Οptimisatiοn de l'οxygénatiοn tissulaire par l'apprοche métabοlique dans les états d

Keywords: Tissue hypoxia, oxygen delivery, oxygen consumption, oxygen extraction, tissue oxygenation, acute circulatory failure, septic shock, veinous oxygen saturation, veinous- quotient, postoperative complications, microcirculation monitoring

insuffisances circulatoires aiguës

Abstract (English)

Acute circulatory failure is associated with an inadequacy between arterial oxygen delivery (DO2) and oxygen consumption (VO2) that, if left untreated, leads to tissue hypoxia and, ultimately, multi-organ failure. Tissue oxygenation is adequate when tissue oxygen demand is met. When DO2 is severely compromised, a critical DO2 level is reached, below which VO2 falls and becomes dependent on DO2, leading to tissue hypoxia. The different mechanisms of tissue hypoxia are circulatory, anemic, and hypoxic, characterized by reduced DO2 but with a preserved capacity to increase oxygen extraction. Cytopathic hypoxia is another tissue hypoxia mechanism caused by impairment of mitochondrial respiration and can be observed in septic conditions with normal overall DO2. Rapid detection of tissue hypoperfusion and tissue hypoxia is crucial for early management to increase the likelihood of survival. Also, monitoring the effectiveness of treatments is essential to ensure the appropriateness of the management. Different parameters and tools were proposed for this purpose. This review describes the advantages and limitations of these tools with a focus on the carbon dioxide (CO2) and oxygen-derived variables approach (metabolic approach) to detect and monitor the treatments of tissue hypoperfusion/tissue hypoxia in patients with acute circulatory failure.

REMERCIEMENTS

Pour évaluer cette adéquation entre DO2 et VO2, l'examen clinique a encore une valeur limitée.

La diurèse peut refléter la perfusion rénale, mais de nombreux autres facteurs peuvent l'altérer au cours des états de choc. De plus, la présence d'une insuffisance rénale antérieure modifie l'interprétation et le diagnostic de la nécrose tubulaire aiguë. Les signes d'hypoperfusion cutanée comme les marbrures ont été corrélées à une diminution de l'oxygénation tissulaire et à une mortalité augmentée chez les patients en état de choc septique. Cependant, la présence des marbrures n'est pas constante chez les patients en insuffisance circulatoire aiguë, puisque seulement la moitié des patients en choc septique présentent des marbrures. Un temps de recoloration élevé, suggérant une diminution de perfusion tissulaire, a été associé, chez les patients en insuffisance circulatoire aiguë, a une mortalité plus élevée que chez les patients avec un temps de recoloration normal. Néanmoins, seulement 30% des patients en état de choc septique avaient un temps de recoloration élevé. Un taux de lactate sanguin élevé est souvent reconnu comme un marqueur d'activation de métabolisme anaérobique (dépendance VO2/DO2) et donc d'hypoxie tissulaire. Cependant, le lactate sanguin peut augmenter en raison de nombreux mécanismes non liés à l'oxygénation tissulaire, ce qui conduit à de faux positifs. De plus, la concentration de lactate dans le sang dépend de l'équilibre entre la production et la clairance du lactate, de sorte que le retard requis par son métabolisme empêche l'utilisation du lactate en tant que marqueur en temps réel du métabolisme tissulaire. Ainsi, étant donné le caractère non spécifique de l'élévation du taux de lactate, l'hyperlactatémie n'est pas un facteur discriminant dans l'établissement de la cause de l'insuffisance circulatoire. Récemment, il a été démontré qu'une stratégie de réanimation visant à normaliser le temps de recoloration cutané était associée à une réduction de dysfonction d'organe qu'une approche visant à normaliser ou à diminuer le taux de lactate chez les patients en choc septique.

Introduction

A shock is a form of acute circulatory failure which is associated with an imbalance between arterial oxygen transport (DO2) and oxygen consumption (VO2), resulting in tissue hypoxia [START_REF] Cecconi | Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine[END_REF].

Early recognition and adequate resuscitation of tissue hypoperfusion are of particular importance in the management of shock to prevent the development of tissue hypoxia and progression to multi-organ failure.

In patients with acute circulatory failure, one of the goals of treatment is to increase cardiac output. This aims to improve the oxygen supply to the tissues and correct the imbalance between oxygen demand and supply [START_REF] Vincent | Oxygen transport-the oxygen delivery controversy[END_REF]. However, no absolute values of cardiac output or DO2 can be defined since their adequate values depend essentially on the oxygen requirements of the tissue.

The correct value of cardiac output is that which ensures an oxygen flow that meets the metabolic demand. Thus, any treatment aimed at modifying cardiac output, such as fluid replacement or inotropes, must be determined by assessing the adequacy between oxygen demand and supply.

The clinical examination still has a limited value in assessing the adequacy between DO2 and VO2.

Urine output may reflect renal perfusion, but many other factors may alter its value in shock states. In addition, it depends on the presence or absence of previous renal failure, and it can no longer be used as an indicator of renal perfusion in acute tubular necrosis [START_REF] Legrand | Understanding urine output in critically ill patients[END_REF]. Different tools exist to detect and monitor tissue hypoperfusion or tissue hypoxia. However, most of them require specific devices and are used for research purposes. The metabolic approach is based on carbon dioxide (CO2), and oxygen (O2) derived variables such as venous to arterial partial pressure in CO2 (PCO2) difference (PCO2) [START_REF] Zhang | Arteriovenous differences in PCO2 and pH are good indicators of critical hypoperfusion[END_REF] and PCO2 over the difference between arterial and venous O2 content (PCO2/O2) ratio [START_REF] Mekontso-Dessap | Combination of venoarterial PCO2 difference with arteriovenous O2 content difference to detect anaerobic metabolism in patients[END_REF] have been proposed to assess the adequacy between oxygen intake and requirements and to guide the hemodynamic management in acute circulatory failure patients [START_REF] Mallat | Use of venous-to-arterial carbon dioxide tension difference to guide resuscitation therapy in septic shock[END_REF].

In this work, the first section reviewed the concept of DO2, the relationship between VO2 and DO2, the mechanisms of tissue oxygen alterations, and different therapeutic approaches. The second section described the various tools of tissue perfusion/oxygenation monitoring and their limitations. The third section presented the metabolic approach for tissue oxygenation monitoring in patients with acute circulatory failure. Finally, the last section reviewed the different perspectives of the metabolic approach and its limitations.

First Part

Pathophysiology of altered tissue oxygenation

I. Background

Vital cellular activities, including deoxyribonucleic acid (DNA) and protein synthesis, need energy, which is mainly derived from the breakdown of adenosine triphosphate (ATP) [START_REF] Astiz | Early impairment of oxidative metabolism and energy production in severe sepsis[END_REF]. Aerobic ATP production happens in the mitochondria through oxidative phosphorylation, which is generated by the electron transport chain, in which the final electron acceptor is oxygen [START_REF] Bertram | A simplified model for mitochondrial ATP production[END_REF]. Therefore, a constant oxygen supply is required to support vital cell functions. DO2 is the total amount of oxygen delivered to the tissues per minute. In the below manuscript [START_REF] Mallat | Pathophysiology, mechanisms, and managements of tissue hypoxia[END_REF], we reviewed the concept of oxygen delivery, the relationship between oxygen consumption and delivery, tissue oxygen alterations' mechanisms, and different therapeutic approaches.

Second Part

Limitations of tissue oxygenation monitoring

I. Background

Resuscitation goals in shocked patients traditionally aim to normalize the systemic hemodynamic variables and oxygenation (macrocirculation). While this approach is necessary, it might not result in a parallel improvement of the microcirculation perfusion and restoration of tissue oxygenation. Indeed, in conditions with damaged microcirculation, tissue hypoperfusion can persist despite correcting the systemic hemodynamic variables by fluid resuscitation and vasopressor drugs leading to tissue hypoxia and death. This situation is defined as a loss of hemodynamic coherence. Many studies reported situations of a loss of hemodynamic coherence where the perfusion of the microcirculation and tissue oxygenation did not improve after the normalization of systemic circulation variables [START_REF] Backer | Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome[END_REF][START_REF] Edul | Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock[END_REF][START_REF] Trzeciak | Early increases in microcirculatory perfusion during protocoldirected resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis[END_REF][START_REF] Tachon | Microcirculatory alterations in traumatic hemorrhagic shock[END_REF][START_REF] Lima | The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients[END_REF].

Resuscitation targeting microcirculatory and tissue oxygenation variables is needed to restore the hemodynamic coherence and improve the organs' function. However, this requires the use of different specific technologies to be able to monitor tissue perfusion and oxygenation. This section will discuss the different methods used for this purpose with their advantages and limitations.

Near-Infrared Spectroscopy

Near-Infrared Spectroscopy (NIRS) is a system consisting of a light source, optodes for light emission and reception, a processor, and a display system. NIRS technology used near-infrared light (700-900 nanometers wavelengths) to measure chromophores (hemoglobin, myoglobin, and cytochrome aa3) present in the sampled tissue. By choosing specific lengths, the impact of myoglobin and cytochrome is minimized. Thus, NIRS measures the concentrations of oxyhemoglobin and deoxyhemoglobin based on light attenuation using a predefined algorithm. Tissue oxygen saturation (StO2) is calculated from the fractions of oxyhemoglobin and deoxyhemoglobin and displayed on the NIRS screen device [START_REF] Myers | Noninvasive method for measuring local hemoglobin oxygen saturation in tissue using wide gap second derivative near-infrared spectroscopy[END_REF]. By the Beer-Lambert law, the NIRS signal is limited to vessels with a diameter < 1 mm (arterioles, capillaries, and venules).

Skeletal muscle StO2 is assumed to be a potential early sensor for occult hypoperfusion. The thenar eminence is the primary area where StO2 is measured, as this site is less affected by subcutaneous fat thinness and edema [START_REF] Myers | Noninvasive method for measuring local hemoglobin oxygen saturation in tissue using wide gap second derivative near-infrared spectroscopy[END_REF]. In normal conditions, around 75% of blood in skeletal muscle is venous; therefore, the NIRS StO2 value reflects mainly the venous oxygen saturation rather than that of the tissue. StO2 represents the balance between local oxygen supply and consumption, and therefore, changes in StO2 may be related to a change in microcirculatory perfusion and/or variation in regional oxygen consumption [START_REF] Mesquida | Skeletal muscle oxygen saturation (StO2) measured by near-infrared spectroscopy in the critically ill patients[END_REF].

StO2 values were lower in septic patients compared to healthy subjects. However, considerable overlap was observed between the two populations [START_REF] Creteur | The prognostic value of muscle StO2 in septic patients[END_REF][START_REF] Mulier | Nearinfrared spectroscopy in patients with severe sepsis: correlation with invasive hemodynamic measurements[END_REF]. These findings may be explained by the heterogeneity of microcirculatory perfusion resulting in the co-occurrence of ischemic and well perfused/highly oxygenated areas (microcirculatory shunting). However, some authors reported that persistent low StO2 values after initial fluid resuscitation were associated with increased mortality [START_REF] Lima | Low tissue oxygen saturation at the end of early goal-directed therapy is associated with worse outcome in critically ill patients[END_REF][START_REF] Leone | Oxygen tissue saturation is lower in nonsurvivors than in survivors after early resuscitation of septic shock[END_REF]. More utility can be derived from the analysis of changes in StO2 during a dynamic vascular occlusion test (VOT) that consists of applying an arterial occlusion proximal to the NIRS probe until a pre-defined ischemic point is achieved, and then after the occlusion is removed. An initial de-oxygenation slope (DeO2) is observed following ischemia and has been suggested as an indicator of regional oxygen extraction. A re-oxygenation slope (ReO2) is observed after the occlusion is unleashed, which has been suggested to reflect the endothelial function as it depends on regional blood flow and capillary recruitment after the hypoxic stimulus [START_REF] Gómez | Characterization of tissue oxygen saturation and the vascular occlusion test: influence of measurement sites, probe sizes and deflation thresholds[END_REF]. Interestingly, a correlation between ReO2 and perfusion pressure was reported, suggesting that ReO2 is derived from the interaction between the endothelium and regional perfusion pressure [START_REF] Skarda | Dynamic near-infrared spectroscopy measurements in patients with severe sepsis[END_REF].

