Otherwise stated, is the expression ^oVO₂/ⁿVO₂ = 1 true? Three levels of complexity may be defined.

First, clinical improvement is a good indicator of adequate resuscitation 7. In practice, the ⁿVO₂ is usually met by decreasing metabolic requirement, optimizing the haematocrit and arterial haemoglobin oxygen saturation, and increasing blood flow empirically until the clinical status improves. This situation does not require invasive haemodynamic investigation.

Second, a clear improvement in blood lactate clearance is also a good and minimally invasive indicator of adequate resuscitation 7. The blood lactate concentration alone fails to discriminate between dysoxia and aerobiosis 8. Although more reliable, the time course of lactate levels is not an ideal marker 279. The limitations of lactate were recently reviewed 8. Diabetes mellitus, liver dysfunction, tissue reperfusion, catecholamine infusion, cellular metabolic alterations and inhibition of pyruvate dehydrogenase can all result in a marked increase in blood lactate concentrations, despite improvement in tissue dysoxia.

Finally, in more complex situations in which clear clinical improvement and normalization in blood lactate are not observed, evaluation of oxygenation is required, followed by an evaluation of ^oVO₂ and ⁿVO₂. The ^oVO₂ can be measured at the bedside using expired gases 10 or it may be calculated from the product of CO and the arteriovenous difference in blood oxygen content. Demonstrating that ^oVO₂/ⁿVO₂ = 1 requires one to evaluate ⁿVO₂ concomitantly. When ^oVO₂ is evaluated alone, this provides no information of prognostic interest 2.

Needs can initially be estimated as the sum of VO₂ at basal metabolism, as indicated by age-specific and sex-specific normative data, and the additional VO₂ that results from other metabolic requirements. The latter can be approximated based on a number of factors, such as body temperature (ⁿVO₂ changes by ± 13% for each 1°C above or below 37°C). Pathologic situations such as respiratory failure and severe sepsis also increase metabolic needs. Based on metabolic conditions, ⁿVO₂ can vary from 0.7-fold to 3-fold the basal metabolism.

Needs can also be estimated by using the specific VO₂/DO₂ relationship (Figure 1). A biphasic relationship between oxygen use and resources has been established 6. When DO₂ is greater than a threshold value, VO₂ remains stable (oxygen supply independency) because the EO₂ changes proportionally. When DO₂ falls below this threshold, a proportionate increase in EO₂ cannot be maintained and the VO₂ drops linearly to zero (oxygen supply dependency). There is consensus that the inflection point between the two slopes indicates the critical level of DO₂ (Figure 1). Oxygen supply dependency is associated with increased blood lactate concentration, denoting possible activation of the anaerobic pathway.

Assessment of the VO₂/DO₂ relationship is a theoretical means to evaluate the gap between actual VO₂ and ⁿVO₂. When DO₂ increases, an increase in VO₂ suggests that oxygen supply is inadequate. In contrast, a stable VO₂ value when DO₂ increases suggests either that VO₂ matches needs when it is associated with decreasing lactate levels 1112 or that VO₂ is limited by mechanisms other than oxygen supply when it is associated with increasing lactate levels 1314.

In pathophysiology, two mechanisms delay achievement of the VO₂ plateau and account for a rightward shift in the critical DO₂ point (Figure 1). When VO₂ needs are excessive (uncoupling and/or increased metabolic activity), the VO₂ plateau is reached at a higher level of VO₂ 1516. When oxygen tissue diffusion is impaired (impaired microcirculation and/or impaired oxygen mitochondrial use), the slope of the dependant part of the VO₂/DO₂ relationship is decreased 1718.

Three other mechanisms result in an increase in VO₂ as DO₂ increases beyond the critical point, so that a slight upward slope – usually of less than 5% – replaces the expected VO₂ plateau. Although more difficult, identification of the critical DO₂ inflection point remains possible when these mechanisms are operative because the slope of the VO₂/DO₂ dependency segment ranges from 20% to 50% 19. The first mechanism occurs during a DO₂ challenge involving an increase in CO, because the VO₂ needs of kidneys 20, stomach 21 and muscle 22 increase in direct proportion to flow. Furthermore, infusion of inotropic agents increases myocardial oxygen consumption 111219. Another mechanism is additional oxygen uptake due to non-mitochondrial oxidase systems when dysoxia has resolved 23. The final mechanism, termed conformance, is a decrease in the metabolic needs of cells that occurs in response to a gradual decline in available oxygen. Although secondary to a chronic change, this phenomenon has been observed in acute situations 24. Schumacker and coworkers 25 reported that a VO₂ increase occurred in unshocked patients after aortic stenosis valvuloplasty.

