Combination of O₂ and CO₂-derived variables to detect tissue hypoxia in the critically ill patient

Introduction

Early detection and prompt reversion of tissue hypoperfusion are key factors to prevent progression to multiorgan dysfunction and death during shock states (1). Techniques commonly used to monitor tissue perfusion have focused mainly on systemic blood flow and the balance between oxygen demand and supply to the tissues (2,3). Indeed, quantitative resuscitation targeting central venous oxygen saturation (ScvO₂) and some macro hemodynamic parameters was related with a significant reduction of mortality in an initial single-center randomized controlled trial including patients with septic shock (4). Subsequent studies on implementation of resuscitation bundles targeting similar hemodynamic goals in septic shock were also apparently beneficial (5,6). Nevertheless, the utility of oxygen-derived parameters was promptly challenged (7), and recent clinical trials failed to demonstrate their clinical benefit (8-10). In fact, ScvO₂ is often normal at the ICU admission (11), and attaining macro hemodynamic goals and/or normalization of global oxygen-derived parameters in septic shock do not exclude the occurrence or persistence of tissue hypoxia. In this context, other variables such as carbon dioxide (CO₂)-derived parameters could provide very important information about macro and micro hemodynamics, even when oxygen- derived variables resemble corrected. Importantly, variations in CO₂ occur faster than changes in lactate levels, which make the CO₂-derived parameters an attractive tool to monitor tissue perfusion and potentially, cell oxygenation during the early stages of shock.

The theoretical basics of the venous-arterial CO₂ to arterial-venous O₂ ratio (Cv-aCO₂/Ca-vO₂ ratio)

Aerobic carbon dioxide production and the physiological rationale of the Cv-aCO₂/Ca-vO₂ ratio

Under normoxic conditions, carbon dioxide (CO₂) is generated during the tricarboxylic acid or Krebs cycle. The total CO₂ production (VCO₂) is directly related to the global oxygen consumption (VO₂), by the relationship: VCO₂ = RQ × VO₂, where RQ symbolizes the respiratory quotient and represents the relationship between the total CO₂ generated and the oxygen (O₂) consumed throughout metabolic processes. Under normal rest conditions, RQ fluctuates from 0.6 to 1.0 depending on the predominant energetic substrate utilized (i.e., amino acids, lipids or carbohydrates). Thus, under resting aerobic conditions RQ should not be >1.0 since VCO₂ should not exceed the O₂ availability. Indeed, RQ remains <1.0 even during metabolic rate rises (as long as aerobic metabolism is maintained), because the proportional increase in VCO₂ and VO₂.

According to the Fick equation, VO₂ and VCO₂ are directly proportional to the cardiac output and their respective arterial-to-venous and venous-to-arterial content differences. Following this rationale, the quotient between the venous-to-arterial CO₂ content difference (Cv-aCO₂) and the arterial-to-venous O₂ content difference (Ca-vO₂), i.e., the Cv-aCO₂/Ca-vO₂ ratio, should reflect the VCO₂/VO₂ fraction and it should be theoretically independent of flow variations, as cardiac output is present at both numerator and denominator components of the formula (Figure 1).

Figure 1 Normal resting conditions. Normal macro and micro hemodynamics lead to homogeneous distribution of oxygen to the tissues. Under preserved mitochondrial function, CO₂ is generated during the Krebs cycle (aerobic VCO₂). The ATP generated predominantly during the oxidative phosphorylation (and in a lesser extend, during glycolysis) is hydrolyzed thus liberating free hydrogenions (H+), which are normally recycled into the mitochondria to synthetize again ATP. Minor quantities of H+ pass the cell membrane reaching the circulation. Such H+ are buffered by the HCO₃- system and finally transformed into CO₂ and water. However, this last process accounts minimally for the total VCO₂ when oxidative phosphorylation functions normally. The relationship between the total CO₂ production (VCO₂) and oxygen consumption (VO₂) should be <1.0 under aerobic conditions. According to the Fick equation, VCO₂ and VO₂ are directly proportional to the cardiac output and their respective venous-to-arterial and arterial-to-venous content differences, respectively. Thus, the quotient between the venous-to-arterial CO₂ content difference (Cv-aCO₂) and the arterial-to-venous O₂ content difference (Ca-vO₂), i.e., the Cv-aCO₂/Ca-vO₂ ratio, should reflect in some extend the VCO₂/VO₂ fraction, independently of flow variations (since cardiac output is present at both numerator and denominator components of the formula).