VOT-derived variables have shown much better performance when considering prognosis than the baseline StO2. Some studies observed that a slighter decrease in DeO2, which reflects impairment in regional oxygen extraction, was associated with organ dysfunction and increased mortality [START_REF] Mesquida | Prognostic implications of tissue oxygen saturation in human septic shock[END_REF][START_REF] Donati | Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study[END_REF]. Furthermore, decreased ReO2 slope, which reflects vascular reactivity derangements, was linked to increased mortality in septic shock patients (Figure 1) [START_REF] Creteur | The prognostic value of muscle StO2 in septic patients[END_REF][START_REF] Donati | Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study[END_REF][START_REF] Gruartmoner | Microcirculatory monitoring in septic patients: Where do we stand?[END_REF][START_REF] Payen | Is thenar tissue hemoglobin oxygen saturation in septic shock related to macrohemodynamic variables and outcome?[END_REF].

Several methodological and technological limitations exist to the routine use of NIRS at the bedside. NIRS requires a specific device that might not be routinely available in ICUs. Also, NIRSderived measurements are affected by adipose tissue thickness and the existence of edema. Furthermore, baseline StO2 values showed high variability among healthy subjects, which makes NIRS a valuable device for trend monitoring rather than based on absolute StO2 values.

Moreover, NIRS technology does not directly measure microcirculatory blood flow. In addition, different NIRS devices differ in some technological points and are not interchangeable. StO2 value, the response to ischemia is different. The DeO2 slope is slower, and a longer period is needed to reach a predetermined ischemic threshold. The vascular reactivity is also altered, resulting in a slower StO2 recovery rate (ReO2) and a blunted hyperemic response before returning to baseline StO2 [START_REF] Donati | Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study[END_REF].

Laser Doppler Flowmetry

Laser Doppler Flowmetry (LDF) is a non-invasive method that continuously measures the microvascular blood flow in different types of tissue, including muscle, skin, and intestine. The principle of this technique is to measure the doppler shift, which is the change in frequency that laser light experiences when it reflects off moving objects, such as red blood cells. LDF operates by lighting the tissue under examination with a monochromatic laser probe. Laser light is delivered fiber-optically and diffusely scatters through tissue, some reflecting back with no change in wavelength and some encountering moving red blood cells undergo a Doppler shift that is also detected by the monitor. As a result, LDF provides an output signal proportional to the microcirculatory blood flow [START_REF] Schabauer | Cutaneous laser Doppler flowmetry: applications and findings[END_REF] (Figure 2). Depending on the device, LDF can be used to evaluate blood flow in muscle and gastric, rectal, and vagina mucosa [START_REF] Kiessling | Real-time measurement of rectal mucosal microcirculation during cardiopulmonary bypass[END_REF][START_REF] Salgado | Effectiveness of laser Doppler perfusion monitoring in the assessment of microvascular function in patients undergoing on-pump coronary artery bypass grafting[END_REF]. However, as a noninvasive measurement of peripheral blood flow, its use is restricted to the skin [START_REF] Schabauer | Cutaneous laser Doppler flowmetry: applications and findings[END_REF].

LDF has been helpful in assessing endothelium-dependent vascular responses in the skin microcirculation during reactive hyperemia after transient ischemia obtained arterial occlusion with a cuff positioned around the arm [START_REF] Koller | Role of endothelium in reactive dilation of skeletal muscle arterioles[END_REF]. The rate of flow restoration is primarily determined by the capacity of the microvasculature to recruit arterioles and capillaries. The ascending slope after transient occlusion is a marker of endothelial reactivity and consequently can be utilized as a substitute for the functional integrity of the microvasculature [START_REF] Lamblin | Microcirculatory alterations induced by sedation in intensive care patients. Effects of midazolam alone and in association with sufentanil[END_REF][START_REF] Backer | Monitoring the microcirculation in the critically ill patient: current methods and future approaches[END_REF]. A decreased hyperemic response was observed in septic patients, and a link between changes in vasculature tone and severity of sepsis was also reported [START_REF] Hartl | Reactive hyperemia in patients with septic conditions[END_REF][START_REF] Young | Dynamics of skin blood flow in human sepsis[END_REF][START_REF] Sair | Tissue oxygenation and perfusion in patients with systemic sepsis[END_REF]. Furthermore, restoration of vasoreactivity in septic patients assessed by LDF appears to be linked with a better outcome [START_REF] Young | Dynamics of skin blood flow in human sepsis[END_REF]. The capacity of LDF to assess altered skin perfusion in sepsis could be of clinical utility for the early detection of microcirculatory disorders in high-risk patients.

Scanning laser Doppler and reflection-mode confocal laser scanning microscopy are attractive developments, as they both can visualize the field of interest and allow semi-quantitative assessment of perfusion heterogeneity. With a confocal technique, vessel density, diameter, and blood flow measurements can be obtained. Due to the device's size, it can currently only be used on humans to study skin blood flow.

LDF technique has numerous limitations. It provides blood flow measurements in relative units; thus, only relative changes from baseline can be evaluated. Also, this technique cannot consider the microvascular heterogeneity as the device measures the average blood flow in all vessels (at least 50 vessels, including arterioles, capillaries, and venules of variable size, direction, and perfusion) of the sampling volume.

Videomicroscopic imaging techniques

Orthogonal polarization spectral (OPS) and sidestream darkfield (SDF) are two video-microscopic imaging methods incorporated into handled microscopes that can be employed to directly assess the microcirculation at the bedside. After applying a light source on a surface, the light reflects off the deeper layers of tissue, delivering trans-illumination of the superficial layers of tissue (thus restricting its use to organs or tissue surfaces covered by slim layers of epithelium). As the selected wavelength (530 nm) is absorbed by the hemoglobin, red blood cells look like black/gray bodies streaming inside capillaries (absorbed light) over a white tissue environment (reflected light). Hence, only functional capillaries (with red blood cells flow) will be seen as opposed to nonfunctional capillaries (with no red blood cells flow). In OPS, an externally filtered light source illuminates the organ surface with linearly polarized light and reflected light is stopped by an orthogonally polarized analyzer [START_REF] Groner | Orthogonal polarization spectral imaging: a new method for study of the microcirculation[END_REF][START_REF] Slaaf | A versatile incident illuminator for intravital microscopy[END_REF]. OPS devices are no longer commercially available. The SDF technique uses pulsed green light, and illumination is achieved by surrounding the tip of the light guide with light-emitting diodes creating dark-field illumination [START_REF] Goedhart | Sidestream Dark Field (SDF) imaging: a novel stroboscopic LED ring-based imaging modality for clinical assessment of the microcirculation[END_REF]. Both devices provide good-quality images of microvascular vessels filled with red blood cells. However, SDF delivers a more precise visualization of capillaries, with more sharp and less granular images than OPS [START_REF] Goedhart | Sidestream Dark Field (SDF) imaging: a novel stroboscopic LED ring-based imaging modality for clinical assessment of the microcirculation[END_REF].

These techniques can only be used on organs that are covered by a thin layer of epithelium. In the sublingual area, which has been the most studied area, capillaries and venules of different sizes (2-3 µm) can be visualized; arterioles are usually not seen because they are situated in deeper layers. Red blood cells are recognized as black bodies, and tissue perfusion can be characterized in individual vessels. Microcirculatory image analysis has been challenging, primarily due to hardware limitations but also because different scoring systems have been suggested. According to the second expert consensus conference [START_REF] Ince | Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine[END_REF], the microcirculation analysis report should evaluate microvascular blood flow, vascular density, and perfusion heterogeneity. Microcirculatory perfusion is evaluated by assessing the microvascular flow index (MFI) and the proportion of perfused vessels (PPV). Vascular density, which is related to the diffusion distance of oxygen between the red blood cells and the tissue cells, is evaluated by assessing the functional capillary density (FCD), including total vessel density (TVD) and perfused vessel density (PVD). Notably, tissue perfusion depends on FCD and blood flow (reflected by MFI).

Lastly, heterogeneity of perfusion is reflected by PPV in the examined area and the heterogeneity index in the studied organ. Evaluating perfusion heterogeneity is a crucial key aspect of assessing the shunted fraction in septic shock [START_REF] Ellis | Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis[END_REF]. Most of these variables are quantitative, except for the flow-related parameters, which are semi-quantitative but have nonetheless been shown in the literature to be sensitive enough to assess microcirculatory performance.

A significant reduction in vessel density and a rise of non-perfused/under-perfused vessels were observed in the sublingual microcirculation in the early period of sepsis and septic shock patients compared to the control group [START_REF] Edul | Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock[END_REF][START_REF] Backer | Microvascular blood flow is altered in patients with sepsis[END_REF]. Also, increased heterogeneity of blood flow and vascular density between concurrent areas was reported in those studies. Furthermore, these derangements were more pronounced in non-survivors, and the speedy recovery of these microcirculatory alterations following interventional treatment was also linked to improved outcomes, including mortality [START_REF] Backer | Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome[END_REF][START_REF] Backer | Microvascular blood flow is altered in patients with sepsis[END_REF][START_REF] Trzeciak | Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival[END_REF]. On the contrary, the persistence of these microcirculatory derangements beyond the first 24 hours was strongly and independently associated with mortality related to circulatory failure in the initial stage and to multi-organ failure in the late stage [START_REF] Sakr | Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock[END_REF].

Handheld videomicroscopes present several limitations. Optimal sublingual videomicroscopy is only possible in cooperative or sedated patients. It is also not feasible to evaluate the sublingual microcirculation in patients treated with non-invasive mechanical ventilation. Furthermore, motion artifacts can also change the quality of the recorded video and make image analysis more complex, making stable video recording imperative. In addition, avoiding excessive pressure while applying the videomicroscope to the tissue surface is essential, as this can impair flow in the microvessels and result in underlining microcirculatory perfusion [START_REF] Ince | Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine[END_REF].

Moreover, the microcirculation cannot be monitored continuously with a videomicroscope, and recorded video clips should be analyzed offline. However, with the introduction of a thirdgeneration portable video microscope called Cytocam (Incident Dark Field) Imaging [START_REF] Aykut | Cytocam-IDF (incident dark field illumination) imaging for bedside monitoring of the microcirculation[END_REF], a realtime bedside examination of microcirculation is available with a reasonable agreement with traditional image analysis (Figure 3) [START_REF] Tanaka | Qualitative realtime analysis by nurses of sublingual microcirculation in intensive care unit: the MICRONURSE study[END_REF]. A point of care microcirculation (POEM) 5-point-scoring system for real-time assessment of sublingual microcirculation was introduced by Naumann et al. [START_REF] Naumann | Real-time point of care microcirculatory assessment of shock: design, rationale and application of the point of care microcirculation (POEM) tool[END_REF]. These authors demonstrated that the POEM scoring system could be used at the bedside to assess sublingual microcirculatory flow and heterogeneity with minimal inter-user variability amongst healthcare professionals [START_REF] Naumann | Real-time point of care microcirculatory assessment of shock: design, rationale and application of the point of care microcirculation (POEM) tool[END_REF]. However, despite the new significant technological advancements that have been accomplished in this domain, additional developments are required before it can be integrated into routine clinical practice. tPO2 monitoring has been extensively investigated in animal models in multiple organs, including the brain, gut, kidney, liver, muscle, and bladder [START_REF] Vallet | Gut and muscle tissue PO2 in endotoxemic dogs during shock and resuscitation[END_REF][START_REF] Dyson | Tissue oxygen monitoring in rodent models of shock[END_REF][START_REF] Dyson | Bladder tissue oxygen tension monitoring in pigs subjected to a range of cardiorespiratory and pharmacological challenges[END_REF], and peripheral tissues such as skin or skeletal muscle in human studies. Even though it seems to be a sensitive marker of organ perfusion, static tPO2 values show an inconsistent response between organs and different shock states, as well as discrepancies depending on the timing of sepsis progression and the use of simultaneous supportive treatments (fluid resuscitation) [START_REF] Dyson | Tissue oxygen monitoring in rodent models of shock[END_REF]. This high inconsistency has led to using a dynamic challenge to reveal tissue hypoxia, the so-called oxygen challenge test (OCT).