A controversy arose during the late 1980s from several studies on acute respiratory distress syndrome and/or sepsis, in which the expected VO₂ plateau was not observed in patients who were recovering from shock and had high DO₂ values 2627. This was interpreted as evidence of 'pathologic oxygen supply dependency', possibly related to hidden oxygen deficit and contributing to multiorgan failure and death. However, increasing DO₂ to supranormal values was beneficial in some studies 2829 but not in others 3031. Furthermore, it has been suggested this so-called 'pathologic supply dependency' may result from spurious up-sloping of the VO₂/DO₂ relationship due to mathematical coupling of measurement errors when using a pulmonary artery catheter (PAC), because in some studies simultaneous independent VO₂ assessment revealed a plateau 5632. In addition, VO₂ and DO₂ assessment are limited by theoretical and practical concerns 56. However, these limitations were recently reviewed 4. Use of the most recent generation of devices for continuous CO monitoring and blood gas analysis minimizes the variability in measurement. It has been proposed that the relevance of the VO₂/DO₂ relationship could be increased by combined analysis of the VO₂/time relationship (Figure 2) 4. Thus, although difficult, acceptable identification of the VO₂ plateau, and of the ⁿVO₂, is possible when necessary.

Finally, it may be concluded that ^oVO₂ = ⁿVO₂ when one or several of the following factors is present: clinical improvement, decrease in blood lactate concentration, and ^oVO₂ inside the expected range and/or inflexion point in the ^oVO₂/DO₂ curve. The two methods can be combined. When the ^oVO₂ plateau is reached at a value close to the estimated needs, the patient's real needs are probably met. Handling the large amount of information required to assess oxygen needs can be difficult 3334, and computer assistance may be helpful 23536.

Some investigators have recommended that DO₂ be increased to supranormal values, greater than the usual critical level, without paying much attention to VO₂. This simplification of the method based on the VO₂/DO₂ relationship was associated with favourable outcomes in homogeneous populations of patients undergoing high-risk surgery 3738, with cardiogenic shock following myocardial infarction 39 and with acute respiratory failure 1540. However, those studies failed to demonstrate any beneficial effects after the onset of organ failure 38 or when different aetiologies of shock were pooled together 1540.

Other studies suggest that sequential DO₂ and VO₂ calculations can be advantageously replaced by continuous measurement of CO 41, SvO₂ 42, or central venous oxygen saturation 43. The use of these variables avoids compounding of measurement errors and allows for continuous comparison between measured values and targeted values.

However, targeting a pre-established value for DO₂, CO, or SvO₂ does not prove that these values meet the needs of an individual patient 16. These pre-established targets are derived from normal findings or from survivors in selected populations of patients 4445. Determination of the needed value of one given variable must take into consideration the limitation in other variables that are specific to the patient, his past history, the actual pathologic event, the delay before onset of shock and often recent therapeutic interventions (Figure 3). Intuitive evaluation of the needed value of each variable in each specific case requires considerable expertise. Misinterpretation of information derived from PAC placement and heterogeneity in the medical decision process is frequent 3031. Even for experts, intuitive evaluation of needs may be subject to errors 16. In some conditions, such as coronary disease, efforts to increase CO in order to 'normalize' the cardiac index to more than 2.5 l/min per m² or the SvO₂ value to more than 70% can be harmful (see examples given below). In addition, there is some evidence that an excessive oxygen supply may be deleterious, either via the useless metabolic cost of an excessive increase in DO₂ or via activation of nonoxidative systems. Failure to consider these latter two mechanisms may also account for the poor results obtained in controlled studies targeting nonspecific 'supranormal' values of DO₂ 3031. Thus, treatment efforts should be limited to what is necessary – no less and no more.

All haemodynamic variables are interrelated, and ensuring that VO₂ meets needs is the best tool to ensure that global haemodynamic status is adequate. VO₂, whether calculated by spirometry, indirect calorimetry, or using a PAC, is similar to the plateau of VO₂ in the VO₂/DO₂ relationship. No other relationship between two variables allows a clear identification of a plateau or a clear inflection point between anaerobiosis and aerobiosis. The shape of the CO/SvO₂ relationship or the CO/EO₂ relationship is bi-curvilinear and similar to the DO₂/EO₂ relationship shown in Figure 1. A clear inflexion point between aerobiosis and anaerobiosis is much more difficult to identify than the VO₂/DO₂.

