Intensive Care Med (2014) 40:1643–1648 DOI 10.1007/s00134-014-3472-8
MY PAPER 20 YEARS LATER
Jean-Louis Vincent Daniel De Backer
My paper 20 years later: effects of dobutamine on the VO2/DO2 relationship
Received: 7 July 2014 Accepted: 26 August 2014 Published online: 30 September 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014
Abstract Introduction: Oxygen uptake (VO2) is independent of oxygen delivery (DO2) over a wide range of values, because O2 extraction can readily adapt to changes in DO2. However, VO2 can become DO2dependent in acute circulatory failure. Methods: Various methods of evaluating the presence of VO2/DO2 dependency were conducted, but criticized because of potential problems with mathematical coupling of data. Some 20 years ago, we proposed using a dobutamine test and showed similar relationships using direct and indirect measurements. Since these studies on the systemic VO2/DO2 relationship, investigators have also explored regional alterations.
J.-L. Vincent ()) D. De Backer Department of Intensive Care, Erasme Hospital, Universite´ libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium e-mail: [email protected] Tel.: ?32 2 555 3380
The concept of adequate oxygen delivery Most cellular activities require energy, which is primarily obtained from adenosine triphosphate (ATP) and other high-energy compounds. ATP is formed from the oxidation of glucose, and sufficient amounts of oxygen must, therefore, be present in the mitochondria to ensure adequate concentrations of ATP. Certain cellular processes are essential for cell survival, including membrane transport, growth, cell repair and maintenance processes. Other functions may also be performed, for example electrolyte or protein transport, contractility, motility, or various biosynthetic activities. In normal conditions, local metabolic requirements drive local, and subsequently systemic, flow. In circulatory failure, blood flow may become limited. If there is insufficient oxygen availability, oxygen consumption in the cells may decrease. The
Conclusion: The relationship between VO2 and DO2 remains an important concept. Abnormal global VO2/DO2 dependency does not exist in stable, critically ill patients, but can exist in circulatory shock of all etiologies. It can also occur regionally in septic patients, and microcirculatory alterations may contribute. Patient management should be titrated individually with careful assessment to identify those who will benefit from increased DO2. Keywords Oxygen uptake Oxygen delivery Oxygen extraction Microcirculation Lactate
first cellular processes that will be affected are facultative functions, leading to organ dysfunction. If oxygen concentrations decrease further, essential cellular functions will also be impaired, leading to irreversible cellular malfunction and death. Insuring adequate cellular oxygen delivery (DO2) is, therefore, a critical component of preserving organ function. DO2 is determined by cardiac index, the hemoglobin concentration and the hemoglobin saturation [and, therefore, arterial partial pressure of oxygen (PaO2)] (Box 1). Cardiac output is the most important determinant of DO2, because a decrease in hemoglobin concentration or arterial oxygen saturation (SaO2) can be compensated for by an increase in cardiac output, whereas the opposite is not true. Likewise, to increase DO2, SaO2 is normally close to 100 % and hemoglobin concentration cannot change acutely. Moreover, administration of a blood transfusion
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distribution of cardiac output to different organs, the regulation of the microcirculation by autonomic control of vascular tone and local microvascular responses, and DO2 = CI 9 Hb 9 SaO2 9 C 9 10 VO2 = CI 9 CaO2 - CvO2 9 10 or CI 9 Hb 9 (SaO2 - SvO2) the degree of affinity of the hemoglobin molecule for oxygen. The microcirculation can be altered substantially 9 C (neglecting the dissolved oxygen) O2ER = VO2/DO2 = (CaO2 - CvO2)/CaO2 or (SaO2 - SvO2)/ in inflammatory conditions (including sepsis), with an SaO2 (neglecting the dissolved oxygen) alteration in local control of vascular tone together with CI cardiac index, Hb hemoglobin concentration, SaO2 and SvO2 rolling and adhesion of white blood cells and other cirarterial and mixed venous oxygen saturations, respectively, C a culating cells to endothelial cells, leading to the shutconstant value representing the amount of oxygen bound to 1 g of down of some capillaries while others are overperfused Hb (usually 1.34 or 1.39) [1]. Box 1 The determinants of oxygen delivery (DO2), oxygen consumption (VO2) and oxygen extraction ratio (O2ER)
The concept of VO2/DO2 dependency Our understanding of the relationship between oxygen consumption (VO2) and DO2 in circulatory failure is largely based on the results of early animal studies [2–5]. From these studies, it became clear that VO2 is independent of DO2 over a wide range of values, because O2 extraction (O2ER, which is the ratio of VO2 over DO2) can readily adapt to changes in DO2. When DO2 is acutely reduced by a decrease in blood flow (cardiac output), anemia or hypoxemia, the O2ER increases and VO2 can, therefore, remain stable for a long time. It is only when DO2 decreases below a critically low value (DO2crit), that VO2 starts to decrease (Fig. 1). At this Fig. 1 Relationship between oxygen consumption (VO2) and point, anaerobic metabolism begins to take over from oxygen delivery (DO2) when DO2 is acutely reduced by tamponade or hemorrhage in anesthetized animals. Note that blood lactate aerobic metabolism and there is an abrupt increase in blood lactate concentrations. These experimental inveslevels increase as soon as DO2 falls below DO2crit tigations also led to another important finding: extraction capabilities are impaired after administration of endotoxin or live bacteria [2, 3] leading to a shift to the right of the point at which VO2 becomes dependent on DO2. Hence, VO2 becomes dependent on DO2 at higher values of DO2. These observations helped to characterize the 4 principal types of circulatory shock (Fig. 2).