The test consists of analyzing the aptitude of the vascular system to transport high PO2 to the tissues, which is reflected in a downstream increase in tPO2 after a rise in PaO2 [START_REF] Tremper | Effects of hypoxia and shock on transcutaneous PO2 values in dogs[END_REF]. A poor increase in tPO2 would reflect an inadequate blood flow. Thus, the adequacy of tissue perfusion can be evaluated by examining the appropriateness of response observed in all organs to the OCT. Accordingly, the existence of an altered tPO2 response to an OCT may signify local microcirculatory dysfunction in well-resuscitated septic patients. Indeed, it has been observed that the rise in tPO2 induced by an OCT was associated with less organ failure and decreased mortality in septic shock patients [START_REF] Yu | Transcutaneous pressure of oxygen: a noninvasive and early detector of peripheral shock and outcome[END_REF]. Also, the inclusion of OCT as an endpoint in a resuscitation protocol was associated with better survival compared to resuscitation according to the hemodynamic parameters of oxygen delivery and mixed venous oxygen saturation in patients with septic shock [START_REF] Yu | A prospective randomized trial comparing oxygen delivery versus transcutaneous pressure of oxygen values as resuscitative goals[END_REF].

Several limitations of tPO2 should be acknowledged. Matched rises or declines in local oxygen delivery and consumption will not influence tPO2. Tissue PO2 electrodes measure PO2 on a tissue surface of 8 mm 2 over a depth of a few microns [START_REF] Dyson | The impact of inspired oxygen concentration on tissue oxygenation during progressive haemorrhage[END_REF]. This corresponds to a sampling volume of at least 0.5 mm 3 . Such a volume encompasses at least 100 microvessels, including arterioles, capillaries, venules, interstitium, and other cells, all of which contribute to PO2. Even if tPO2 monitoring may be of potential interest, it still needs to be fully validated before it evolves into a bedside tool for the clinical management of septic patients.

Temperature gradients

Skin temperature is a standard marker of peripheral vasoconstriction. It has been reported that critically ill patients with cool extremities had a significantly lower cardiac index and higher lactate levels than patients with warm skin temperature [START_REF] Kaplan | Start with a subjective assessment of skin temperature to identify hypoperfusion in intensive care unit patients[END_REF]. However, temperature gradients are a better subjective assessment of peripheral perfusion [START_REF] Lima | The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients[END_REF][START_REF] Ait-Oufella | Understanding clinical signs of poor tissue perfusion during septic shock[END_REF].

Central-to-toe temperature is the difference between central temperature measured at the tympanic membrane and temperature at the ventral surface of the big toe measured by a skin probe. This gradient has been used as a measure of peripheral vasoconstriction. However, it has the disadvantage of being affected by hypothermia and room temperature [START_REF] Lima | The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients[END_REF]. The difference between different peripheral skin temperature differences has also been used as a marker of skin perfusion in various studies. Using two skin probes, the gradient between the forearm and fingertip (Tskin-diff) is often used to evaluate peripheral blood flow. Tskin-diff greater than 2 and 4 °C demonstrates the existence of moderate and severe vasoconstriction, respectively [START_REF] Van Genderen | Clinical assessment of peripheral perfusion to predict postoperative complications after major abdominal surgery early: a prospective observational study in adults[END_REF]. The advantage of Tskin-diff is that both fingertip and forearm are equally affected by ambient temperature [START_REF] Lima | The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients[END_REF][START_REF] Van Genderen | Clinical assessment of peripheral perfusion to predict postoperative complications after major abdominal surgery early: a prospective observational study in adults[END_REF]. Tskin-diff has been reported to be associated with skin laser Doppler flow. Also, it has been observed that increased Tskin-diff is associated with worsening organ failure [START_REF] Lima | The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients[END_REF]. In addition, Tskin-diff was linked to worse outcomes in patients following major abdominal surgery [START_REF] Van Genderen | Clinical assessment of peripheral perfusion to predict postoperative complications after major abdominal surgery early: a prospective observational study in adults[END_REF]. While using of peripheral perfusion parameters, including Tskin-diff, as guidelines in clinical resuscitation were shown to be very promising [START_REF] Van Genderen | Early peripheral perfusion-guided fluid therapy in patients with septic shock[END_REF], more studies are needed before adopting this technique in critically ill patients. Furthermore, this method requires more complex technology.

Capillary refill time

Capillary refill time (CRT) is the time it takes for skin color to return to baseline after applying blanching pressure [START_REF] Ait-Oufella | Understanding clinical signs of poor tissue perfusion during septic shock[END_REF]. CRT can be clinically measured over the fingertip [START_REF] Van Genderen | Clinical assessment of peripheral perfusion to predict postoperative complications after major abdominal surgery early: a prospective observational study in adults[END_REF][START_REF] Ait-Oufella | Capillary refill time exploration during septic shock[END_REF] or over the knee area [START_REF] Ait-Oufella | Capillary refill time exploration during septic shock[END_REF]. CRT reflects peripheral capillary blood flow.

After initial resuscitation of septic shock patients, CRT was a strong predictor of 14-day mortality with a cutoff value of 2.4 s when applied on the fingertip and 4.9 s when used on the knee area [START_REF] Ait-Oufella | Capillary refill time exploration during septic shock[END_REF]. Interestingly, in this study, CRT showed a good correlation with other tissue perfusion parameters such as urinary output and serum lactate levels. However, in patients following abdominal surgery, the fingertip CRT cutoff value that was associated with postoperative complications and death was 5 s [START_REF] Van Genderen | Clinical assessment of peripheral perfusion to predict postoperative complications after major abdominal surgery early: a prospective observational study in adults[END_REF]. In a multicenter randomized controlled trial conducted at 28 ICUs (ANDROMEDA-SHOCK trial) and included 424 patients in their early phase of septic shock, CRT-targeted resuscitation during the first 8 hours was associated with lower 28-day mortality compared to lactate-targeted resuscitation (34.9% vs. 43.4%, p= 0.06) [START_REF] Hernández | Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial[END_REF]. Also, CRT-targeted resuscitation was associated with less organ dysfunction at 72 hours. The superiority of this strategy was also supported by a subsequent Bayesian analysis [START_REF] Zampieri | Effects of a Resuscitation Strategy Targeting Peripheral Perfusion Status versus Serum Lactate Levels among Patients with Septic Shock. A Bayesian Reanalysis of the ANDROMEDA-SHOCK Trial[END_REF]. However, 25 to 30% of septic shock patients had a normal CRT at baseline before fluid resuscitation [START_REF] Hernández | Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial[END_REF][START_REF] Lara | Capillary refill time during fluid resuscitation in patients with sepsisrelated hyperlactatemia at the emergency department is related to mortality[END_REF] and might not benefit from the CRT strategy.

Skin mottling

Skin mottling is described as patchy skin discoloration that generally displays on the area around the knees but can develop into other peripheral circulations like fingers and ears [START_REF] Ait-Oufella | Understanding clinical signs of poor tissue perfusion during septic shock[END_REF]. In the absence of diffuse intravascular coagulation yielding to complete microcirculatory block, skin mottling is a marker of skin hypoperfusion. It has been shown that perfusion and tissue oxygenation were compromised in mottling zones by using Laser Doppler Flowmetry and NIRS technologies [START_REF] Ait-Oufella | Alteration of skin perfusion in mottling area during septic shock[END_REF][START_REF] Ait-Oufella | Mottling score predicts survival in septic shock[END_REF]. A higher mottling score (range from 0 to 5) was associated with increased mortality in critically ill patients [START_REF] Coudroy | Incidence and impact of skin mottling over the knee and its duration on outcome in critically ill patients[END_REF] and septic shock patients [START_REF] Ait-Oufella | Mottling score predicts survival in septic shock[END_REF][START_REF] De Moura | Skin mottling score as a predictor of 28-day mortality in patients with septic shock[END_REF] independently of vasopressor doses and other tissue perfusion parameters (Figure 4) [START_REF] Dumas | Mottling score is a strong predictor of 14-day mortality in septic patients whatever vasopressor doses and other tissue perfusion parameters[END_REF]. Also, a decrease in mottling score during resuscitation was significantly associated with better outcomes [START_REF] Dumas | Mottling score is a strong predictor of 14-day mortality in septic patients whatever vasopressor doses and other tissue perfusion parameters[END_REF].

However, the main limitation of using this method is that the incidence of skin mottling is only 29% in the general ICU population and 49% in the subset of patients admitted for septic shock [START_REF] Coudroy | Incidence and impact of skin mottling over the knee and its duration on outcome in critically ill patients[END_REF]. Also, it is not helpful in patients with burns, amputations, and dark skin. score 3, a mild mottling area that does not exceed the middle thigh; score 4, a severe mottling area that does not go beyond the fold of the groin; score 5, an extremely severe mottling area that goes beyond the fold of the groin. Right: Examples of the mottling score [START_REF] Ait-Oufella | Alteration of skin perfusion in mottling area during septic shock[END_REF].

Lactate

During glycolysis, a series of cytosolic enzymatic reactions converts glucose to pyruvate. Pyruvate is either moved into the mitochondria and converted to acetyl-CoA by pyruvate dehydrogenase (PDH) to enter the tricarboxylic acid cycle, which along with O2, drives the synthesis of adenosine triphosphate (ATP), the primary energy source for cellular metabolism, or transformed to lactate by the enzyme lactate dehydrogenase. Produced lactate can be either used locally or secreted into the blood. With these mechanisms (Figure 5) in mind, it is easy to comprehend why lactate levels can rise during shock or other critical illness-related physiological stress.

In situations where oxygen delivery cannot meet the oxygen demand or when cells cannot utilize oxygen, oxygen consumption falls, and tissue hypoxia occurs, resulting in a sharp increase in lactate levels [START_REF] Bakker | The oxygen supply dependency phenomenon is associated with increased blood lactate levels[END_REF]. Microcirculatory alterations, particularly in sepsis, may result in insufficient oxygen that is delivered to the cell, thereby increasing lactate levels [START_REF] Zhang | Oxygen extraction is altered by endotoxin during tamponadeinduced stagnant hypoxia in the dog[END_REF]. This is indirectly demonstrated by the observation that elevated lactate levels have been associated with deranged microcirculatory perfusion [START_REF] Hernandez | Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients[END_REF] and that normalization of capillary perfusion was linked to a decrease in lactate levels in septic shock patients, unrelated to changes in systemic hemodynamic variables [START_REF] Backer | The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects[END_REF]. In addition, restoration of tissue perfusion parameters was linked to a rapid reduction in lactate levels [START_REF] Alegría | A hypoperfusion context may aid to interpret hyperlactatemia in sepsis-3 septic shock patients: a proof-of-concept study[END_REF]. For this reason, hyperlactatemia has traditionally been considered a hallmark of circulatory dysfunction and tissue hypoxia. Elevated lactate level was associated with increased mortality risk in sepsis and in general ICU population [START_REF] Zhang | Predictive value of lactate in unselected critically ill patients: an analysis using fractional polynomials[END_REF][START_REF] Trzeciak | Serum lactate as a predictor of mortality in patients with infection[END_REF][START_REF] Mikkelsen | Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock[END_REF].

