an elevated [SIDEx], the latter being an expression of the [BE] concept, and a more helpful quantity in physiology. The "metabolic" component of a given acid-base disturbance is usually estimated as whole blood [base excess] ([BE]WB), where [BE]WB is defined as the change in [strong acid] or [strong base] needed to restore plasma pH (pHp) to 7.4 at PCO2 of 40 Torr. However, the [BE] approach has been criticized as "inadequate for interpretation of complex acid-base derangements such as those seen in critically ill patients." The proposed alternative is the strong ion difference (SID) method, where a strong ion is one that is always dissociated in solution, and where [SID] = [strong cations] - [strong anions]. On the one hand, it does not seem possible, by the definitions of these entities, to change [SID] without also changing [BE]. On the other hand, a selected group of critically ill patients with hypoproteinemia has been reported in whom [SID] was "normal" (i.e. approximately 40 mEq.l-1) but [BE]WB clearly increased. The idea was that hypoproteinemia caused the alkalosis, due to a deficiency of plasma weak acid buffer, necessitating increased [HCO3-]p to maintain electrical neutrality. How could [SID] be "normal," but [BE] increased? The purpose of the current exercise was to address this question. An [SID excess] ([SIDEx]) formula was developed, conceptually identical to Siggaard-Andersen's [BE], and [SID] was compared to [SIDEx] over the physiological range of plasma [albumin] ([alb]p), plasma [phosphate] ([Pi]p), and plasma pH (pHp).

[Base excess] and [strong ion difference] during O2-CO2 exchange.

Detecting uptake or production of "metabolic acid" by a given tissue is often of interest. [Base excess] ([BE]) is the change in [strong acid] or [strong base] needed to restore pH to normal at normal PCO2. However, [BE] seems to have the potential for minor inaccuracy during hypercarbia, and venous blood is hypercarbic relative to arterial. Another approach is [strong ion difference] ([SID]), where a strong ion is one that is always dissociated in solution, and where [SID] = [strong cation] - [strong anion]. The hypothesis was tested that a-v [SID]p might be used to detect metabolic acid uptake or production by tissue. A computer simulation of O2-CO2 exchange was performed, using the Siggaard-Andersen [BE] equations, which provide an existing conceptual template. It was assumed that a change in [BE] = a change in [SID] (Adv. Exp. Med. Biol., in press). (A-v) [SID]p decreased linearly with decreasing [HbO2] during equimolar O2-CO2 exchange (delta mEq [SID]p.l-1 per delta gHbO2.dl-1 = 0.6, r2 = 1.0), and erythrocyte [BE] ([BE]e) and [SID]e decreased commensurately, such that [BE]WB remained constant. These changes represent ion exchanges between erythrocyte and plasma, governed by the Gibbs-Donnan equilibrium. It is concluded that a-v [SID]p may be used to examine a-v differences in [metabolic acid], based in [BE] concepts. The concentration of "metabolic acid" ([metabolic acid]) in blood increases during endotoxemia, exercise and shock. To identify organ(s) responsible, it is necessary to measure arteriovenous [strong acid]. Two methods are available. Whole blood base excess ([BE]WB), is the change in [strong acid]WB or [strong base]WB needed to restore plasma pH (pHp) to 7.4 at PCO2 of 40 torr, and is an excellent method for distinguishing "respiratory," from "metabolic" acidosis in arterial blood. However, while [BE] is most helpful conceptually, use of [BE] in venous blood presents two problems. First, [BE]WB may employ in vitro assumptions that are slightly inaccurate during hypercarbia in vivo, and venous blood is hypercarbic relative to arterial. The problem seems to be that [BE] assumes greater [hemoglobin] ([Hb]) than is actually effective in vivo, where Hb is diluted in the extracellular volume. The "Van Slyke" version of the [BE]WB equation is: BE]WB = ¿[HCO3-]p - 24.4 + (2.3 x [Hb] + 7.7) x (pHp - 7.4)¿ x (1-0.023 x [Hb]) (1) This equation may be thought of conceptually as: [BE] = ([HCO3-] + [A-]) - (normal [HCO3-] + normal [A-]) (2) where A- is negatively charged non-volatile weak acid. Missing or excess charges are attributed to abnormal [strong acid] or [strong base], and [A-]WB is computed using actual, as opposed to effective, [Hb]. This problem has been adequately addressed in arterial blood by standard [BE]WB ([SBE]WB), by assuming that effective [Hb] in vivo is approximately one third of that in vitro. However, it is not clear whether this assumption is sufficiently accurate to examine arteriovenous differences. A second and related problem with using [BE] to detect (a-v) differences is the magnitude of change in Hb buffering in vivo during O2 desaturation. Desaturation renders Hb a stronger weak acid buffer, i.e. increases its effective pK value. Consequently, [HCO3-]p is greater at any given PCO2, creating the appearance of a larger [BE]WB, whereas [strong acid] or [strong base] has not changed. This artifact can be corrected using the "O2 desaturation transform factor," which is 0.19 mM delta g [HbO2].dl-1 in vitro. In vivo, however, the magnitude of the O2 desaturation transform factor might be different. An alternative approach to acid-base analysis is strong ion difference (SID) where a strong ion is one that is always dissociated in physiologic solution. [SID] can usually be approximated as: [Na+] + [K+] - [Cl-] - [La-]. Although [BE] does not equal [SID], a change in [BE] must always accompany a change in [SID], and vice-versa. While the [SID] approach is tedious, and often unnecessarily so, [SID] ca