Human applications
Fig. 2 The four types of shock represented on a VO2/DO2 diagram; shock is always characterized by a state of VO2/DO2 dependency
does not necessarily result in an increase in DO2, because the associated increase in blood viscosity tends to result in a decrease in cardiac output. The amount of oxygen available in the cell is also influenced by a number of peripheral factors related to the
This type of study, performed in anesthetized animals cannot be reproduced in humans, in whom an acute reduction in DO2 would, in most conditions, be unethical. However, Ronco and collaborators demonstrated the phenomenon in dying patients undergoing withdrawal of life sustaining treatment [6]. Early human studies also suggested that patients with acute respiratory distress syndrome (ARDS) may have O2 uptake/supply dependency [7–9]. However, these studies had methodological problems in that data were obtained and pooled from multiple patients. This approach is inappropriate, as a correlation between VO2 and DO2 may be purely
1645
physiological in the presence of changes in oxygen requirements due, for example, to degree of sedation, body temperature, breathing patterns. Subsequent investigations used various tests to explore VO2/DO2 dependency. The tested hypothesis was that patients with acute circulatory failure associated with increased blood lactate concentrations would show the VO2/DO2 dependency phenomenon when DO2 was acutely increased. Haupt et al. [10] showed that this occurred following fluid infusion, and Gilbert et al. [11] with blood transfusions. We thought short-term administration of dobutamine would be the easiest and also most reversible method to explore VO2/DO2 dependency [12]; doses of dobutamine were limited to 5 mcg/kg/min to avoid a thermogenic effect of the catecholamine. Indeed, adrenergic agents can increase VO2 by a thermogenic effect increasing cellular metabolism or simply by an increase in the myocardial work needed to increase the cardiac output, and an increase in the oxygen demand of some organs exposed to higher blood flows. This effect can induce physiological dependence of DO2 on VO2, mimicking VO2/DO2 dependence. This principle was used by Vallet et al. [13] and Rhodes et al. [14], who demonstrated that patients in whom VO2 increased following dobutamine at a dose of 10 mcg/kg/min had better outcomes than those in whom it did not. In this metabolic test, performed with higher doses of dobutamine than in our initial study [12], it is the ability of cells to respond to an exogenous stimulation and the cardiovascular response to this increased O2 demand that are evaluated. When tissues are ‘‘exhausted’’ or already maximally stimulated by the stress response, VO2 cannot increase further; this limitation concerns primarily the most severely ill patients, and thus the non-survivors. Low doses of dobutamine, however, have minimal impact on metabolism [15, 16]. In the flow test, as we described it initially, a limited dose of dobutamine (5 lg/kg/min) was used, causing an increase in blood flow but with minimal impact on tissue metabolism. In these conditions, the increase in VO2 primarily reflects the recruitment of previously underperfused areas in which metabolism was limited; this occurs in the sickest patients, with the worst outcomes. From the various studies, it was possible to conclude that VO2 increased when DO2 was increased with intravenous fluids or vasoactive agents in patients with high lactate concentrations but not in those with normal lactate concentrations [10–12, 17]. Using a prostacyclin infusion, Bihari et al. [18] also related the VO2/DO2 dependency phenomenon to survival, because it was observed primarily in the non-survivors in their study of 27 critically ill patients with acute respiratory failure. The limitations to this approach are that hyperlactatemia may not be due only to tissue hypoxia but also to other factors; for example, increased glycolysis, altered lactate clearance or abnormal pyruvate metabolism may
Fig. 3 Cardiac index/O2ER diagram during a short-term dobutamine infusion in patients with sepsis. The curved lines represent isopleths of different VO2 levels. VO2/DO2 dependency is demonstrated in patients with increased lactate levels (B data points cross the isopleths) and not in those with normal lactate levels (A data points move parallel to the isopleths) (data from [12])
contribute to the hyperlactatemia observed in septic states. Moreover, hyperlactatemia may reflect recent, more than ongoing, cellular alterations. Importantly, hyperlactatemia alone is, therefore, not sufficient to affirm the presence of VO2/DO2 dependency, but should complement the clinical signs of altered tissue perfusion. After all, the VO2/DO2 phenomenon is a hallmark of acute circulatory failure (shock) [19]. The most important criticism of these early studies was related to the potential methodological problems when assessing the VO2/DO2 relationship. Most studies evaluating the relationship between VO2 and DO2 calculated VO2 and DO2 from the same variables, i.e., cardiac output, hemoglobin concentrations and SaO2, resulting in potential mathematical coupling of data. Some therefore argued that VO2 should be estimated from analysis of expired gases using indirect calorimetry rather than ‘‘calculated’’ from blood gas analysis. To evaluate the potential role of mathematical coupling of data, we performed a dobutamine test and used expiratory gases to measure VO2 and pulmonary artery catheter data to calculate it [20]. After baseline measurements, dobutamine was increased by increments of 2 lg/kg/min up to 10 lg/kg/min. VO2 measured from the expiratory gases and VO2 calculated from hemodynamic data evolved in a similar fashion, and the slope of the VO2/DO2 relationship was similar with the two methods. So, where do we go from this study? This was a proof of concept study demonstrating that, in well-controlled conditions (we intentionally designed this study to have six time points, which minimized the potential interference of random errors in measurements), VO2 calculated from hemodynamic data can be used as a valuable alternative to VO2 computed from respiratory gases.