Under aerobic steady state conditions, VCO₂ approaches VO₂, whereby the Cv-aCO₂ and the Ca-vO₂ should also do it. Consequently, VCO₂ should not exceed O₂ availability whereby the VCO₂/VO₂ ratio [i.e., the respiratory quotient (RQ)] should not be >1.0. Thus, VCO₂/VO₂ and Cv-aCO₂/Ca-vO₂ ratio >1.0 should be considered as abnormal and these could potentially reflect anaerobic CO₂ generation.

Anaerobic carbon dioxide production

Under hypoxia conditions, aerobic VCO₂ decreases while anaerobic VCO₂ turns on. Such anaerobic VCO₂ reflects the proton (H+) buffering by cytosolic and plasmatic bicarbonate (HCO₃–). The “gross H+ release” results from the sum of all cellular reactions liberating H+ [e.g., the ATPase, hexokinase (HK), phosphofructokinase (PFK), and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) reactions], which are counterbalanced by metabolic reactions consuming H+ [e.g., AMP deaminase (AMPDase), the creatine kinase (CK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) reactions]. Thus, the balance between the “gross H+ release” and chemical reactions consuming H+ (i.e., the “metabolic buffering”) results in the “net H+ release”, which is ultimately regulated by the intra and extracellular structural buffering (e.g., amino acids) and the bicarbonate buffering system (12).

Interestingly, the hydrolysis of the ATP has been proposed as the most important source of hydrogen ions during intense exercise (13), prolonged ischemia (14) or increased Na+-K+ ATPase activity (15-19). Thus, non-recycled H+ due either to slowdown, blocking or overshoot of oxidative phosphorylation, progressively accumulate to be finally buffered by the bicarbonate system. This later will be responsible for the anaerobic VCO₂ as the protons are captured by HCO₃– leading to carbonic acid (H₂CO₃) generation with subsequent dissociation into CO₂ and H₂O (Figure 2). Nevertheless, although anaerobic VCO₂ is a biologically plausible process, its clinical demonstration is quite complex since the efferent venous blood flow might be sufficient to wash out the total CO₂ produced at the tissues, thus masking the portion of increased anaerobic CO₂.

Figure 2 Abnormal conditions. When macro hemodynamics and/or microcirculatory blood distribution are inadequate or when mitochondrial machinery is blocked, the H+ generated during the ATP hydrolysis are not recycled during the oxidative phosphorylation. Thus, the excess of H+ will cross the cell membrane to finally be buffered by the HCO₃- system and thus, to be transformed into CO₂ and H₂O. This leads to increase VCO₂/VO₂ fraction and its surrogate, the Cv-aCO₂/Ca-vO₂ ratio. To minimize the influence of Haldane effect, CO₂ contents should be calculated instead of CO₂ partial pressures (for details, see at the text).

The hypothetical meaning of the Cv-aCO₂/Ca-vO₂ ratio

Experimental blockade of mitochondrial O₂ utilization and limitation of O₂ availability during severe tissue hypoperfusion have been related with “non-symmetrical” reductions in VCO₂ and VO₂ with the subsequent RQ increase. Such “asymmetric” VCO₂/VO₂ fall might be explained by an increase in anaerobic CO₂ production resulting from the buffering of protons delivered from the ATP hydrolysis that are not recycled during oxidative phosphorylation (Figure 2). Similarly, when anaerobic threshold is achieved after an excessive increased metabolic demand, total VCO₂ can exceed the adaptive increment in VO₂ (20), thus leading to RQ values >1.0. Similar data have been described during experimental shock in which VCO₂ decreases slightly less than the VO₂ reduction, leading to increases in the VCO₂/VO₂ ratio (21,22). Interestingly, reversion of shock was related with returning VCO₂/VO₂ ratio to values <1.0. Thus, if considering the Cv-aCO₂/Ca-vO₂ ratio as a surrogate of the VCO₂/VO₂ ratio, a Cv-aCO₂/Ca-vO₂ ratio >1.0 could potentially identify the presence of anaerobic metabolism.