The effects of lactate-guided therapy on outcomes are controversial. Two randomized clinical trials (RCT) have used hemodynamic approaches based on lactate reduction. Jansen et al.

randomized 348 patients with blood lactate ≥ 3 mmol/L to two hemodynamic strategies, one of which targeted a reduction in lactate level of ≥ 20% every 2 hours for the first 8 hours of admission [START_REF] Jansen | Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial[END_REF]. The lactate-guided therapy group received a larger fluid volume over the 8 hours.

However, the lactate levels over the 72 hours did not differ between the two groups. Also, there was no significant difference in the unadjusted mortality rate even though hospital mortality was decreased when adjusted for risk factors. In the second RCT that included 300 patients with severe sepsis, the lactate-guided hemodynamic strategy did not improve patients' outcomes compared to a strategy based on the central venous oxygen saturation [START_REF] Jones | Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial[END_REF]. However, different meta-analyses that included these RCTs observed that early lactate clearance-guided therapy was associated with an improved survival rate [START_REF] Gu | Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials[END_REF][START_REF] Ding | Early goal-directed and lactate-guided therapy in adult patients with severe sepsis and septic shock: a meta-analysis of randomized controlled trials[END_REF].

However, elevated blood lactate level or persistent hyperlactatemia is particularly difficult to interpret. At least four possible pathophysiological mechanisms might be involved: anaerobic glycolysis in tissue hypoperfusion areas, particularly in the presence of severe microcirculatory derangements [START_REF] Ding | Early goal-directed and lactate-guided therapy in adult patients with severe sepsis and septic shock: a meta-analysis of randomized controlled trials[END_REF]; stress-related adrenergic-induced aerobic glycolysis; impaired hepatic lactate clearance; and mitochondrial dysfunction limiting pyruvate metabolism [START_REF] Garcia-Alvarez | Sepsis-associated hyperlactatemia[END_REF]. Identifying a clinical pattern of hypoperfusion-related hyperlactatemia is important as optimizing systemic blood flow in this situation could reverse persistent hypoperfusion and ameliorate the prognosis.

On the opposite, in cases unrelated to hypoperfusion, additional resuscitation could result in the harmful of over-resuscitation. In line with this idea, a study [START_REF] Hernandez | When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring[END_REF] suggested that the time course of lactate normalization during a successful resuscitation follows a biphasic curve: an early rapid response (a flow-responsive phase) followed by a later slower recovery trend potentially explained by non-flow-dependent mechanisms. In addition, it has been observed that limiting fluid resuscitation in patients with a persistent increased lactate level but with normal peripheral perfusion was safe and associated with an improvement in organ function [START_REF] Van Genderen | Early peripheral perfusion-guided fluid therapy in patients with septic shock[END_REF].

Therefore, a general recommendation to target the circulation in patients with increased lactate levels is too simplistic and not adequately supported by clinical studies. The complexity of lactate as a molecule, substrate, biomarker, and energy source, makes it inconceivable to define what goal it should be a marker or target of. Attempting to reduce lactate levels (by whatever means, given the numerous events regulating its blood levels) has no credibility or logic in terms of hemodynamics, bioenergetics, or tissue protection [START_REF] Hernandez | The ten pitfalls of lactate clearance in sepsis[END_REF].

Venous oxygen saturation

Assessment of mixed venous oxygen saturation (SvO2) from a pulmonary artery catheter has been proposed as an indirect marker of global tissue oxygenation [START_REF] Krafft | Mixed venous oxygen saturation in critically ill septic shock patients. The role of defined events[END_REF]. SvO2 reflects the balance between oxygen demand and supply. A low SvO2 represents a high ERO2 in order to maintain aerobic metabolism and VO2 constant in response to an acute decrease in DO2. However, when DO2 drops under a critical value, ERO2 is no longer capable of upholding VO2, and global tissue hypoxia appears, as indicated by the occurrence of lactic acidosis [START_REF] Zhang | Oxygen extraction is altered by endotoxin during tamponadeinduced stagnant hypoxia in the dog[END_REF][START_REF] Schumacker | The concept of a critical oxygen delivery[END_REF][START_REF] Nelson | Pathological supply dependence of systemic and intestinal O2 uptake during endotoxemia[END_REF].

Since the assessment of central venous oxygen saturation (ScvO2) can be achieved more easily and is less risky than from a pulmonary artery catheter, it would be helpful if ScvO2 could function as an accurate reflection of SvO2. In fact, SvO2 is not similar to ScvO2 because the latter primarily reflects the oxygenation of the upper side of the body. In normal patients, ScvO2 is lower than SvO2 by about 2% to 3%, largely because of the less rate of oxygen extraction by the kidneys [START_REF] Bloos | Venous oximetry[END_REF].

In shock state, the absolute value of ScvO2 was more often reported to be higher than ScvO2, probably due to increased oxygen extraction in splanchnic and renal tissues [START_REF] Chawla | Lack of equivalence between central and mixed venous oxygen saturation[END_REF][START_REF] Reinhart | Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill[END_REF][START_REF] Varpula | Mixed venous oxygen saturation cannot be estimated by central venous oxygen saturation in septic shock[END_REF][START_REF] Van Beest | No agreement of mixed venous and central venous saturation in sepsis, independent of sepsis origin[END_REF]. This suggests that the existence of a decreased ScvO2 implies an even smaller SvO2. Because of the lack of agreement regarding absolute values, some authors questioned the clinical utility of ScvO2 [START_REF] Martin | Monitoring of central venous oxygen saturation versus mixed venous oxygen saturation in critically ill patients[END_REF][START_REF] Edwards | Importance of the sampling site for measurement of mixed venous oxygen saturation in shock[END_REF]. However, despite absolute, values differ, trends in ScvO2 closely mirror trends in SvO2 [START_REF] Reinhart | Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill[END_REF][START_REF] Dueck | Trends but not individual values of central venous oxygen saturation agree with mixed venous oxygen saturation during varying hemodynamic conditions[END_REF], suggesting that monitoring ScvO2 makes sense in critically ill patients.

It has been shown that an early hemodynamic optimization using a resuscitation bundle aimed at increasing ScvO2 > 70% was related to an important reduction in septic shock mortality [START_REF] Rivers | Early goal-directed therapy in the treatment of severe sepsis and septic shock[END_REF]. However, three large multicenter studies [START_REF] Yealy | A randomized trial of protocol-based care for early septic shock[END_REF][START_REF] Peake | Goal-directed resuscitation for patients with early septic shock[END_REF][START_REF] Mouncey | Trial of early, goal-directed resuscitation for septic shock[END_REF] failed to demonstrate any benefits of the early goal-directed therapy approach. Nevertheless, the design of these trials was not to answer the question of whether targeting an ScvO2 > 70% was effective. Also, in these studies, the mean baseline ScvO2 values were already above 70%. Thus, these findings do not indicate that clinicians should stop monitoring ScvO2 and adjust DO2 by optimizing ScvO2 levels, particularly in septic shock patients with low ScvO2, who are at the highest risk of death [START_REF] Boulain | Prevalence of low central venous oxygen saturation in the first hours of intensive care unit admission and associated mortality in septic shock patients: a prospective multicentre study[END_REF].

On the other hand, normalization of ScvO2 does not rule out persistent tissue hypoperfusion and does not preclude evolution to multi-organ dysfunction and death [START_REF] Puskarich | Outcomes of patients undergoing early sepsis resuscitation for cryptic shock compared with overt shock[END_REF]. The obvious limitation of ScvO2 is that normal/high values cannot distinguish if DO2 is sufficient or in excess to demand. In septic conditions, normal/high ScvO2 values might be due to the heterogeneity of the microcirculation that generates capillary shunting and/or mitochondrial damage responsible of disturbances in tissue oxygen extraction. Because ScvO2 is measured downstream from tissues, when a given tissue receives inadequate DO2, the resulting low local oxygen venous saturations may be "masked" by admixture with highly saturated venous blood from tissues with better perfusion and DO2, resulting overall in normal or even high ScvO2. Although ScvO2 may thus not miss any global DO2 dysfunction, it may stay "blind" to local perfusion disturbances, which exist in abundance in sepsis due to damaged microcirculation. Indeed, high ScvO2 values have been associated with increased mortality in septic shock patients [START_REF] Pope | Multicenter study of central venous oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis[END_REF]100]. Thus, in some circumstances, using ScvO2 might erroneously drive a clinician to conclude that the patient's physiologic state has improved when, in fact, it may not have improved. Tissue PCO2 (Capnometry) Tissue CO2 monitoring has been, for decades, the cornerstone of regional and microcirculatory evaluation in critically ill patients. This technology is based on the principle that tissue CO2 depends on three factors: tissue CO2 production, blood flow to the tissue, and arterial CO2 content. Presuming that arterial CO2 is constant (stable respiratory conditions), tissue CO2 reflects the balance between local CO2 production (dependent on basal metabolism) and blood flow to the tissue (CO2 washout phenomenon). Given that arterial CO2 influences tissue CO2, the gradient between the two is usually calculated and expressed as the PCO2 gap. This parameter reflects the adequacy of blood flow to the tissue and has been proposed as a hypoperfusion CO2 is transported in the blood in three figures [103]: Dissolved, in combination with proteins as carbamino compounds, and as bicarbonate. Physically dissolved CO2 is a function of CO2 solubility in blood, which is about 20 times that of O2; therefore, considerably more CO2 than O2 is present in simple solution at equal partial pressures. However, dissolved CO2 shares only around 5% of the whole CO2 concentration in arterial blood.

The bicarbonate ion (HCO3 -) is the most significant form of CO2 carriage in the blood. CO2 combines with water (H2O) to form carbonic acid (H2CO3), and this dissociates to HCO3 -and hydrogen ion (H + ): CO2 + H2O = H2CO3 = HCO3 -+ H + . Carbonic anhydrase is the enzyme that catalyzes the first reaction, making it almost instantaneous. Carbonic anhydrase occurs mainly in red blood cells, but it also occurs on pulmonary capillary endothelial cells, which accelerates the reaction in plasma and in the lungs. The uncatalyzed reaction will occur in plasma but at a much slower rate. The second reaction happens immediately inside the red blood cells and does not require any enzyme. The H2CO3 dissociates to H + and HCO3 -, and the H + is buffered primarily by hemoglobin while the excess HCO3 -is transported out of the red blood cells into plasma by an electrically neutral bicarbonate-chloride exchanger. The fast conversion of CO2 to HCO3 -results in nearly 90% of the CO2 in arterial blood being transported in that manner.

Hemoglobin-O2 saturation is the main factor affecting the capacity of hemoglobin to fix CO2 (Haldane effect). Consequently, CO2 concentration increases when blood is deoxygenated, or CO2 concentration diminishes when blood is oxygenated at any assumed PCO2 [103]. H + ions from CO2 can be deemed as competing with O2 for hemoglobin binding. Accordingly, rising oxygen reduces the affinity of hemoglobin for H + and blood CO2 concentration (Haldane effect). The physiological assets of the Haldane effect are that it promotes removing CO2 in the lungs when blood is oxygenated and CO2 filling in the blood when oxygen is delivered to tissues. Additionally, the Haldane effect leads to a sharper physiologic CO2 blood equilibrium curve that has the physiologic interest of rising CO2 concentration differences for a given PCO2 difference.