Methods for detecting local intestinal ischemic anaerobic metabolic acidosis by PCO2.

Gut ischemia is often assessed by computing an imaginary tissue interstitial Ph from arterial plasma HCO3- and the PCO2 in a saline-filled balloon tonometer after equilibration with tissue PCO2 and (PtiCO2). PtiCO2 may alternatively be assumed equal to venous PCO2 (PVCO2) in that region of gut. The idea is that as blood flow decreases, gut PtiCO2 and PVCO2 will increase to the maximum aerobic value, i.e., maximum respiratory PVCO2 (PVCO2rmax). Above a "critical" anaerobic threshold, lactate (La-) generation, by titration of tissue HCO3-, should raise PtiCO2 above PVCO2rmax. During progressive selective whole intestinal flow reduction in six pentobarbital-anesthetized pigs, we used PCO2 electrodes to test the hypotheses that critical PtiCO2 is achieved earlier in mucosa than in serosa and that PVCO2rmax, computed using an in vitro model, predicts critical PtiCO2. We defined critical PtiCO2 as the inflection of PtiCO2-PVCo2 vs. O2 delivery (QO2) plots. Critical QO2 for O2 uptake was 12.55 +/- 2 ml.kg-1.min-1. Critical PtiCO2 for mucosa and serosa was achieved at similar whole intestine QO2 (13.90 +/- 5 and 13.36 +/- 5 ml.kg-1.min-1, P = NS). Critical PtiCO2 (129 +/- 24 and 96 +/- 21 Torr) exceeded PVCO2rmax (62 +/- 3 Torr). During ischemia, La- excretion into portal venous blood was matched by K+ excretion, causing PVCO2 to increase only slightly, despite PtiCO2 rising to 380 +/- 46 (mucosa) and 280 +/- 38 (serosa) Torr. These results suggest that mucosa and serosa become dysoxic simultaneously, that ischemic dysoxic gut is essentially perfused, and that in vitro predicted PVCO2rmax underestimates critical PtiCO2.

Tissue-arterial PCO2 difference is a better marker of ischemia than intramural pH (pHi) or arterial pH-pHi difference.