Patient 1, receiving sedative drugs and mechanical ventilation, was admitted to an ICU immediately after an aortic valve replacement. He was hypothermic, with marbled and cold extremities. Haemodynamic variables are listed in Table 1. In this patient, cold extremities may be due to hypothermia, and the supranormal serum lactate may result from postoperative washout. Therefore, clinical evaluation including lactate level is not relevant in evaluating macrocirculatory performance relative to metabolic needs. Other means to explore the balance between VO₂ and needs are conflicting. The SvO₂ (65%) was below the expected value and may be considered a marker of unacceptably low CO and oxygen flow 4546. In contrast the calculated ^oVO₂ (88 ml/min per m²) is close to expected ⁿVO₂ (90 ml/min per m²) when assessed using the basal VO₂ value for this 82-year-old man (119 ml/min per m², as indicated by age-specific and sex-specific normative data), corrected according to the low body temperature. It would be difficult to exploit the VO₂/DO₂ relationship. No VO₂ plateau is expected in the early postoperative period because of increasing metabolic needs.

The clinician on duty disregards the SvO₂ threshold and concluded that the haemodynamic status was adequate to the patient's needs and no specific treatment was given. Two hours later (Table 1), a decrease in lactate serum value, normalization in SvO₂ and a calculated ^oVO₂ = basal VO₂ demonstrate that metabolic needs were probably covered.

In this case, a rough interpretation of SvO₂ below 70% as an indicator of insufficient CO as compared with needs would have led to an unjustified increase in CO. An SvO₂ below 70% can be normal in elderly patients, especially if haemoglobin level is low, as is frequently observed postoperatively.

Patient 2, requiring sedation and mechanical ventilation, was admitted to an ICU with a history of sudden shock and hyperkinetic state (Table 1). Was VO₂ adequate to needs? There is agreement between the clinical signs of shock with elevated lactate level and a calculated ^oVO₂ below the needed value (216 ml/min per m²) according to basal VO₂ fora 24-year-old man (152 ml/min per m²) corrected for the high temperature. In contrast, the SvO₂ value, higher than normal values, suggests that CO and oxygen flow are adequate.

Once again, the clinician on duty disregards the SvO₂ threshold and concluded that the haemodynamic status was inadequate for the patient's needs. A resuscitation regimen combining cooling, fluid optimization, and dobutamine and noradrenaline (norepinephrine) was instituted in addition to antibiotics. CO increased, SvO₂ remained stable (Table 1) and calculated ^oVO₂ increased over its needed value, whereas lactate serum decreased, suggesting that metabolic needs were covered.

In this case, an interpretation of the SvO₂ above 70% as an indicator that the hyperkinetic state was adequate to needs would have led to insufficient resuscitation. SvO₂ can be above 70% in pathological states, for instance involving severe impairment in tissue oxygen diffusion.

Shock responds better to haemodynamic resuscitation in the early stages 43. Although the final objective is to provide sufficient oxygen to each cell, there is some evidence that rapidly achieving a sufficient total body VO₂ is a prerequisite. Late-stage shock is a far more complex situation that involves not only the macrocirculation and microcirculation but also cell metabolism and the consequences of cell necrosis, which cannot be corrected by haemodynamic resuscitation alone.

In most situations, targeting a clinical improvement, a decrease in lactate level, or a pre-established value for CO or SvO₂, or both, is an acceptable and intuitive means of achieving adequate VO₂. In complex situations, by plotting VO₂/DO₂ over time during a DO₂ challenge, the critical DO₂ value can be evaluated rapidly by identifying the inflection point on the curve, and resuscitation efforts can then be limited to what is necessary. Because the critical DO₂ value can be determined visually with a 95% confidence interval of 20%, it is reasonable to limit DO₂ to its observed critical value +20%. When lactate remains high despite evidence that a VO₂ plateau has been reached, increasing DO₂ further does not seem to add benefit 1314. Continuous efforts to decrease oxygen demand and to improve the microcirculation may be more appropriate 47. Combined analysis of the VO₂/DO₂ and VO₂/time relationships provides the most useful approach, because the effects of mathematical coupling of errors and the theoretical limitations resulting from DO₂ variability in the regression line derivations are minimized. A mild up-sloping of the VO₂ plateau (slope <10%) should not be confused with oxygen dependency. When necessary, the critical DO₂ point can be determined more accurately using the method developed by John-Alder and coworkers 48.

Hyperthermia, acute respiratory failure and/or pain all increase VO₂ needs sharply. In contrast, cooling, sedation and mechanical ventilation often produce a 50% decrease in VO₂ needs. The latter has exactly the same favourable effect as doubling the CO or doubling the EO₂. Improving EO₂ must be always considered, although this rarely produces a rapid increase in VO₂. Treating infection, excessive sedation, or excessive water retention, for example, may increase EO₂ 43. When the only possibility is to increase DO₂, clinicians must choose among various agents that presumably differ in their caloric effects. Arterial vasodilatation improves DO₂ and decreases myocardial oxygen requirements. In contrast, inotropic agents and vasoconstrictors have major caloric effects. Whatever the method used, a metabolic price must be paid for improving VO₂ and DO₂ up to critical values. This metabolic price (a part of VO₂ needs) must also be limited to what is strictly necessary.