Determinant of venous-to-arterial CO2 tension difference

The mixed PCO2 (PCO2_Mix) is the gradient between PCO2 in mixed venous blood (PvCO2) and PCO2 in arterial blood (PaCO2): PCO2_Mix = PvCO2 -PaCO2; PvCO2 and PaCO2 are partial pressures of the dissolved CO2 in the mixed venous and arterial blood, respectively. The application of the Fick equation to CO2 shows that the CO2 elimination (identical to CO2 generation in a stable condition) equals the product of the difference between mixed venous blood CO2 content (CvCO2) and arterial blood CO2 content (CaCO2) and cardiac output: Total CO2 production (VCO2) = cardiac output × (CvCO2 -CaCO2). Despite of a global curvilinear shape of the relation between PCO2 and the total CCO2, there is a rather linear association between CCO2 and PCO2 over the general physiological range of CO2 content so that CCO2 can be substituted by PCO2 Under steady states of both VO2 and VCO2, PCO2_Mix was observed to increase in parallel with the reduction in cardiac output [START_REF] Zhang | Arteriovenous differences in PCO2 and pH are good indicators of critical hypoperfusion[END_REF]108,109]. In other words, when cardiac output is adapted to VO2, PCO2_Mix should not increase due to increased clearance of CO2, whereas PCO2_Mix should rise following cardiac output reduction because of a low flow-induced tissue CO2 stagnation phenomenon. Due to the decreasing of transit time, a higher than usual addition of CO2 per unit of blood passing the efferent microvessels results in hypercapnia in the venous blood. As long as alveolar respiration is sufficient, a gradient will occur between PvCO2 and PaCO2. This finding underscores the utility of calculating PCO2_Mix rather than simply assessing PvCO2, particularly in the case of spontaneous breathing [111].

The relationship between PCO2 and the total blood CCO2 is curvilinear even though more linear than the oxygen dissociation curve [103]. Oxygen saturation, hematocrit, temperature, and the degree of metabolic acidosis influence the PCO2/CCO2 relationship [103]. Hence, for a given value of CCO2, PCO2 is higher in the case of metabolic acidosis than in the case of normal pH.

Can PCO2_Mix be used as a marker of tissue hypoxia?

It has been suggested that PCO2_Mix can be used to detect the presence of tissue hypoxia in patients with acute circulatory failure [START_REF] Zhang | Arteriovenous differences in PCO2 and pH are good indicators of critical hypoperfusion[END_REF]108]. In fact, under conditions of tissue hypoxia with a decreased VO2, the relationship between changes in cardiac output and PCO2_Mix is much more complex. Indeed, in these circumstances, the increase in CO2 production related to the anaerobic pathway is counterbalanced by a reduced aerobic CO2 production, so that VCO2 and hence PCO2_Mix could be at best unchanged or decreased [109]. Nevertheless, since the k factor should rise during tissue hypoxia [START_REF] Zhang | Arteriovenous differences in PCO2 and pH are good indicators of critical hypoperfusion[END_REF] while VCO2 must fall, the resultant effect on PCO2_Mix depends mainly on the flow state (cardiac output) [104].

Under conditions of tissue hypoxia with a maintained flow state, venous blood flow should be sufficiently elevated to assure adequate clearance of the CO2 generated by the hypoxic cells so that PCO2_Mix should not increase even if the CO2 production is not decreased. Conversely, low flow states can result in a widening of PCO2_Mix due to the tissue CO2 stagnation phenomenon [112], even if no additional CO2 production occurs. This point was nicely demonstrated by Vallet et al. [113] in a canine model of an isolated limb in which a diminished DO2 by reducing blood flow (ischemic hypoxia) was related to a rise in regional PCO2. On the other hand, when blood flow was preserved, but arterial PO2 was decreased by lowering the input oxygen concentration (hypoxic hypoxia), PCO2 did not rise despite a significant decline in VO2. This is because the preserved blood flow was sufficient to clear the generated CO2 [114] (Figure). Accordingly, Nevière et al. [115] demonstrated that for the same level of induced oxygen supply dependency, regional PCO2 was risen only in ischemic hypoxia but not in hypoxic hypoxia, indicating that elevated PCO2 was mainly linked to the reduction in cardiac output. These studies clearly show that the absence of elevated PCO2 does not preclude the presence of tissue hypoxia and hence underline the good value of PCO2 to detect inadequate tissue perfusion related to its metabolic production but also its poor sensitivity to detect tissue hypoxia. A mathematical model analysis also established that cardiac output plays a crucial role in the widening of PCO2 [116].

Ratio of PCO2_Mix to O2_Mix (PCO2_Mix/O2_Mix) as a marker of tissue hypoxia

In experimental conditions of tissue hypoxia, the drop in VO2 leads to decreased total VCO2 generation, mainly related to the decrease in aerobic CO2 production. However, in situations of hypoxia, tissue CO2 increases as hydrogen ions generated by anaerobic sources of energy (hydrolysis of high-energy phosphates) are buffered by bicarbonate existing in the cells (anaerobic CO2 production) [108]. Therefore, VCO2 being reduced less than VO2, the respiratory quotient (VCO2/VO2) should increase. Accordingly, the increase in respiratory quotient has been shown to be a valuable marker of global tissue hypoxia [109,117]. Indeed, Groeneveld et al. [109] observed, in an experimental model of a graded increase in positive end-expiratory pressureinduced a decrease in cardiac output and oxygen delivery in pigs, that the decline in VCO2 (by 21 ± 2%) was less than in VO2 (by 27 ± 2%). Cohen et al. [117] reported in an experimental graded hemorrhage in swine that the airway respiratory quotient (VCO2/VO2) raised from 0.87 ± 0.07 to 1.16 ± 0.07 at the maximum bleeding due to a lesser decrease in VCO2 than of VO2 [117]. After retransfusion of the blood, the respiratory quotient came back to its baseline value [117]. Because VO2 is equal to the product of cardiac output by the difference between arterial and mixed venous O2 content O2_Mix, and VCO2 is proportional to the product of cardiac output and PCO2_Mix so the PCO2_Mix/O2_Mix ratio could be utilized as a surrogate of respiratory quotient and an indicator of the presence of global tissue hypoxia in critically ill patient. In this line, Dubin et al. [119] found that in sheep that were subject to graded hemorrhage, PCO2_Mix/O2_Mix significantly increased at the time of the fall in VO2 and the sharp increase in respiratory quotient (measured by indirect calorimetry), and thus, it was a good indicator of anaerobic metabolism.

Nevertheless, the use of PCO2_Mix/O2_Mix ratio as a surrogate of respiratory quotient supposes that the PCO2/CCO2 relationship is quasi-linear, which may be true over the physiological range of PCO2 [120]. However, this relationship can be influenced by the degree of metabolic acidosis [121], the hematocrit [122], and oxygen saturation (Haldane effect) [123,124], and it becomes nonlinear if these factors change [106]. Indeed, severe metabolic acidosis, low hematocrit, and high oxygen saturation can increase PCO2 for a given CO2 content since less CO2 is bound to hemoglobin [123]. Furthermore, these effects are more pronounced at a higher range of CCO2 since the PCO2/CCO2 relationship becomes flatter. Thus, PCO2_Mix/O2_Mix ratio might be increased due to several factors unrelated to anaerobic metabolism. Therefore, some authors questioned its reliability in reflecting the development of anaerobic metabolism in some specific conditions [118,119]. In this regard, Dubin et al. found, in a normovolemic hemodilution model of tissue hypoxia in pigs, that PCO2_Mix/O2_Mix ratio was a misleading indicator of anaerobic metabolism [119]. Indeed, the authors found that this ratio was increased before the occurrence of oxygen supply dependency phenomenon. The authors attributed the rise in the ratio, even in the absence of VO2/DO2 dependency, to the effects of anemia on O2_Mix and on CO2 hemoglobin dissociation curve that led to enlarged PCO2_Mix [122]. However, according to the results of that study [119], the slight increase in PCO2_Mix compared to the baseline in the hemodilution group was noted to be statistically significant only at the end of the protocol (DO2 ≈ 5 mL/min/kg) far beyond the occurrence of oxygen supply dependency (DO2 critique ≈ 12 mL/min/kg). Thus, it seems that the effects of anemia on PCO2_Mix were minimal, and the increase in PCO2_Mix/O2_Mix ratio observed before the VO2/DO2 dependency could mainly be explained by the decrease in O2_Mix induced by the severe hemodilution anemia [125]. Of note, in that study, the PCO2_Mix/O2_Mix ratio increased only at the appearance of VO2/DO2 dependency, at the same time as the increase in airway respiratory quotient, and, therefore, it was a very good indicator of the development of anaerobic metabolism in the hemorrhage group [119]. The same team, in a recent experimental graded bleeding and blood retransfusion study, in mechanically ventilated sheep [118], found that the time course of PCO2_Mix/O2_Mix ratio was different from the airway respiratory quotient. Nevertheless, the results of that study show that, in the hemorrhagic group, the PCO2_Mix/O2_Mix ratio suddenly increased along with the airway respiratory quotient at the occurrence of oxygen supply dependency (90 minutes after bleeding). However, the ratio took a bit longer time to return to its baseline value after retransfusion (30 minutes) than the airway respiratory quotient (2 minutes) [118]. Thus, we believe that those findings are instead in favor of the PCO2_Mix/O2_Mix ratio as a good indicator to depict the development of global anaerobic metabolism.

Moreover, other authors suggested that PCO2_Mix/O2_Mix ratio might not rise during tissue hypoxia conditions when associated with normal/high blood flow because venous blood flow seemed to guarantee a sufficient clearance of CO2 generated by the anaerobic metabolism [126].

In an experimental model of progressive tissue hypoxia induced by reducing either flow [ischemic hypoxia (IH)] or arterial oxygen tension [hypoxic hypoxia (HH)], we observed [127] that regional PCO2/O2 significantly increased at critical DO2 value where VO2 start to decrease (DO2crit) and not before, suggesting that these variables were able to depict the occurrence of oxygen supply dependency (DO2crit) in both IH and HH groups. The increases in these variables were mainly due to the decline in O2 in the HH group and the rise in PCO2 in the IH group induced by the decrease in blood flow. We also found that metabolic acidosis significantly influenced the PCO2/CO2 content relationship, but not the Haldane effect. Furthermore, at very low DO2 values, PCO2/O2 did not only reflect the ongoing anaerobic metabolism; it was confounded by the effects of metabolic acidosis on the CO2-hemoglobin dissociation curve, and then it should be interpreted with caution. [START_REF] Reinhart | Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill[END_REF] Metformin inhibits mitochondrial respiration in the liver and other tissues in a dose-dependent manner [128,129]. Thus, metformin intoxication induces the occurrence of anaerobic metabolism and lactate overproduction (metformin-associated lactic acidosis) by decreasing global oxygen extraction and consumption without affecting the oxygen delivery [128,129]. In an experimental model of metformin intoxications in pigs [130], we investigated if the PCO2_Mix/O2_Mix ratio could reflect the development of anaerobic metabolism when the oxygen delivery and cardiac output remained unchanged. We found an excellent individual correlation coefficient (R=0.8) between the metformin-induced increases in lactate levels and the increases in PCO2_Mix/O2_Mix. We, also, observed that PCO2_Mix/O2_Mix detected overt lactic acidosis with an area under the ROC curve of 0.81 (95%-CI: 0.70-0.92) (p < 0.001) with a best cut-off value of 2.0 mmHg/ml/dl, sensitivity was 0.81 (95%-CI: 0.65-0.94) and specificity 0.74 (95%-CI: 0.46-0.94).