Gastric intramucosal pH (pHi) is often calculated by the Henderson-Hasselbalch equation, using arterial plasma [HCO3-]ap and PCO2 measured in saline obtained from a silastic balloon tonometer after equilibration in the lumen of the stomach. A pHi value less than approximately 7.3 pH units is often taken as evidence of intestinal ischemia. An alternative measure is tissue PCO2 (PtCO2)-PaCO2 difference [P(t-a)CO2]. The idea is that PtCO2 will increase slightly relative to PaCO2 as O2 supply decreases, and then increase strikingly when flow decreases to a critical value, because of liberation of CO2 from tissue Hco3- by anaerobically generated strong acid. A third method is arterial plasma pH (pHap)-pHi difference [pH(ap-i)]. We used mathematical simulations to test the hypotheses that calculated pHi is independent of arterial acid-base status; and pH(ap-i) provides the same information as does P(t-a) CO2. Using the Van Slyke version of the arterial whole blood [standard base excess] ([SBE]aWB) equation, it was found that a change in [SBE]aWB at constant PaCO2 and constant PtCO2 produces a change in calculated pHi (P = 0), such that the relation between changing [SBE]aWB and changing pHi is predictable by a single polyomial equation (R2 = .999). pH(ap-i) avoids this confounding influence of [SBE]aWB. However, it was further shown that pH(ap-i) can be associated with a wide range of P(t-a)CO2, depending on the magnitude of pH(ap-i), and on the PaCO2 at which P(t-a)CO2 is measured. We conclude that P(t-a)CO2 is a more reliable index of gastric oxygenation than is pHi alone or pH(ap-i).

Resuscitation from severe hemorrhage.

The potential to be successfully resuscitation from severe traumatic hemorrhagic shock is not only limited by the "golden 1 hr", but also by the "brass (or platinum) 10 mins" for combat casualties and civilian trauma victims with traumatic exsanguination. One research challenge is to determine how best to prevent cardiac arrest during severe hemorrhage, before control of bleeding is possible. Another research challenge is to determine the critical limits of, and optimal treatments for, protracted hemorrhagic hypotension, in order to prevent "delayed" multiple organ failure after hemostasis and all-out resuscitation. Animal research is shifting from the use of unrealistic, pressure-controlled, hemorrhagic shock models and partially realistic, volume-controlled hemorrhagic shock models to more realistic, uncontrolled hemorrhagic shock outcome models. Animal outcome models of combined trauma and shock are needed; a challenge is to find a humane and clinically realistic long-term method for analgesia that does not interfere with cardiovascular responses. Clinical potentials in need of research are shifting from normotensive to hypotensive (limited) fluid resuscitation with plasma substitutes. Topics include optimal temperature, fluid composition, analgesia, and pharmacotherapy. Hypotensive fluid resuscitation in uncontrolled hemorrhagic shock with the addition of moderate resuscitative (28 degrees to 32 degrees C) hypothermia looks promising in the laboratory. Regarding the composition of the resuscitation fluid, despite encouraging results with new preparations of stroma-free hemoglobin and hypertonic salt solutions with colloid, searches for the optimal combination of oxygen-carrying blood substitute, colloid, and electrolyte solution for limited fluid resuscitation with the smallest volume should continue. For titrating treatment of shock, blood lactate concentrations are of questionable value although metabolic acidemia seems helpful for prognostication. Development of devices for early noninvasive monitoring of multiple parameters in the field is indicated. Molecular research applies more to protracted hypovolemic shock followed by the systemic inflammatory response syndrome or septic shock, which were not the major topics of this discussion.

Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms.

Both the period of total circulatory arrest to the brain and postischemic-anoxic encephalopathy (cerebral postresuscitation syndrome or disease), after normothermic cardiac arrests of between 5 and 20 mins (no-flow), contribute to complex physiologic and chemical derangements. The best documented derangements include the delayed protracted inhomogeneous cerebral hypoperfusion (despite controlled normotension), excitotoxicity as an explanation for selectively vulnerable brain regions and neurons, and free radical-triggered chemical cascades to lipid peroxidation of membranes. Protracted hypoxemia without cardiac arrest (e.g., very high altitude) can cause angiogenesis; the trigger of it, which lyses basement membranes, might be a factor in post-cardiac arrest encephalopathy. Questions to be explored include: What are the changes and effects on outcome of neurotransmitters (other than glutamate), of catecholamines, of vascular changes (microinfarcts seen after asphyxia), osmotic gradients, free-radical reactions, DNA cleavage, and transient extracerebral organ malfunction? For future mechanism-oriented studies of the brain after cardiac arrest and innovative cardiopulmonary-cerebral resuscitation, increasingly reproducible outcome models of temporary global brain ischemia in rats and dogs are now available. Disagreements exist between experienced investigative groups on the most informative method for quantitative evaluation of morphologic brain damage. There is agreement on the desirability of using not only functional deficit and chemical changes, but also morphologic damage as end points.