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Moreover, direct determination of VO2 may not be better than calculated values for several reasons. First, measuring VO2 using indirect calorimetry is quite complex, and indirect calorimetry has its own limitations and sources of error, especially when high inspired fractions of oxygen (FiO2) are required so that it is not feasible to use it in the most severely ill patients. Second, because indirect calorimetry is a cumbersome method, it takes time to prepare the equipment, so that, by the time the data are generated, the patient has already been resuscitated and the VO2/DO2 dependency phenomenon is not observed in stabilized patients. Another way to avoid mathematical coupling of data is to evaluate the relationship between CI and O2ER; indeed, similar observations were made when this was done (Fig. 3) [20]. The use of these variables also prevents the cumbersome VO2 and DO2 calculations, because cardiac index is a primary variable and O2ER can be very simply calculated (Box 1).
Clinical implications: supranormal DO2 versus the ‘‘titrated’’ approach
Fig. 4 Regional VO2/DO2 relationship in the splanchnic circulation in patients with severe sepsis (adapted from [26] with permission). DShO2 Gradient between mixed venous and hepatic venous oxygen saturation
surrogate for the respiratory quotient, could identify patients who would increase their VO2 during a fluid challenge [24].
The supranormal DO2 approach Based on observations that those who do well usually have higher DO2 values than those who develop complications, William Shoemaker and his colleagues suggested that supranormal DO2 values should be achieved and maintained in all patients at risk of complications to ensure sufficient oxygen availability to the cells [21]. The proposed strategy was to maintain DO2 above predetermined levels, usually above 600 mL/min/m2. Although this approach may have merit in some populations, increasing DO2 to supranormal values in all patients ‘‘at risk’’ is not warranted. Administering large quantities of fluid and adrenergic agents to patients who do not need these treatments may actually be harmful. This approach was based on an oversimplification of a complex phenomenon. When applied to a mixed group of critically ill patients, the strategy was shown to be ineffective [22], and even harmful when very high doses (up to 200 lg/kg/min!) of dobutamine were administered [23]. The titrated approach Like other investigators, we prefer a titrated, individualized approach, with the aim of identifying which patients may benefit from increased DO2 by careful clinical evaluation and additional tests, including cardiac index, SvO2, and blood lactate concentrations. Recently, Monnet et al. suggested that the ratio between veno-arterial differences in PCO2 and arterio-venous difference in O2, as a
The VO2/DO2 relationship 20 years later In addition to systemic alterations in the VO2/DO2 relationship, regional alterations can also occur. Animal experiments have nicely shown that alterations in critical oxygen extraction occur in various organs [25]. In septic patients, we have shown that hepatosplanchnic VO2/DO2 dependency can occur in patients with a widened gradient between mixed-venous and hepatic vein O2 saturations [26] (Fig. 4). These observations suggested that redistribution of flow between different vascular beds did not play a major role in VO2/DO2 dependency, but rather that alterations in tissue perfusion at the organ level could be the major contributor to this phenomenon. Alterations in microvascular perfusion are now considered the leading cause of alterations in oxygen extraction capabilities and in the right shift of critical DO2. Using a mathematical simulation, Walley [27] demonstrated that heterogeneity of perfusion led to a decrease in critical extraction and increase in critical DO2. Interestingly, this effect was more pronounced when capillaries were totally unperfused than when they were transiently perfused. The findings were confirmed in an accompanying experiment in pigs: sepsis was associated with an increase in gut perfusion heterogeneity which led to a decrease in oxygen extraction [28]. Regarding the consequences of VO2/DO2 dependency, whether this condition is always associated with tissue