The potential clinical use of the Cv-aCO₂/Ca-vO₂ ratio

Although hyperlactatemia has been traditionally used as a marker of anaerobic metabolism, lactate levels might frequently increase by causes different to tissue hypoxia (23). Indeed, high lactate levels can result from increased glycolytic activity, abnormal pyruvate metabolism and altered metabolic lactate reuptake (24-26). Thus, interpretation of hyperlactatemia during the resuscitation and post resuscitation periods of septic shock is not straightforward. In this sense, the use of combined CO₂ and O₂-derived parameters could theoretically help to identify, in some extend, the persistence or reversion of anaerobic metabolism.

Using CO₂ partial pressures (pCO₂) instead of CO₂ contents (CCO₂), Mekontso-Dessap et al. (27) demonstrated a good agreement between the Pv-aCO₂/Ca-vO₂ ratio (as surrogate of the Cv-aCO₂/Ca-vO₂ ratio) and lactate levels ≥2.0 mmol/L (accepting it as indicator of anaerobic metabolism). Nevertheless, far beyond a simple agreement, the Cv-aCO₂/Ca-vO₂ ratio might provide additional information to that offered by lactate levels. A recent study (28) suggested that combination of persistent hyperlactatemia and Cv-aCO₂/Ca-vO₂ ratios >1.0 is related with more severe multiorgan dysfunction and higher mortality rates in patients with septic shock. Remarkably, patients attaining normalization of lactate levels but with Cv-aCO₂/Ca-vO₂ ratios >1.0 depicted similar clinical outcomes than those with persistent hyperlactatemia but with normal Cv-aCO₂/Ca-vO₂ ratios. Nevertheless, this study did not elucidate whether Cv-aCO₂/Ca-vO₂ ratios >1.0 might anticipate increases in lactate levels.

Subsequent studies corroborated the prognostic value of the Pv-aCO₂/Ca-vO₂ ratio in sepsis and septic shock (29,30). Importantly, an increased Pv-aCO₂/Ca-vO₂ ratio was related with delayed lactate clearance (29,30), which suggests that Cv-aCO₂/Ca-vO₂ ratio could anticipate lactate variations. Other studies showed that combined hyperlactatemia and high Cv-aCO₂/Ca-vO₂ ratio (or its equivalent, the Pv-aCO₂/Ca-vO₂ ratio) could identify ongoing supply dependency of O₂ consumption (i.e., VO₂/DO₂ dependency) (31,32). In agreement with this concept, oxygen consumption (VO₂) was increased after a fluid load only in patients with acute circulatory failure and an abnormal Pv-aCO₂/Ca-vO₂ ratio at the baseline (31,32).

An experimental model of septic shock secondary to peritonitis demonstrated that regional mesenteric Cv-aCO₂/Ca-vO₂ ratio tracks the instauration and reversion of anaerobic metabolism following the variations in microcirculatory blood flow distribution at jejunal mucosa and serosa and also tracking the variations in mesenteric lactate levels (33). Hence, anaerobic metabolism reflected by increases in Cv-aCO₂/Ca-vO₂ ratio can be reversed by improvement of O₂ distribution at microcirculatory level, at least during very early stages of septic shock (33).

Combined CO₂ and O₂-derived variables might add prognostic information to that provided by lactate levels during early stages of shock. In fact, Cv-aCO₂/Ca-vO₂ ratio reacts faster than lactate levels to short-term hemodynamic changes, which makes it an attractive variable to be monitored and, although difficult to be calculated, its interpretation is easier, with values >1.0 suggesting ongoing anaerobic metabolism. Thus, an increased lactate accompanied by a Cv-aCO₂/Ca-vO₂ ratio >1.0 might suggest “ongoing” tissue hypoxia, whereby clinicians should be encouraged to optimize macro and micro hemodynamics. Conversely, increased lactate levels accompanied by Cv-aCO₂/Ca-vO₂ ratios ≤1.0 could suggest that such lactate increase results from slow lactate clearance more than from ongoing tissue hypoxia, whereby additional resuscitation efforts should be discouraged. Nevertheless, such hypothesis must be tested in prospective clinical trials before to translate into the clinical practice.