Simulation of maximum respiratory venous PCO2 in vitro.

PvCO2 that would result from full O2Hb desaturation at a given O2-CO2 exchange ratio, in the absence of metabolic acid, may be termed maximum respiratory venous PCO2 (PvmrCO2). This theoretical condition of 100% O2 extraction, in the absence of metabolic acid, should simulate maximum aerobic PCO2 in tissue, provided that PCO2 of tissues and large veins is similar. Hence, the value of PvmrCO2 is of interest in identifying critical tissue PCO2. Analysis of the Dill nomogram indicates that PvmrCO2 is 77 torr at RQ = 1.0, PaCO2 = 40 torr in vitro, and that the PvCO2 versus SO2 relation is linear. Since the Dill nomogram is confined to the condition. [Hb] = 15 g.dL-1, [BE] = 0, the goal of the present analysis was to determine variability of PvmrCO2 with [Hb], arterial [base excess] ([BE]), and PaCO2. Venous CO2 titrations for multiple arterial conditions were simulated using published in vitro [BE] and whole blood [total CO2] formulae. In the RQ range of 0.7 to 1.0, the simulation yielded PvCO2 values that were essentially identical to those obtainable from the Dill nomogram. The simulation predicted that PvmrCO2 should decrease in direct proportion to [Hb], and increase non-linearly with decreasing arterial [BE]. The simulation further predicted that venoarterial PCO2 difference should increase linearly with increasing PaCO2. Simulated PvmrCO2-PaCO2 difference varied from 5 torr at arterial [BE] = +10 mmol/L, [Hb] = 6 g.dL-1, PaCO2 = 25 torr, RQ = 0.7 to 67 torr at [BE] = -20 mmol/L, [Hb] = 15 g.dL-1, PaCO2 = 65 torr, RQ = 1.0. It is concluded that the PvCO2 versus SO2 relation is not linear when arterial [Hb] and/or [BE] vary. An equation that predicts in vitro PvmrCO2 as a function of arterial [BE], [Hb], RQ, and PaCO2 is provided. It's accuracy in vivo should be testable.

Adult respiratory distress syndrome associated with epidural fentanyl infusion.

OBJECTIVE: To determine the cause of unexplained postoperative adult respiratory distress syndrome (ARDS). DESIGN: Case-control study of postoperative ARDS. SETTING: Intensive care unit (ICU) of a Veterans Affairs hospital. PATIENTS: Six postoperative patients recovering from uncomplicated vascular or cardiothoracic surgery developed unexplained ARDS. Controls were 17 patients having similar procedures without the development of ARDS. INTERVENTION: Infusion of fentanyl with a tamper-proof device. MEASUREMENTS AND MAIN RESULTS: Development of ARDS. ARDS began 1 to 4 days after surgery, was characterized by maximum alveolar-arterial oxygen gradient that ranged from 232 to 544 torr (30.9 to 72.5 kPa), and was associated with death of two patients. We observed no association with patient location before ARDS onset, nonanalgesic medication administered, staff assignment, or mode of respiratory therapy. All six patients who developed unexplained ARDS had received epidural fentanyl compared with none of 17 control patients without ARDS (p = .0002). We instituted a tamper-proof mode of parenteral fentanyl administration, and subsequently observed one case of ARDS in 26 consecutive surgical patients (p = .000014). CONCLUSIONS: Based on these findings, as well as a prior history of fentanyl theft at our institution, we conclude that tampering with fentanyl infusate was responsible for the ARDS epidemic that we observed.

Distinguishing between aerobic and anaerobic appearance of dissolved CO2 in intestine during low flow.

