Tolerance of unusually low mixed venous oxygen saturation. Adaptations in the chronic low cardiac output syndrome.

Introduction of a reliable method for continuous monitoring of mixed venous oxygen saturation has focused attention on the therapeutic and prognostic implications of this value. It is generally agreed that mixed venous oxygen saturation in the 40 to 60 percent range is associated with substantial patient morbidity and mortality if not rapidly corrected. However, several patients with chronic low cardiac output syndrome who have had mixed venous oxygen saturation of less than 40 percent for prolonged periods of time and who have not had decompensation were observed. Three representative patients with these findings are described and mechanisms put forth that may account for the observed relations between mixed venous oxygen saturation and mortality in these and other patients.

Auto-PEEP during CPR. An "occult" cause of electromechanical dissociation?

A 64-year-old man with severe COPD developed refractory nonperfusing sinus rhythm after intubation and positive-pressure ventilation. Fifteen minutes after resuscitative efforts were halted, the patient was noted to have spontaneous respirations and blood pressure, suggesting that dynamic hyperinflation was responsible for the observed electromechanical dissociation (EMD). We recommend a brief trial of apnea for patients with COPD and EMD when conventional measures are unsuccessful.

Regional oxygen delivery in oxygen supply-dependent states.

Assessment of the adequacy of systemic O2 delivery (DO2) is central in the evaluation of critically ill patients, but estimates of systemic DO2 do not assess the effectiveness of regional DO2 to all vascular beds whose functions may require different degrees of blood flow depending on their metabolic and functional demands. The oxygen supply-consumption curve includes a supply-independent portion, which represents the reserve capacity of the body to maintain oxygen consumption (VO2) despite inadequate increases in DO2, and a supply-dependent portion, which represents the physiologic adaptation that occurs once DO2 is unable to meet the metabolic demands of the body. Experiments in dogs revealed that when systemic DO2 was progressively reduced, blood flow was maintained in the vital organs (heart and brain) and redistributed away from the kidneys and liver, enhancing the ability of the whole organism to use oxygen efficiently. Disease states and iatrogenic conditions that alter this vasoregulatory process may directly impair organ system function.

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).

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.

Flow redistribution during progressive hemorrhage is a determinant of critical O2 delivery.

O2 consumption (VO2) of anesthetized whole mammals is independent of O2 delivery (DO2) until DO2 declines to a critical value (DO2c). Below this value, VO2 becomes O2 supply dependent. We assessed the influence of whole body DO2 redistribution among organs with respect to the commencement of O2 supply dependency. We measured DO2, VO2, and DO2c of whole body, liver, intestine, kidney, and remaining carcass in eight mongrel dogs during graded progressive hemorrhage. Whole body DO2 was redistributed such that the organ-to-whole body DO2 ratio declined for liver and kidney and increased for carcass. We then created a mathematical model wherein each organ-to-whole body DO2 ratio remained approximately constant at all values of whole body DO2 and assigned organ VO2 to predicted organ DO2 by interpolation and extrapolation of observed VO2-DO2 plots. The model predicted that O2 supply dependency without redistribution would have commenced at a higher value of whole body DO2 for whole body (8.11 +/- 0.89 vs. 6.98 +/- 1.16 ml.kg-1.min-1, P less than 0.05) and carcass (6.83 +/- 1.16 vs. 5.06 +/- 1.15 ml.kg-1.min-1, P less than 0.01) and at a lower value of whole body DO2 for liver (6.33 +/- 1.86 vs. 7.59 +/- 1.95, ml.kg-1.min-1, P less than 0.02) and kidney (1.25 +/- 0.64 vs. 4.54 +/- 1.29 ml.kg-1.min-1, P less than 0.01). We conclude that redistribution of whole body DO2 among organs facilitates whole body O2 regulation.

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.

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.

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.

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.

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).

Nutritional support of the mechanically ventilated patient.

Mechanically ventilated patients generally depend on artificial means for nutritional supplementation. In this article we review the magnitude, pathophysiology, and clinical significance of proteolysis, and evidence that nutritional repletion is beneficial. Methods for assessing nutritional status and response to nutritional intervention are briefly discussed, as well as basic principles of anabolic and anticatabolic therapy.

[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