II. Clinical studies

Venous-to-arterial PCO2 difference

Results from clinical studies in septic shock patients have also supported that the decreased cardiac output is the primary determinant in the elevation of PCO2_Mix. Indeed, septic patients with PCO2_Mix > 6 mmHg had a significantly lower mean cardiac output when compared to patients with PCO2_Mix ≤ 6 mmHg [131]. Moreover, the changes in cardiac output induced by volume expansion were correlated with changes in PCO2_Mix (r = 0.46, P < 0.01). The authors rightly concluded that in patients with septic shock, an elevated PCO2_Mix is related to a decreased systemic blood flow. Similarly, Bakker et al. found a significant negative correlation between cardiac output and PCO2_Mix. Therefore, a strong association between cardiac output and PCO2_Mix is also well documented in septic shock [132]. Interestingly, many patients in those studies [131,132] had normal PCO2_Mix despite the presence of tissue hypoxia, presumably since their elevated cardiac output had simply washed out the CO2 generated in the peripheral circulation. Creteur et al. [133] examined the association between impairment in microcirculatory perfusion and tissue PCO2. They showed that the reperfusion of damaged microcirculation (assessed using orthogonal polarized spectroscopy) was associated with normalized sublingual tissue PCO2 levels.

Thus, there is a clear relation between tissue CO2 accumulation and blood flow, leading to increasing venous-arterial CO2 gradients. Furthermore, Ospina-Tascon et al. [134], using a sidestream dark-field device, observed that sublingual PCO2 was closely associated with microvascular blood flow parameters during the early phases of resuscitation of septic shock. Indeed, sublingual PCO2 was the best predictor of the microcirculatory blood flow maldistribution as suggested by the alterations in the percentage of perfused small vessels (PPV), the heterogeneity blood flow index, and consequently functional capillary density. In addition, changes in sublingual PCO2 were significantly associated with changes in PPV. However, sublingual PCO2 was poorly related to systemic hemodynamic variables such as cardiac output, which was also not associated with microcirculatory variables.

Ospina-Tascon et al. [135] have shown that the persistence of high PCO2_Mix (≥ 6 mmHg) during the first six hours of resuscitation of septic shock patients was linked to more severe multiple organ failure and higher mortality rate (Relative Risk = 2.23, P = 0.01). However, The measurement of PCO2_Mix requires the presence of a pulmonary artery catheter, which is rarely practiced nowadays [136]. Since the central venous catheter is implanted in most septic shock patients, using central venous-arterial carbon dioxide partial pressure difference (∆PCO2_Cent) is significantly easier and similarly helpful. Interestingly, a strong agreement between PCO2_Mix and ∆PCO2_Cent, calculated as the difference between central venous PCO2 sampled from a central vein catheter and arterial PCO2, was reported in critically ill patients [137] and severe sepsis and septic shock patients [138].

As emphasized previously, high values of ScvO2 do not preclude the presence of tissue hypoperfusion and hypoxia in cases of impaired ERO2 capabilities that can occur in septic shock [START_REF] Pope | Multicenter study of central venous oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis[END_REF]100]. Since the solubility of CO2 is very high (around 20 times that of O2), its capability of spreading out of ischemic tissues into the efferent veins is phenomenal, making it an extremely sensitive indicator of hypoperfusion. Consequently, in conditions with O2 diffusion difficulties (resulting from shunted and obstructed capillaries), ''covering'' reduced ERO2 and increased tissue O2 debt, CO2 still diffuses to the efferent veins, ''uncovering'' the hypoperfusion situation for the clinician when ∆PCO2 is evaluated [139]. Accordingly, Vallée et al. [140] tested the hypothesis that the ∆PCO2_Cent can be used as a global indicator of tissue hypoperfusion in resuscitated septic shock patients in whom ScvO2 was already greater than 70%. They showed that despite a normalized DO2/VO2 ratio, patients who had impaired tissue perfusion with blood lactate concentration > 2 mmol/L remained with an elevated ∆PCO2_Cent (> 6 mmHg). Also, patients with low ∆PCO2_Cent values greater lactate decrease and cardiac index values and exhibited a significantly higher reduction in SOFA score than patients with high ∆PCO2_Cent. In a prospective study that included 80 patients, we recently examined the usefulness of measuring ∆PCO2_Cent during the initial resuscitation period of septic shock [141]. We found that during the very early period of septic shock, patients who reached a normal ∆PCO2_Cent (≤ 6 mmHg) after six hours of resuscitation had greater decreases in blood lactate and in SOFA score than those who failed to normalize ∆PCO2_Cent (> 6 mmHg). Interestingly, patients who achieved the goals of both ∆PCO2_Cent ≤ 6 mmHg and ScvO2 > 70% after the first six hours of resuscitation had the greatest blood lactate decrease, which was found to be an independent prognostic factor of ICU mortality [141]. In addition, Du et al. [142], in a retrospective study, showed that the normalization of both ScvO2 and ∆PCO2_Cent seems to be a better prognostic factor of outcome after reanimation from septic shock than ScvO2 only. Patients who achieved both targets seemed to clear blood lactate more efficiently [142]. Recently, Wang et al. [143] reported that in septic patients secondary to a bloodstream infection, ∆PCO2_Cent was independently associated with 28-day mortality in multivariable regression analysis.

Several observational studies found an association between ∆PCO2_Cent and outcomes in highrisk non-cardiac surgical patients. In a retrospective study that included 70 patients who underwent major abdominal surgery with an individualized goal-directed fluid replacement therapy, Futier et al. [144] observed that ∆PCO2_Cent was the only parameter associated with postoperative septic complications that occurred in 34% of cases. Also, a ∆PCO2_Cent > 5 mmHg was able to predict postoperative complications with an AUROC of 0.785. In a prospective study that included 66 high-risk non-cardiac surgical patients [145], the authors found that ∆PCO2_Cent values > 5 mmHg preoperatively were associated with worse postoperatively outcomes. Later, Robin et al. [146] performed a prospective study that included 115 high-risk non-cardiac surgery patients (mainly abdominal surgery). The authors reported that ∆PCO2_Cent on ICU admission immediately after surgery was significantly higher in patients who developed postoperative complications compared to those who did not. In addition, ∆PCO2_Cent on ICU admission predicted the development of postoperative complications with an AUROC of 0.86 and a best cuff value of 5.8 mmHg. Furthermore, the ability of ∆PCO2_Cent to predict postoperative complications was significantly better than the arterial lactate levels.

However, clinical studies have shown contradicting findings in cardiac surgery patients. In a retrospective study that included 60 cardiac surgery patients, high ∆PCO2_Cent values (≥ 8 mmHg) were associated with worse postoperative outcomes, including worse splanchnic functions, longer mechanical ventilation, and longer ICU stays [147]. In another retrospective study that included 220 cardiac surgery patients, the authors reported a low ability of ∆PCO2_Cent to predict outcomes [148]. Also, ∆PCO2_Cent did not predict the occurrence of major postoperative complications and was poorly correlated with tissue perfusion parameters and arterial lactate clearance in a prospective study that included 339 cardiac surgery patients [149]. In addition, in a prospective study that included 308 cardiac surgery patients, Moussa et al. observed that ∆PCO2_Cent was independently associated with lower major postoperative complications [150]. However, the ability of ∆PCO2_Cent to predict major postoperative complications was not good (AUROC of 0.64). In contrast, a retrospective study that included 1,019 cardiac surgery patients showed that ∆PCO2_Cent on ICU admission was independently associated with ICU mortality [151]. Also, recent studies reported the good ability of ∆PCO2_Cent to predict adverse outcomes after cardiac surgery. Mukai et al., in a prospective study that included 110 cardiac surgery patients, found that postoperatively ∆PCO2_Mix was independently associated with major organ morbidity and mortality (MOMM). Also, ∆PCO2_Mix was the best predictor of MOMM with an AUROC of 0.80 and a cut-off of 5. In a recent meta-analysis that included 21 studies (n= 2,155 patients) from medical (n=925), cardiovascular (n=685), surgical (n=483), and mixed (n=62) ICUs, a high PCO2_Cent was associated with higher lactate levels, lower cardiac output and central venous oxygen saturation Also, a high PCO2_Cent was associated with increased mortality (OR of 2.22, 95% CI: 1.3-3.82; p=0.004) in patients with shock, but in only medical and surgical patients [155]. No association with outcomes was found for cardiac surgery patients. However, the meta-analysis included only 2 studies in cardiac surgery studies, and these negative results should be interpreted with caution. Thus, the relationship between PCO2_Cent or PCO2_Mix and outcomes in cardiac surgery patients remains so far unclear.

PCO2_Cent or PCO2_Mix reflects the adequacy between cardiac index and oxygen demand and can help titrate inotropes in critically ill patients. Dobutamine is a synthetic catecholamine with strong inotropic effects on the myocardium owing to its predominately 1-adrenergic properties [156]. Dobutamine administration in these patients aims to restore an appropriate cardiac index to provide adequate oxygen supply to meet the tissue oxygen requirements.

However, dobutamine, in parallel to its effects on systemic hemodynamics, may increase VO2 and, therefore, tissue VCO2 through its direct cellular metabolic effects [112,157]. Two studies investigated the impact of an incremental increase of dobutamine by 5, from 0 to 15 µg/kg/min, one in stable septic shock patients [158] and the other in stable cardiogenic shock patients [112]. In a retrospective study that included a mixed population of critically ill patients, Mekontso-Dessap et al. [START_REF] Mekontso-Dessap | Combination of venoarterial PCO2 difference with arteriovenous O2 content difference to detect anaerobic metabolism in patients[END_REF] found that PCO2_Mix/O2_Mix ratio was significantly higher in patients with elevated blood arterial lactate levels (> 2 mmol/L) than in patients with normal lactate levels.

PCO2_Mix/O2_Mix was able to detect the presence of hyperlactatemia, considered to reflect tissue hypoxia (anaerobic metabolism) with an AUROC of 0.85 and a best cutoff value of 1.4 mmHg/mL. Moreover, patients with PCO2_Mix/O2_Mix < 1.4 mmHg/mL had better 30-day survival than patients with a ratio ≥ 1.4 mmHg/mL. The authors concluded that this ratio could be utilized as a reliable indicator of the presence of global anaerobic metabolism in critically ill patients. Monnet et al. [160] found that this ratio, calculated from central venous blood, PCO2_Cent/O2_Cent, predicted (AUROC of 0.91) an increase in VO2 after a fluid-induced increase in DO2 (VO2/DO2 dependency), and thus, can be able to detect the presence of global tissue hypoxia as accurately as the blood lactate level and far better than ScvO2. In a prospective study that included 98 septic shock patients, Mallat et al. also found that the baseline PCO2_Cent/O2_Cent ratio had an excellent ability to predict tissue hypoxia better than lactate levels (AUROC of 0.96 vs. 0.745, respectively)) defined as the increase in VO2 ≥ 15% induced by volume expansion with a best cutoff value of 1.68 mmHg/mL [161]. In a population of 35 septic shock patients with normalized mean arterial pressure and ScvO2, Mesquida et al. [162] showed that the presence of elevated PCO2_Cent/O2_Cent values at baseline was associated with the absence of lactate clearance within the following hours, and this condition was also associated with mortality. However, this was a retrospective study and it was not powered to explore the prognostic value of the PCO2_Cent/O2_Cent ratio. In a prospective study that included 135 septic shock patients [126], OspinaTascon et al. [135] found that the mixed venous-to-arterial CCO2 difference/O2_Mix ratio at baseline and six hours after resuscitation was an independent prognostic factor of 28-day mortality, but not PCO2_Mix/O2_Mix ratio. The authors attributed this discrepancy to the fact that the PCO2/CCO2 relationship is curvilinear rather than linear and is influenced by many factors such as pH and oxygen saturation (Haldane effect), and under these conditions, the mixed venous-to-arterial CCO2 difference/O2_Mix ratio might not be equivalent to PCO2_Mix/O2_Mix ratio.