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hypoxia has also been challenged. An alternative, or 1. Abnormal global VO2/DO2 dependency does NOT exist in stable, critically ill patients, even those with additional possibility, is that O2 conformance may occur. sepsis or ARDS. In experimental settings, an acute decrease in O2 is associated with a major decrease in non-essential cellular 2. VO2/DO2 dependency DOES exist in severe cases of circulatory shock, when blood flow is significantly reactions so that VO2 decreases and cells survive without reduced. developing hypoxia [29–31]. A final consideration relates to the decreased use of 3. Abnormal VO2/DO2 dependency MAY exist globally in patients with septic shock and regionally in patients the pulmonary artery catheter: could the central venous with severe sepsis. Unfortunately, global determinaO2 saturation (ScvO2) be used as a surrogate for SvO2? tions of DO2 and VO2 are not precise or sensitive Although ScvO2 cannot be used to precisely measure enough to guide therapy effectively and regional VO2, a recent study has suggested that changes in VO2 measurements cannot be obtained routinely in critican be assessed using ScvO2 [24]. cally ill patients. 4. Microcirculatory alterations are a key contributor to pathological VO2/DO2 dependency. 5. The study of the time course of blood lactate levels Conclusions may represent a surrogate for the evaluation of cellular oxygen deficit. The relationship between VO2 and DO2 remains an 6. In addition to tissue hypoxia, O2 conformance may important concept, even though application to guide also contribute to VO2/DO2 dependency. therapy may be too simplistic. Six key points can summarize our current understanding of the VO2/DO2 Conflicts of interest The authors declare they have no conflicts relationship in critically ill patients: of interest to declare related to this article.
References 6. Ronco JJ, Fenwick JC, Tweeddale MG, 1. De Backer D, Creteur J, Preiser JC, Wiggs BR, Phang PT, Cooper DJ, Dubois MJ, Vincent JL (2002) Cunningham KF, Russell JA, Walley Microvascular blood flow is altered in KR (1993) Identification of the critical patients with sepsis. Am J Respir Crit oxygen delivery for anaerobic Care Med 166:98–104 metabolism in critically ill septic and 2. Nelson DP, Samsel RW, Wood LD, nonseptic humans. JAMA Schumacker PT (1988) Pathological 270:1724–1730 supply dependence of systemic and 7. Powers SR Jr, Mannal R, Neclerio M, intestinal O2 uptake during English M, Marr C, Leather R, Ueda H, endotoxemia. J Appl Physiol Williams G, Custead W, Dutton R 64:2410–2419 (1973) Physiologic consequences of 3. Nelson DP, Beyer C, Samsel RW, positive end-expiratory pressure (PEEP) Wood LD, Schumacker PT (1987) ventilation. Ann Surg 178:265–272 Pathological supply dependence of O2 8. Mohsenifar Z, Goldbach P, Tashkin DP, uptake during bacteremia in dogs. Campisi DJ (1983) Relationship J Appl Physiol 63:1487–1492 between O2 delivery and O2 4. Cain SM (1977) Oxygen delivery and consumption in the adult respiratory uptake in dogs during anemic and distress syndrome. Chest 84:267–271 hypoxic hypoxia. J Appl Physiol Respir 9. Danek SJ, Lynch JP, Weg JG, Dantzker Environ Exerc Physiol 42:228–234 DR (1980) The dependence of oxygen 5. De Backer D, Zhang H, Vincent JL uptake on oxygen delivery in the adult (1995) Models to study the relation respiratory distress syndrome. Am Rev between oxygen consumption and Respir Dis 122:387–395 oxygen delivery during an acute reduction in blood flow: comparison of 10. Haupt MT, Gilbert EM, Carlson RW (1985) Fluid loading increases oxygen balloon filling in the inferior vena cava, consumption in septic patients with tamponade, and hemorrhage. Shock lactic acidosis. Am Rev Respir Dis 4:107–112 131:912–916
11. Gilbert EM, Haupt MT, Mandanas RY, Huaringa AJ, Carlson RW (1986) The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis 134:873–878 12. Vincent JL, Roman A, De Backer D, Kahn RJ (1990) Oxygen uptake/supply dependency. Effects of short-term dobutamine infusion. Am Rev Respir Dis 142:2–7 13. Vallet B, Chopin C, Curtis SE, Dupuis BA, Fourrier F, Mehdaoui H, LeRoy B, Rime A, Santre C, Herbecq P (1993) Prognostic value of the dobutamine test in patients with sepsis syndrome and normal lactate values: a prospective, multicenter study. Crit Care Med 21:1868–1875 14. Rhodes A, Lamb FJ, Malagon I, Newman PJ, Grounds RM, Bennett ED (1999) A prospective study of the use of a dobutamine stress test to identify outcome in patients with sepsis, severe sepsis, or septic shock. Crit Care Med 27:2361–2366