The Haldane effect, the CO₂ dissociation curves and the criticism about the Cv-aCO₂/Ca-vO₂ ratio as a marker of anaerobic metabolism

The phenomenon whereby hemoglobin increases or decreases its affinity for CO₂ according to variations in its oxygenated or deoxygenated state is known as Haldane effect. Thus, when blood enters systemic capillaries and releases O₂, the CO₂-carrying capacity rises so that blood picks up extra CO₂. Conversely, as blood enters pulmonary capillaries and binds O₂, the CO₂-carrying capacity falls, thus facilitating pulmonary elimination of CO₂.

According to the Haldane effect, the total CO₂ content (CCO₂) rises at a given pCO₂ as O₂ hemoglobin saturation falls, thus indicating a non-linear relationship between pCO₂ and CCO₂. Likewise, changes in tissue oxygen extraction, pH, tissue VCO₂, and hemoglobin concentration can also influence the relationships between pCO₂ and CCO₂, making difficult the interpretation of the venous-to-arterial pCO₂ difference. In addition, depending on baseline SvO₂, the Haldane effect may increase or decrease Pv-aCO₂ in response to the same changes in blood flow or metabolism (34).

Admittedly, Pv-aCO₂/Ca-vO₂ could be equivalent to the Cv-aCO₂/Ca-vO₂ ratio when PCO₂, pH, and SvO₂ approximate to normality, which occurs in many cases. Nevertheless, during low pCO₂ and SvO₂ conditions, Cv-aCO₂ might profoundly differ from Pv-aCO₂. Indeed, clinical observations during very early stages of resuscitation of septic shock suggest that persistence of a high Cv-aCO₂/Ca-vO₂ ratio is related to unfavorable clinical outcomes but not its equivalent, the Pv-aCO₂/Ca-vO₂ ratio (28). Thus, although the influence of the Haldane effect is negligible at low Pv-aCO₂, the disagreement of Cv-aCO₂ and Pv-aCO₂ increases at higher Pv-aCO₂ values (28).

Some authors have proposed that high Pcv-aCO₂/Ca-vO₂ ratio does not reflect anaerobic metabolism and obeys mainly to variations in hemoglobin levels (35), according to observations based on the analysis of expired gases by indirect calorimetry. Nevertheless, under non-steady-state conditions such as during shock states, RQ is easily influenced by a number of physiologic events that can alter the agreement between measurements of RQ by indirect calorimetry (RQic) and the true metabolic activity. Thus, the high solubility of CO₂ in tissues and blood, and the variations in pulmonary ventilation/perfusion (V/Q) relationships might lead to momentary discordant results between RQic and the true RQ, until a new stead- state is attained (36). Consequently, the relationship between venous-arterial CO₂ to arterial-venous O₂ differences and anaerobic metabolism should not be rejected based just on measurements of VCO₂ by RQic. Similarly, attributing high Pv-aCO₂/Ca-vO₂ ratios just to variations in hemoglobin levels could be physiologically misleading, since at very low hemoglobin values, small errors in hemoglobin measurements will amplify the error of calculation of Pv-aCO₂/Ca-vO₂ or Cv-aCO₂/Ca-vO₂ values.

Conclusions

Physiological determinants of combined CO₂ and O₂-derived variables are quite complex. Theoretically, the Cv-aCO₂/Ca-vO₂ ratio is independent of systemic blood flow variations and it should approach the RQ or at least, it should approximates cell respiration state. Although venous-arterial CO₂ to arterial-venous O₂ differences have demonstrated to predict fluid responsiveness in terms of VO₂, to anticipate slowly lactate clearance and to be related with clinical outcomes, its potential application in the clinical practice needs to be confirmed.

Acknowledgments

Centro de Investigaciones clínicas, Fundación Valle del Lili. Cali, Colombia.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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