However, the relationship between PCO2/O2 ratio with tissue hypoxia is less evident in cardiac surgery patients. Indeed, in 72 cardiac surgery patients, PCO2_Cent/O2_Cent ratio was able to reliably predict the presence of tissue hypoxia defined by an increase in VO2 > 10% induced by fluid resuscitation with an AUROC of 0.77 ± 0.1 and a best cutoff ≥ 1.6 mmHg/mL with a sensitivity Also, PCO2_Mix/O2_Mix was not associated with arterial lactate level in this study. Also, several studies did not find an association between PCO2_Cent/O2_Cent or PCO2_Mix/O2_Mix ratio and outcomes in cardiac surgery patients. In a prospective study that included 114 critically ill patients after elective cardiac surgery with cardiopulmonary bypass, PCO2_Cent/O2_Cent could not predict organ dysfunction's development 48 hours after ICU admission [165]. In another prospective study that included 308 ICU patients after cardiac surgery with cardiopulmonary bypass, PCO2_Cent/O2_Cent was not associated with major postoperative complications that occurred in 56.5% of patients [150]. The discrepancies in findings between the septic and cardiac surgery populations might be explained by the fact that cardiac surgery with cardiopulmonary bypass is a specific physiological condition with several factors that might affect the PCO2/CCO2 relationship. Background Early identification and improvement of tissue hypoperfusion are critical factors in the treatment of septic shock patients. The deficit in tissue perfusion with reduced blood flow should be considered as the primary determinant of an increase in ∆PCO2. ∆PCO2 should be seen as an indicator of the adequacy of venous blood flow (cardiac output) to clear the CO2 generated by the peripheral tissues rather than as a marker of tissue hypoxia. Thus, monitoring ∆PCO2 could be a useful complementary tool to guide the resuscitation in the early phase of septic shock (Figure 6). It can also be combined with the O2-derived parameters in order to calculate the ∆PCO2/O2, which can be used to detect the presence of global anaerobic metabolism. In such a situation, the presence of low ScvO2 (< 70%) should push the physician to increase DO2, and if ∆PCO2_Cent is increased (≥ 6 mmHg), that indicates that increasing cardiac output is the rational choice to achieve this target (Figure 6). In the presence of a normal/high ScvO2 (≥ 70%), an elevated ∆PCO2_Cent still suggests that rising cardiac output can be indicated with the purpose of reducing global tissue hypoxia (Figure 6). However, if both ScvO2 and ∆PCO2_Cent are normal in a state of global anaerobic metabolism, manipulating the microcirculation will probably be ineffective in reducing oxygen deficit (Figure 6) [START_REF] Mallat | Use of venous-to-arterial carbon dioxide tension difference to guide resuscitation therapy in septic shock[END_REF]. Unfortunately, there is no RCT that compared the efficacy of hemodynamic optimization using the metabolic approach to the usual care in septic shock patients. Thus, the effectiveness of the proposed hemodynamic approach in Figure 6 needs to be validated in a multicentric RCT.

II. Metabolic approach and weaning from mechanical ventilation

The metabolic approach can be used to detect the imbalance between VO2

III. Metabolic approach and detection of fluid responsiveness

In the same line, PCO2 might help identify patients who responded or did not to fluid challenges in cases where cardiac output monitoring is unavailable. In post-cardiac surgery sedated and mechanically ventilated patients with cardiac index < 2.5 L/min/m 2 , the changes in cardiac index (CI) induced by fluid challenge (500-mL bolus of crystalloid given over 30 min) were found to be significantly correlated with changes in PCO2_Cent (-PCO2_Cent) (r = -0.53, p = 0.001) [171].

However, the AUROC for changes in PCO2_Cent to define fluid responsiveness was not determined in that study. Also, in 30 cardiogenic shock or postoperative cardiac surgery patients, the authors observed that changes in ScvO2 (ScvO2) were significantly correlated with CI induced by a bolus of 500 mL of normal saline administered over 10-min (r = 0.67, p < 0.001)14.

Also, ScvO2 had an excellent ability to define an increase in CI ≥ 15% after volume expansion (Figure 8). Indeed, severe metabolic acidosis, low hematocrit, and high oxygen saturation can increase PCO2 for a given CCO2 since less CO2 is bound to hemoglobin.

In conditions of very low venous oxygen saturation (< 30%), Jakob et al. [124] found that changes in ΔPCO2 might not parallel changes in CCO2 differences or blood flow due in part to the Haldane effect. However, in an experimental study of vascularly isolated, innervated, and perfused dog hindlimb, Mallat et Vallet [127] observed that the Haldane effect did not influence the PCO2/CCO2 relationship as the latter was the same, accounting or not for the changes in venous oxygen saturation even when the latter decreased far below 30%. In healthy subjects, during heavy exercise, Sun et al. [174] also reported that Haldane effect (changes in venous oxygen saturation) had a minor impact on the PCO2/CCO2 relationship. Furthermore, in septic shock patients, Mesquida et al. [175] found that venous oxygen saturation (Haldane effect) had a minimal impact on the PCO2/CCO2 relationship.

In the experimental study of perfused dog hindlimb [127], the degree of metabolic acidosis impacted the PCO2/CCO2 relationship significantly. Indeed, when the changes in venous pH were ignored, the PCO2/CCO2 relationship was almost linear. However, CCO2 was not linearly related to PCO2 when the changes in pH were acknowledged. In fact, PCO2 and CCO2 changed in opposite directions as metabolic acid was added to the blood by the hypoxic cells. That is because metabolic acidosis causes plasma and red blood cell CCO2 and bicarbonates to decrease. Also, changes in pH had a significant influence on the PCO2/CCO2 relationship with CCO2 not linearly related to PCO2 and even varied in opposite directions after the lactic acidosis threshold was reached during heavy exercise in healthy subjects [174]. In addition, metabolic acidosis (pH) was the only best predictor of the discrepancy found between PCO2_Mix/O2_Mix and ΔCCO2/C(av)O2 in septic shock patients [175]. Thus, in situations with moderate/severe metabolic acidosis, an elevated ∆PCO2 might not reflect only low or inadequate blood flow but could also be ascribed to modifications of the CO2-hemoglobin dissociation curve.

The impact of hemoglobin on the PCO2/CCO2 relationship was less studied. In surgical patients with sepsis and different degrees of illness, Chiarla et al. [122] observed that the decrease in hemoglobin increased ΔPCO2 for any given CCO2. However, the impact was less evident in normal conditions, and it becomes relevant only in extreme conditions where several combinations of low hemoglobin concentration, with low-flow state, acidosis, and hypercapnia, may synergistically act to disturb the physiological balance.

Limitations related to errors in PCO2 measurement

There are many pre-analytical sources of errors in PCO2 measurement that should be avoided to interpret ∆PCO2 correctly: inappropriate sample container, insufficient sample volume compared to anticoagulant volume, and contaminated sample with resident fluid in the line or with air or venous blood, etc. Even after having taken all precautions to minimize the pre-analytical and analytical errors, Mallat et found, in a prospective study [178], that the measurement error for ∆PCO2_Cent was ± 1.4 mmHg and the smallest detectable difference, which is the least change that requires to be measured by a laboratory analyzer to identify a genuine change of measurement, was ± 2 mmHg. This means that the changes in ∆PCO2_Cent should be more than ± 2 mmHg to be considered as real changes and not due to natural variation [178]. Differences between the curves result in higher CO2 content in the blood, and smaller PCO2 differences between arterial and venous blood. Hemoglobin-O2 saturation affects the position of the CO2 dissociation curve (Haldane effect) [START_REF] Mallat | Use of venous-to-arterial carbon dioxide tension difference to guide resuscitation therapy in septic shock[END_REF].

V. Conclusions

Acute circulatory failure leads to tissue hypoperfusion, which, if unrecognized and treated rapidly, will result in tissue hypoxia and eventually death. Indeed, if oxygen availability is limited or oxygen utilization by the cell is altered, cellular oxygen consumption may fall, leading to organ dysfunction. Vital cellular functions can no longer be sustained, and irreversible impairments may develop if the situation persists. Moreover, tissue hypoxia occurs when tissue cells have abnormal oxygen utilization, resulting in anaerobic metabolism. Thus, rapid recognition of tissue hypoperfusion and tissue hypoxia is of utmost importance to avoid the progression to a dreadful outcome. Many tools exist to detect and monitor the presence of tissue hypoperfusion/tissue hypoxia. Many of these require using specific devices that are usually unavailable in many ICUs or used for research purposes. The metabolic approach based on CO2 and O2-derived variables is attractive as it necessitates the presence of only a central venous catheter and an arterial line that many critically ill patients are usually equipped with these catheters. Many experimental and clinical observational studies demonstrated the reliability of PCO2 and PCO2/O2 ratio in detecting tissue hypoperfusion and tissue hypoxia, mainly in septic shock or postoperative noncardiac surgery patients, and their association with outcomes. However, multicenter RCTs are required to demonstrate the efficacy of the metabolic approach compared to the standard of care in the hemodynamic management of patients with acute circulatory failure.

( 1 .

 1 Abbreviations…………………………………………………………………………………………………………………….150

24 25

 24

Figure 1 .

 1 Figure 1. Distinct StO2 patterns in response to a vascular occlusion test (VOT) in healthy subjects and septic shock.Figure A shows a normal StO2 response to a VOT, whereas figure B shows an impaired response in a septic shock patient. Note that, independently of the baseline absoluteStO2 value, the response to ischemia is different. The DeO2 slope is slower, and a longer period is needed to reach a predetermined ischemic threshold. The vascular reactivity is also altered, resulting in a slower StO2 recovery rate (ReO2) and a blunted hyperemic response before returning to baseline StO2[START_REF] Donati | Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study[END_REF].

  Figure 1. Distinct StO2 patterns in response to a vascular occlusion test (VOT) in healthy subjects and septic shock.Figure A shows a normal StO2 response to a VOT, whereas figure B shows an impaired response in a septic shock patient. Note that, independently of the baseline absoluteStO2 value, the response to ischemia is different. The DeO2 slope is slower, and a longer period is needed to reach a predetermined ischemic threshold. The vascular reactivity is also altered, resulting in a slower StO2 recovery rate (ReO2) and a blunted hyperemic response before returning to baseline StO2[START_REF] Donati | Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study[END_REF].

Figure 2 .

 2 Figure 2. Principle of Laser Doppler Flowmetry. red light is emitted from a light source; if the light beam is scattered-off of stationary tissue or cells, there is no shift in the light spectrum. If, however, the light hits a moving cell in a blood vessel there is a shift in the light spectrum of the scattered light according to the Doppler flowmetry.

Figure 3 .

 3 Figure 3. Cytocam-Incident Dark Field (IDF) images of sublingual microcirculation. A: early phase septic shock patient.A decrease of vessel density and of perfused vessels, and an increase of nonperfused/under-perfused vessels can be observed. B: healthy volunteer. A normal vessel density and proportion of perfused vessels can be observed[START_REF] Donati | Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study[END_REF].

Figure 4 .

 4 Figure 4. Left: the mottling score is based on a mottling area extension on the legs. Score 0 indicates no mottling; score 1, a modest mottling area (coin size) localized to the center of the knee; score 2, a moderate mottling area that does not exceed the superior edge of the kneecap;

Figure 5 .

 5 Figure 5. Lactate metabolism.

  marker and an additional endpoint for resuscitation [101]. Gastric intramucosal PCO2, as measured by gastric tonometry, has been recognized to be of clinical value as a prognostic factor in assessing the effects of particular therapeutic interventions and as an end-point of resuscitation. However, this technique has several limitations that have hampered its implementation in clinical practice. The sublingual tissue bed has been shown to be damaged in models of shock, and microcirculatory changes in this area may indicate imminent changes in other important organs. Sublingual mucosal PCO2 (PslCO2) measurement by sublingual capnography is technically simple, noninvasive, and gives near-instantaneous results. Clinical studies have established that high PslCO2 values and, more especially, high PslCO2 gap (PslCO2arterial PCO2) values are correlated with impaired microcirculatory blood flow and a poor outcome in critically ill patients. Sublingual capnography seems to be the ideal noninvasive monitoring tool to evaluate the severity of shock states and the adequacy of tissue perfusion. However, clinical studies are needed to determine the clinical utility of PslCO2 gap monitoring as an endpoint target to guide resuscitation in critically ill patients. In the below manuscript, we reviewed the tissue capnometry for assessing tissue hypoperfusion in critically ill patients [102].