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15. De Backer D, Berre J, Zhang H, Kahn RJ, Vincent JL (1993) Relationship between oxygen uptake and oxygen delivery in septic patients: effects of prostacyclin versus dobutamine. Crit Care Med 21:1658–1664 16. De Backer D, Berre J, Moraine JJ, Melot C, Vanfraechem J, Vincent JL (1996) Effects of dobutamine on the relationship between oxygen consumption and delivery in healthy volunteers: comparison with sodium nitroprusside. Clin Sci (Lond) 90:105–111 17. Bakker J, Coffernils M, Leon M, Gris P, Vincent JL (1991) Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock. Chest 99:956–962 18. Bihari D, Smithies M, Gimson A, Tinker J (1987) The effects of vasodilation with prostacyclin on oxygen delivery and uptake in critically ill patients. N Engl J Med 317:397–403 19. Vincent JL, De Backer D (1995) Oxygen uptake/oxygen supply dependency: fact or fiction? Acta Anaesthesiol Scand Suppl 107:229–237 20. De Backer D, Moraine JJ, Berre J, Kahn RJ, Vincent JL (1994) Effects of dobutamine on oxygen consumption in septic patients. Direct versus indirect determinations. Am J Respir Crit Care Med 150:95–100
21. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS (1988) Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 94:1176–1186 22. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R (1995) A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 333:1025–1032 23. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D (1994) Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 330:1717–1722 24. Monnet X, Julien F, Ait-Hamou N, Lequoy M, Gosset C, Jozwiak M, Persichini R, Anguel N, Richard C, Teboul JL (2013) Lactate and venoarterial carbon dioxide difference/ arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders. Crit Care Med 41:1412–1420 25. Zhang H, Smail N, Cabral A, Cherkaoui S, Peny MO, Vincent JL (1999) Hepato-splanchnic blood flow and oxygen extraction capabilities during experimental tamponade: effects of endotoxin. J Surg Res 81:129–138
26. De Backer D, Creteur J, Noordally O, Smail N, Gulbis B, Vincent JL (1998) Does hepato-splanchnic VO2/DO2 dependency exist in critically ill septic patients? Am J Respir Crit Care Med 157:1219–1225 27. Walley KR (1996) Heterogeneity of oxygen delivery impairs oxygen extraction by peripheral tissues: theory. J Appl Physiol 81:885–894 28. Humer MF, Phang PT, Friesen BP, Allard MF, Goddard CM, Walley KR (1996) Heterogeneity of gut capillary transit times and impaired gut oxygen extraction in endotoxemic pigs. J Appl Physiol 81:895–904 29. Boutilier RG (2001) Mechanisms of cell survival in hypoxia and hypothermia. J Exp Biol 204:3171–3181 30. Schumacker PT, Chandel N, Agusti AG (1993) Oxygen conformance of cellular respiration in hepatocytes. Am J Physiol 265:L395–L402 31. Heerlein K, Schulze A, Hotz L, Bartsch P, Mairbaurl H (2005) Hypoxia decreases cellular ATP demand and inhibits mitochondrial respiration of a 549 cells. Am J Respir Cell Mol Biol 32:44–51
MY PAPER 20 YEARS LATER
Jean-Louis Vincent Daniel De Backer
My paper 20 years later: effects of dobutamine on the VO2/DO2 relationship
Received: 7 July 2014 Accepted: 26 August 2014 Published online: 30 September 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014
Abstract Introduction: Oxygen uptake (VO2) is independent of oxygen delivery (DO2) over a wide range of values, because O2 extraction can readily adapt to changes in DO2. However, VO2 can become DO2dependent in acute circulatory failure. Methods: Various methods of evaluating the presence of VO2/DO2 dependency were conducted, but criticized because of potential problems with mathematical coupling of data. Some 20 years ago, we proposed using a dobutamine test and showed similar relationships using direct and indirect measurements. Since these studies on the systemic VO2/DO2 relationship, investigators have also explored regional alterations.