Increased intestinal mucosal PCO2 is used to detect the condition of inadequate O2 delivery, i.e., "dysoxia." However, mucosal PCO2 (PmCO2) can arise from oxidative phosphorylation, in which case it would detect metabolism that persists as blood stagnates, and/or from HCO3- neutralization by anaerobically produced metabolic acid, in which event it could represent dysoxia. We measured portal venous PCO2 (PVCO2) directly and PmCO2 indirectly with saline-filled CO2-permeable Silastic balloon tonometers in the intestinal lumen during progressive lethal cardiac tamponade in six pentobarbital-anesthetized dogs. PVCO2 and PmCO2 were relatively constant, differing by approximately 10 Torr until an O2 delivery (DO2) of approximately 1.3 ml.kg-1.min-1 was reached, below which PVCO2 and PmCO2 diverged strikingly, achieving a final difference of 78.7 +/- 35.81 (SD) Torr. To determine whether PCO2 arose from aerobic or anaerobic metabolism, we used the Dill nomogram to predict venous oxyhemoglobin (HbO2v) saturation (%HbO2v) from PVCO2. Portal venous %HbO2 predicted by the Dill nomogram agreed well with measured portal venous %HbO2 during all but the final values, indicating primarily aerobic appearance of PCO2 in venous blood, suggesting that portions of intestine that remained perfused at very low flow produced dissolved CO2 mainly by oxidative phosphorylation. As PmCO2 increased below critical DO2, however, predicted mucosal %HbO2v became strikingly negative, achieving a final value of -192 +/- 106.1%, indicating anaerobic dissolved CO2 production in mucosa. We conclude that PCO2 measured in intestinal lumen can be used to detect dysoxia.

Hepatic dysoxia commences during O2 supply dependence.

Hepatic O2 consumption (VO2) remains relatively constant (O2 supply independent) as O2 delivery (DO2) progressively decreases, until a critical DO2 (DO2c) is reached below which hepatic VO2 also decreases (O2 supply dependence). Whether this decrease in VO2 represents an adaptive reduction in O2 demand or a manifestation of tissue dysoxia, i.e., O2 supply that is inadequate to support O2 demand, is unknown. We tested the hypothesis that the decrease in hepatic VO2 during O2 supply dependence represents dysoxia by evaluating hepatic mitochondrial NAD redox state during O2 supply independence and dependence induced by progressive hemorrhage in six pentobarbital-anesthetized dogs. Hepatic mitochondrial NAD redox state was estimated by measuring hepatic venous beta-hydroxybutyrate-to-acetoacetate ratio (beta OHB/AcAc). The value of DO2c was 5.02 +/- 1.64 (SD) ml.100 g-1.min-1. The beta-hydroxybutyrate-to-acetoacetate ratio was constant until a DO2 value (3.03 +/- 1.08 ml.100 g-1.min-1) was reached (P = 0.05 vs. DO2c) and then increased linearly. Peak liver lactate extraction ratio was 15.2 +/- 14.1%, occurring at a DO2 of 5.48 +/- 2.54 ml.100 g-1.min-1 (P = NS vs. DO2c). Our data support the hypothesis that the decrease in VO2 during O2 supply dependence represents tissue dysoxia.

Renal O2 consumption during progressive hemorrhage.

Most mammalian tissues regulate O2 utilization such that O2 consumption (VO2) is relatively constant at O2 delivery (DO2) higher than a critical value (DO2c). We studied the relationship between VO2 and DO2 of kidney and whole body during graded progressive exsanguination. The relationship between whole body VO2 and DO2 was biphasic, and whole body VO2 decreased by 5.6 +/- 14.4% (P = NS) from the initial value to the value nearest whole body DO2c. Kidney DO2 decreased in direct proportion to whole body DO2 such that the average R2 value describing the linear regression of kidney DO2 vs. whole body DO2 was 0.94 +/- 0.02. The relationship between kidney, like whole body, VO2 and DO2 appeared biphasic; however, kidney VO2 decreased by 63.3 +/- 10.4% (P less than 0.0001) from the initial value to the value nearest kidney DO2c. Renal O2 extraction ratio was relatively constant over a wide range of kidney DO2, whereas whole body O2 extraction ratio increased progressively at all whole body DO2 values as whole body DO2 decreased. However, final values of O2 extraction ratio were indistinguishable for whole body (0.86 +/- 0.1) and kidney (0.86 +/- 0.06) (P = NS). We conclude that the pattern of kidney and whole body VO2 response to decreasing DO2 differs during hemorrhage, particularly in the range of DO2 normally associated with tissue wellness.