(

  PCO2 = k × CCO2) [104-106]. Therefore, VCO2 can be calculated from a modified Fick equation as: VCO2 = cardiac output × k × PCO2_Mix so that PCO2_Mix = k × VCO2/cardiac output, where k is the pseudo-linear coefficient supposed to be constant in physiological states [104]. Therefore, PCO2_Mix would be linearly linked to CO2 generation and inversely associated with cardiac output. Under normal conditions, PCO2_Mix values range between 2 and 6 mmHg [107].

  However, during spontaneous breathing, hyperventilation, stimulated by the decreased blood flow, may reduce PaCO2 and thus may prevent the CO2 stagnation-induced rise in PvCO2[110].

Furthermore,

  Ferrera et al. [118] observed an increase in airway respiratory quotient (median 0.96 [IQR: 0.91-1.06]) during the last step of graded hemorrhage in sheep, and it was normalized after retransfusion.

  2 mmHg [152]. In a propensitymatched study, Chen et al. found that ∆PCO2_Mix predicted the occurrence of poor outcomes with an AUROC of 0.84 and a cut-off of 7.1 mmHg [153]. Nevertheless, in a recent retrospective study that included 1,933 patients, we found that ∆PCO2_Cent had poor diagnostic performance (AUROC of 0.55) to predict postoperative complications even though it was independently associated with postoperative adverse outcomes [154]. 110

PCO2_Cent 2 .

 2 was a good indicator of the change of VCO2 induced by dobutamine and was able to depict the hemodynamic effects of the thermogenic effects of dobutamine in both populations[159].116 Combination of PCO2 with O2

of 68 .

 68 8% and a specificity of 87.5% [163]. Nevertheless, Abou-Arab et al. found no relationship between PCO2_Mix/O2_Mix ratio and the increase in VO2 ≥ 15% after fluid challenge considered as a marker of tissue hypoxia in 110 postoperative cardiac surgery patients [164].

Figure 6 .

 6 Figure 6. Metabolic approach guided protocol. ScvO2: Central venous oxygen saturation; ∆PCO2: Central venous-to-arterial carbon dioxide tension difference; SaO2: Arterial oxygen saturation; C(a-cv)O2: Central arteriovenous oxygen content difference; DO2: Oxygen delivery; PEEP: Positive end expiratory pressure; red arrows: Increasing [6].

( 1 .

 1 fluid responsiveness) with an AUROC of 0.90[172].Recently, in a prospective study, we investigated if PCO2_Cent or ScvO2 can help classify responders and non-responders to fluid challenge in 49 septic shock patients[173]. Fluid responsiveness was defined as an increase in CI > 10% after fluid challenge. We found that in overall population, -PCO2_Cent and ScvO2 were significantly correlated with CI after fluid challenge (r = -0.30, p = 0.03 and r = 0.42, p = 0.003, respectively). The AUROCs for -PCO2_Cent and ScvO2 to define fluid responsiveness were 0.76 (p < 0.001) and 0.68 (p = 0.02), respectively. However, in the subgroup of patients in whom the oxygen consumption slightly increased (≤ 10%) after fluid challenge (no tissue hypoxia), the abilities of -PCO2_Cent and ScvO2 to define fluid responsiveness improved (AUROC= 0.83, p < 0.001, and 0.73, p = 0.006; respectively). The fact that ScvO2 was less reliable in classifying fluid responders compared to the results obtained in cardiogenic shock postoperative cardiac surgery patients [172] might be due to the reason that venous oxygen saturation may not be a good indicator of tissue hypoperfusion in the setting of sepsis, due to microcirculatory shunting and mitochondrial dysfunction that can result in oxygen extraction abnormalities[139]. Limitations related to the PCO2/CCO2 relationship PCO2_Mix or PCO2_Cent and PCO2_Mix/O2_Mix or PCO2_Cent/O2_Cent ratio might be affected by other factors than blood flow or anaerobic metabolism by influencing the relationship between CCO2 and PCO2, which is quasilinear over the physiological range of PCO2 [120], but it becomes curvilinear if these factors change[106]. These factors are the degree of metabolic acidosis [121] (Figure7), hematocrit[122], and oxygen saturation (Haldane effect)[119, 122]

2 .

 2 Limitations related to acute changes in PCO2Acute changes in PCO2 induced by changes in ventilator settings might influence ΔPCO2. In a small study that included 10 mechanically ventilated postoperative patients,Morel et al. [176] found that acute hyperventilation significantly increased in ΔPCO2_Cent without changes in cardiac index. In septic shock patients, Mallat et al.[177] showed that acute hyperventilation induced an increase in ΔPCO2_Cent independently of the cardiac index. The rise in ΔPCO2_Cent was related to the increase in oxygen consumption caused by acute respiratory alkalosis. The clinician should be aware of the effects of acute elevation of alveolar ventilation on ΔPCO2 when interpreting ΔPCO2 at the bedside.

Figure 7 .

 7 Figure 7. CO2 dissociation curve. CO2 content (mL/100 mL) vs CO2 partial tension (PCO2). Each curve is described at constant base excess (BE). As displayed, for the same CO2 content, changing the BE results in a great change in PCO2[START_REF] Mallat | Use of venous-to-arterial carbon dioxide tension difference to guide resuscitation therapy in septic shock[END_REF].

Figure 8 .

 8 Figure 8. CO2 dissociation curve. CO2 content (mL/100 mL) vs CO2 partial tension (PCO2).Differences between the curves result in higher CO2 content in the blood, and smaller PCO2 differences between arterial and venous blood. Hemoglobin-O2 saturation affects the position of the CO2 dissociation curve (Haldane effect)[START_REF] Mallat | Use of venous-to-arterial carbon dioxide tension difference to guide resuscitation therapy in septic shock[END_REF].

  Néanmoins, la conception de ces essais ne visait pas à répondre à la question de savoir si une cible ScvO2> 70% était efficace pour réduire la morbidité et la mortalité. Dans ces mêmes études, les valeurs moyennes initiales de ScvO2 étaient déjà au-dessus de 70%. Ainsi, ces résultats n'indiquent pas que les cliniciens doivent cesser de surveiller la ScvO2 et d'ajuster la DO2 en optimisant les niveaux de ScvO2, en particulier chez les patients en état de choc septique avec une ScvO2 basse, qui sont les plus à risque de mortalité. D'autre part, la normalisation de ScvO2 peut ne pas exclure une hypoperfusion tissulaire persistante et l'évolution vers un Cependant les résultats ne sont pas très clairs chez les patients après chirurgie cardiaque notamment ceux qui ont le recours à une circulation extracorporelle. D'un autre côté, il a été mis en évidence que l'augmentation de ΔPCO2 et la diminution de la ScvO2 lors d'une épreuve de ventilation spontanée prédit de façon fiable l'échec de l'extubation chez les patients en ventilation mécanique invasive. En effet, les changements de ces paramètres durant une épreuve de ventilation spontanée reflètent l'incapacité du débit cardiaque à s'adapter à l'augmentation de la consommation d'oxygène induite par la ventilation spontanée.Il semble donc que l'intégration des paramètres métaboliques ScvO2, ΔPCO2, et ΔPCO2/O2 dans la réanimation précoce des patients en état de choc septique offre des possibilités intéressantes

	d'optimisation hémodynamique, mais nécessite des travaux de validation clinique à travers des
	études randomisées contrôlées multicentriques pour préciser les modalités d'utilisation de ces
	paramètres.
	Mots-Clés : Hypoxie tissulaire ; oxygénation tissulaire ; transport artérielle en oxygène ;
	consommation tissulaire en oxygène ; extraction d'oxygène ; insuffisance circulatoire aigue ;
	choc septique ; saturation veineuse en oxygène ; gradient veino-artériel de PCO2 ; rapport de
	gradient veino-artériel de PCO2 sur la différence artérioveineuse de contenu en oxygène ;
	quotient respiratoire ; effet Haldane ; monitorage de la microcirculation ; complications
	postopératoires.

Plusieurs techniques ont été proposé pour détecter et monitorer les situations d'hypoperfusion ou d'hypoxie tissulaire comme le « Laser Doppler Flowmetry », le « Orthogonal polarization spectral (OPS ) » et le « Sidestream Dark Field (SDF) ». Chaque technique a ses avantages et ses inconvénients, mais le facteur limitant majeur est le besoin des appareils spécifiques qui ne sont pas disponibles dans de nombreux services de réanimations et leurs utilisations sont limitées à la recherche clinique. La saturation veineuse mêlée en oxygène (SvO2) a été proposée comme un marqueur indirect d'oxygénation tissulaire. La SvO2 reflète la balance entre DO2 et VO2. Il a été démontré qu'une optimisation précoce de l'hémodynamique en utilisant un protocole de réanimation visant à augmenter la saturation veineuse central en oxygène (ScvO2) > 70% était lié à une réduction importante de la mortalité chez les patients en choc septique. Cependant, trois grandes études multicentriques n'ont démontré aucun bénéfice de cette approche thérapeutique ciblée précoce. dysfonctionnement multi-organe et la mortalité. Dans des conditions septiques, des valeurs de ScvO2 normales ou élevées pourraient être dues à l'hétérogénéité de la microcirculation générant un shunt capillaire et/ou une atteinte mitochondriale responsables de perturbations de l'extraction d'oxygène tissulaire. Dans ce contexte, les indices dérivés de la pression partielle du sang artériel et du sang veineux central ou mixte en dioxyde de carbone (CO2) ont été proposés pour surmonter les limites des variables précédentes afin d'indiquer l'adéquation de l'apport et des besoins en oxygène. Le gradient veino-artériel de PCO2 est la différence de pression partielle de CO2 entre le compartiment veineux mêlé ou veineux central (ΔPCO2) et le compartiment artériel. Plusieurs études ont montré l'utilité de ce gradient à détecter les situations d'hypoperfusion tissulaire chez les patients en insuffisance circulatoire aiguë même avec une ScvO2 normale (> 70%). Le rapport de ΔPCO2 sur la différence artérioveineuse de contenu en oxygène (ΔPCO2/O2), considéré comme le reflet du quotient respiratoire, a été démontré comme étant un indice qui permet de prédire de façon fiable l'activation du métabolisme anaérobique et donc la présence d'hypoxie tissulaire. Cette analyse multiparamétrique (ΔPCO2 et ScvO2) était plus prédictive que chaque paramètre pris séparément et que les paramètres non métaboliques comme les critères échographiques et le pro-BNP. Aussi, il a été démontré que les changements de ΔPCO2 et ScvO2 après un remplissage vasculaire pourraient prédire l'augmentation du débit cardiaque induite par le remplissage vasculaire. Il existe plusieurs limitations à l'utilisation des variables dérivées du CO2 qui sont essentiellement liées à la relation entre le contenu de CO2 et la PCO2. En effet, plusieurs facteurs peuvent affecter cette relation notamment l'acidose métabolique, la concentration d'hémoglobine, et la saturation veineuse en oxygène. Ces facteurs peuvent changer le ΔPCO2 indépendamment du changement de la perfusion tissulaire. Aussi, les variations aiguës de la PCO2 induites par des changements aigus de la ventilation alvéolaire peuvent aussi modifier le ΔPCO2 indépendamment du débit cardiaque. Le clinicien doit connaître ces limitations afin de pouvoir interpréter ces paramètres de façon appropriée.