J.-L. Vincent ()) D. De Backer Department of Intensive Care, Erasme Hospital, Universite´ libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium e-mail: [email protected] Tel.: ?32 2 555 3380
The concept of adequate oxygen delivery Most cellular activities require energy, which is primarily obtained from adenosine triphosphate (ATP) and other high-energy compounds. ATP is formed from the oxidation of glucose, and sufficient amounts of oxygen must, therefore, be present in the mitochondria to ensure adequate concentrations of ATP. Certain cellular processes are essential for cell survival, including membrane transport, growth, cell repair and maintenance processes. Other functions may also be performed, for example electrolyte or protein transport, contractility, motility, or various biosynthetic activities. In normal conditions, local metabolic requirements drive local, and subsequently systemic, flow. In circulatory failure, blood flow may become limited. If there is insufficient oxygen availability, oxygen consumption in the cells may decrease. The
Conclusion: The relationship between VO2 and DO2 remains an important concept. Abnormal global VO2/DO2 dependency does not exist in stable, critically ill patients, but can exist in circulatory shock of all etiologies. It can also occur regionally in septic patients, and microcirculatory alterations may contribute. Patient management should be titrated individually with careful assessment to identify those who will benefit from increased DO2. Keywords Oxygen uptake Oxygen delivery Oxygen extraction Microcirculation Lactate
first cellular processes that will be affected are facultative functions, leading to organ dysfunction. If oxygen concentrations decrease further, essential cellular functions will also be impaired, leading to irreversible cellular malfunction and death. Insuring adequate cellular oxygen delivery (DO2) is, therefore, a critical component of preserving organ function. DO2 is determined by cardiac index, the hemoglobin concentration and the hemoglobin saturation [and, therefore, arterial partial pressure of oxygen (PaO2)] (Box 1). Cardiac output is the most important determinant of DO2, because a decrease in hemoglobin concentration or arterial oxygen saturation (SaO2) can be compensated for by an increase in cardiac output, whereas the opposite is not true. Likewise, to increase DO2, SaO2 is normally close to 100 % and hemoglobin concentration cannot change acutely. Moreover, administration of a blood transfusion
1644
distribution of cardiac output to different organs, the regulation of the microcirculation by autonomic control of vascular tone and local microvascular responses, and DO2 = CI 9 Hb 9 SaO2 9 C 9 10 VO2 = CI 9 CaO2 - CvO2 9 10 or CI 9 Hb 9 (SaO2 - SvO2) the degree of affinity of the hemoglobin molecule for oxygen. The microcirculation can be altered substantially 9 C (neglecting the dissolved oxygen) O2ER = VO2/DO2 = (CaO2 - CvO2)/CaO2 or (SaO2 - SvO2)/ in inflammatory conditions (including sepsis), with an SaO2 (neglecting the dissolved oxygen) alteration in local control of vascular tone together with CI cardiac index, Hb hemoglobin concentration, SaO2 and SvO2 rolling and adhesion of white blood cells and other cirarterial and mixed venous oxygen saturations, respectively, C a culating cells to endothelial cells, leading to the shutconstant value representing the amount of oxygen bound to 1 g of down of some capillaries while others are overperfused Hb (usually 1.34 or 1.39) [1]. Box 1 The determinants of oxygen delivery (DO2), oxygen consumption (VO2) and oxygen extraction ratio (O2ER)
The concept of VO2/DO2 dependency Our understanding of the relationship between oxygen consumption (VO2) and DO2 in circulatory failure is largely based on the results of early animal studies [2–5]. From these studies, it became clear that VO2 is independent of DO2 over a wide range of values, because O2 extraction (O2ER, which is the ratio of VO2 over DO2) can readily adapt to changes in DO2. When DO2 is acutely reduced by a decrease in blood flow (cardiac output), anemia or hypoxemia, the O2ER increases and VO2 can, therefore, remain stable for a long time. It is only when DO2 decreases below a critically low value (DO2crit), that VO2 starts to decrease (Fig. 1). At this Fig. 1 Relationship between oxygen consumption (VO2) and point, anaerobic metabolism begins to take over from oxygen delivery (DO2) when DO2 is acutely reduced by tamponade or hemorrhage in anesthetized animals. Note that blood lactate aerobic metabolism and there is an abrupt increase in blood lactate concentrations. These experimental inveslevels increase as soon as DO2 falls below DO2crit tigations also led to another important finding: extraction capabilities are impaired after administration of endotoxin or live bacteria [2, 3] leading to a shift to the right of the point at which VO2 becomes dependent on DO2. Hence, VO2 becomes dependent on DO2 at higher values of DO2. These observations helped to characterize the 4 principal types of circulatory shock (Fig. 2).
Human applications
Fig. 2 The four types of shock represented on a VO2/DO2 diagram; shock is always characterized by a state of VO2/DO2 dependency
does not necessarily result in an increase in DO2, because the associated increase in blood viscosity tends to result in a decrease in cardiac output. The amount of oxygen available in the cell is also influenced by a number of peripheral factors related to the
This type of study, performed in anesthetized animals cannot be reproduced in humans, in whom an acute reduction in DO2 would, in most conditions, be unethical. However, Ronco and collaborators demonstrated the phenomenon in dying patients undergoing withdrawal of life sustaining treatment [6]. Early human studies also suggested that patients with acute respiratory distress syndrome (ARDS) may have O2 uptake/supply dependency [7–9]. However, these studies had methodological problems in that data were obtained and pooled from multiple patients. This approach is inappropriate, as a correlation between VO2 and DO2 may be purely
1645
physiological in the presence of changes in oxygen requirements due, for example, to degree of sedation, body temperature, breathing patterns. Subsequent investigations used various tests to explore VO2/DO2 dependency. The tested hypothesis was that patients with acute circulatory failure associated with increased blood lactate concentrations would show the VO2/DO2 dependency phenomenon when DO2 was acutely increased. Haupt et al. [10] showed that this occurred following fluid infusion, and Gilbert et al. [11] with blood transfusions. We thought short-term administration of dobutamine would be the easiest and also most reversible method to explore VO2/DO2 dependency [12]; doses of dobutamine were limited to 5 mcg/kg/min to avoid a thermogenic effect of the catecholamine. Indeed, adrenergic agents can increase VO2 by a thermogenic effect increasing cellular metabolism or simply by an increase in the myocardial work needed to increase the cardiac output, and an increase in the oxygen demand of some organs exposed to higher blood flows. This effect can induce physiological dependence of DO2 on VO2, mimicking VO2/DO2 dependence. This principle was used by Vallet et al. [13] and Rhodes et al. [14], who demonstrated that patients in whom VO2 increased following dobutamine at a dose of 10 mcg/kg/min had better outcomes than those in whom it did not. In this metabolic test, performed with higher doses of dobutamine than in our initial study [12], it is the ability of cells to respond to an exogenous stimulation and the cardiovascular response to this increased O2 demand that are evaluated. When tissues are ‘‘exhausted’’ or already maximally stimulated by the stress response, VO2 cannot increase further; this limitation concerns primarily the most severely ill patients, and thus the non-survivors. Low doses of dobutamine, however, have minimal impact on metabolism [15, 16]. In the flow test, as we described it initially, a limited dose of dobutamine (5 lg/kg/min) was used, causing an increase in blood flow but with minimal impact on tissue metabolism. In these conditions, the increase in VO2 primarily reflects the recruitment of previously underperfused areas in which metabolism was limited; this occurs in the sickest patients, with the worst outcomes. From the various studies, it was possible to conclude that VO2 increased when DO2 was increased with intravenous fluids or vasoactive agents in patients with high lactate concentrations but not in those with normal lactate concentrations [10–12, 17]. Using a prostacyclin infusion, Bihari et al. [18] also related the VO2/DO2 dependency phenomenon to survival, because it was observed primarily in the non-survivors in their study of 27 critically ill patients with acute respiratory failure. The limitations to this approach are that hyperlactatemia may not be due only to tissue hypoxia but also to other factors; for example, increased glycolysis, altered lactate clearance or abnormal pyruvate metabolism may
Fig. 3 Cardiac index/O2ER diagram during a short-term dobutamine infusion in patients with sepsis. The curved lines represent isopleths of different VO2 levels. VO2/DO2 dependency is demonstrated in patients with increased lactate levels (B data points cross the isopleths) and not in those with normal lactate levels (A data points move parallel to the isopleths) (data from [12])
contribute to the hyperlactatemia observed in septic states. Moreover, hyperlactatemia may reflect recent, more than ongoing, cellular alterations. Importantly, hyperlactatemia alone is, therefore, not sufficient to affirm the presence of VO2/DO2 dependency, but should complement the clinical signs of altered tissue perfusion. After all, the VO2/DO2 phenomenon is a hallmark of acute circulatory failure (shock) [19]. The most important criticism of these early studies was related to the potential methodological problems when assessing the VO2/DO2 relationship. Most studies evaluating the relationship between VO2 and DO2 calculated VO2 and DO2 from the same variables, i.e., cardiac output, hemoglobin concentrations and SaO2, resulting in potential mathematical coupling of data. Some therefore argued that VO2 should be estimated from analysis of expired gases using indirect calorimetry rather than ‘‘calculated’’ from blood gas analysis. To evaluate the potential role of mathematical coupling of data, we performed a dobutamine test and used expiratory gases to measure VO2 and pulmonary artery catheter data to calculate it [20]. After baseline measurements, dobutamine was increased by increments of 2 lg/kg/min up to 10 lg/kg/min. VO2 measured from the expiratory gases and VO2 calculated from hemodynamic data evolved in a similar fashion, and the slope of the VO2/DO2 relationship was similar with the two methods. So, where do we go from this study? This was a proof of concept study demonstrating that, in well-controlled conditions (we intentionally designed this study to have six time points, which minimized the potential interference of random errors in measurements), VO2 calculated from hemodynamic data can be used as a valuable alternative to VO2 computed from respiratory gases.
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Moreover, direct determination of VO2 may not be better than calculated values for several reasons. First, measuring VO2 using indirect calorimetry is quite complex, and indirect calorimetry has its own limitations and sources of error, especially when high inspired fractions of oxygen (FiO2) are required so that it is not feasible to use it in the most severely ill patients. Second, because indirect calorimetry is a cumbersome method, it takes time to prepare the equipment, so that, by the time the data are generated, the patient has already been resuscitated and the VO2/DO2 dependency phenomenon is not observed in stabilized patients. Another way to avoid mathematical coupling of data is to evaluate the relationship between CI and O2ER; indeed, similar observations were made when this was done (Fig. 3) [20]. The use of these variables also prevents the cumbersome VO2 and DO2 calculations, because cardiac index is a primary variable and O2ER can be very simply calculated (Box 1).
Clinical implications: supranormal DO2 versus the ‘‘titrated’’ approach
Fig. 4 Regional VO2/DO2 relationship in the splanchnic circulation in patients with severe sepsis (adapted from [26] with permission). DShO2 Gradient between mixed venous and hepatic venous oxygen saturation
surrogate for the respiratory quotient, could identify patients who would increase their VO2 during a fluid challenge [24].
The supranormal DO2 approach Based on observations that those who do well usually have higher DO2 values than those who develop complications, William Shoemaker and his colleagues suggested that supranormal DO2 values should be achieved and maintained in all patients at risk of complications to ensure sufficient oxygen availability to the cells [21]. The proposed strategy was to maintain DO2 above predetermined levels, usually above 600 mL/min/m2. Although this approach may have merit in some populations, increasing DO2 to supranormal values in all patients ‘‘at risk’’ is not warranted. Administering large quantities of fluid and adrenergic agents to patients who do not need these treatments may actually be harmful. This approach was based on an oversimplification of a complex phenomenon. When applied to a mixed group of critically ill patients, the strategy was shown to be ineffective [22], and even harmful when very high doses (up to 200 lg/kg/min!) of dobutamine were administered [23]. The titrated approach Like other investigators, we prefer a titrated, individualized approach, with the aim of identifying which patients may benefit from increased DO2 by careful clinical evaluation and additional tests, including cardiac index, SvO2, and blood lactate concentrations. Recently, Monnet et al. suggested that the ratio between veno-arterial differences in PCO2 and arterio-venous difference in O2, as a
The VO2/DO2 relationship 20 years later In addition to systemic alterations in the VO2/DO2 relationship, regional alterations can also occur. Animal experiments have nicely shown that alterations in critical oxygen extraction occur in various organs [25]. In septic patients, we have shown that hepatosplanchnic VO2/DO2 dependency can occur in patients with a widened gradient between mixed-venous and hepatic vein O2 saturations [26] (Fig. 4). These observations suggested that redistribution of flow between different vascular beds did not play a major role in VO2/DO2 dependency, but rather that alterations in tissue perfusion at the organ level could be the major contributor to this phenomenon. Alterations in microvascular perfusion are now considered the leading cause of alterations in oxygen extraction capabilities and in the right shift of critical DO2. Using a mathematical simulation, Walley [27] demonstrated that heterogeneity of perfusion led to a decrease in critical extraction and increase in critical DO2. Interestingly, this effect was more pronounced when capillaries were totally unperfused than when they were transiently perfused. The findings were confirmed in an accompanying experiment in pigs: sepsis was associated with an increase in gut perfusion heterogeneity which led to a decrease in oxygen extraction [28]. Regarding the consequences of VO2/DO2 dependency, whether this condition is always associated with tissue
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hypoxia has also been challenged. An alternative, or 1. Abnormal global VO2/DO2 dependency does NOT exist in stable, critically ill patients, even those with additional possibility, is that O2 conformance may occur. sepsis or ARDS. In experimental settings, an acute decrease in O2 is associated with a major decrease in non-essential cellular 2. VO2/DO2 dependency DOES exist in severe cases of circulatory shock, when blood flow is significantly reactions so that VO2 decreases and cells survive without reduced. developing hypoxia [29–31]. A final consideration relates to the decreased use of 3. Abnormal VO2/DO2 dependency MAY exist globally in patients with septic shock and regionally in patients the pulmonary artery catheter: could the central venous with severe sepsis. Unfortunately, global determinaO2 saturation (ScvO2) be used as a surrogate for SvO2? tions of DO2 and VO2 are not precise or sensitive Although ScvO2 cannot be used to precisely measure enough to guide therapy effectively and regional VO2, a recent study has suggested that changes in VO2 measurements cannot be obtained routinely in critican be assessed using ScvO2 [24]. cally ill patients. 4. Microcirculatory alterations are a key contributor to pathological VO2/DO2 dependency. 5. The study of the time course of blood lactate levels Conclusions may represent a surrogate for the evaluation of cellular oxygen deficit. The relationship between VO2 and DO2 remains an 6. In addition to tissue hypoxia, O2 conformance may important concept, even though application to guide also contribute to VO2/DO2 dependency. therapy may be too simplistic. Six key points can summarize our current understanding of the VO2/DO2 Conflicts of interest The authors declare they have no conflicts relationship in critically ill patients: of interest to declare related to this article.
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