How can CO₂-derived indices guide resuscitation in critically ill patients?

Introduction

In patients with acute circulatory failure, one of the goals of the treatment is to increase cardiac output. The aim is to improve the oxygen delivery to the tissues and correct the mismatch between oxygen demand and supply, which is the hallmark of shock (1). However, no absolute normal value of cardiac output or oxygen delivery can be defined, as their adequate value basically depends on the tissue oxygen requirements. The correct value of cardiac output is the one that ensures a flow of oxygen that meets the metabolic demand (2,3). Then, any treatment aimed at changing cardiac output, such as fluid or inotropes, must be driven by the assessment of the adequacy between oxygen demand and supply.

To assess this adequacy, clinical examination has still a limited value. Signs of skin hypoperfusion do not reliably detect tissue hypoxia (4). Urine output may reflect the kidney perfusion, but it might be altered by many other factors during shock. Moreover, it depends on the presence or absence of a prior renal failure, and it cannot be used anymore as an indicator of the kidney perfusion in the case of acute tubular necrosis (5). Blood lactate may increase due to many processes not related to tissue oxygenation, leading to false positives (6). Furthermore, the blood lactate concentration depends on the balance between lactate production and lactate clearance, thus the delay required by its metabolism precludes one using it as a real-time marker of tissue metabolism (7). Oxygen saturation of the mixed (S_vO₂) or the central (S_cvO₂) venous blood is often in the normal range in septic shock despite anaerobic metabolism, because of the alteration of tissue oxygen extraction (8).

In this context, the indices derived from the arterial and central or mixed venous blood partial tension in carbon dioxide (CO₂) were proposed to overcome many of the limitations of the previous variables to indicate the adequacy of oxygen supply and requirements (9).

The meaning of PCO₂ gap

What is the PCO₂ gap?

The difference between the mixed venous content (C_vCO₂) and the arterial content (C_aCO₂) of CO₂ reflects the balance between its production by the tissues and its elimination through the lungs. This venoarterial difference in CO₂ content (CCO₂) can be estimated at the bedside by the venoarterial difference in PCO₂ (P_vCO₂ − P_aCO₂), named PCO₂ gap or ∆PCO₂.

It is not possible to understand its clinical value without understanding how CO₂ is produced, transported and eliminated, in aerobic and anaerobic conditions.

CO₂ production

Under normoxic conditions, CO₂ is produced in the cells during oxidative metabolism. The CO₂ production (VCO₂) is directly related to the global O₂ consumption (VO₂) by the relation:

VCO₂ = R × VO₂ [1]

where R is the respiratory quotient. R may vary from 0.7 to 1 depending on the predominant energetic substrate (0.7 for lipids, 1 for carbohydrates). Therefore, under aerobic conditions, CO₂ production should increase either because the aerobic metabolism increases or, for a given VO₂, because more carbohydrates are used as energetic substrates.

Under hypoxic conditions, CO₂ is produced in the cells through buffering of excessively produced protons by local bicarbonate ions (HCO₃⁻). Protons are generated by two mechanisms (10). First, CO₂ increases because of the hydrolysis of adenosine triphosphate and of adenosine diphosphate that occurs in anaerobic conditions. Second, a potential but minor source of CO₂ production under anaerobic conditions is the decarboxylation of some substrates produced by intermediate metabolism (α ketoglutarate or oxaloacetate) (10).

How is CO₂ transported?

CO₂ is transported in the blood in three forms: dissolved (10%), carried in bicarbonate ions (60%) and associated with proteins as carbamino compounds (30%). Compared to what happens for O₂, the dissolved form of CO₂ plays a more significant role in its transport because CO₂ is approximately 20 to 30 times more soluble than O₂. However, the main proportion of CO₂ is carried in bicarbonates, which result from the reaction of CO₂ and water molecules:

CO₂ + H₂O ↔ H₂CO₃ ↔ HCO₃^- + H⁺ [2]

From the tissues, CO₂ diffuses into the red blood cells, where erythrocytic carbonic anhydrase catalyses CO₂ hydration, converting most CO₂ and H₂O to HCO₃⁻ and H⁺ (11). In the red blood cells, dissolved CO₂ can also be fixed by haemoglobin. This fixation depends on the oxidation state of haemoglobin, since CO₂ has a greater affinity for reduced than for oxygenated haemoglobin (12). This is called the “Haldane effect” (13,14). In the peripheral capillaries this phenomenon facilitates the loading of CO₂ by the blood, while O₂ is delivered to the tissues. By contrast, in the lungs, the Haldane effect enhances the unloading of CO₂ while O₂ is transferred to haemoglobin.

Finally, the carbamino compounds are formed by combining the CO₂ with the terminal NH₂ groups of proteins, especially with the globin of haemoglobin. This reaction is also favoured by haemoglobin deoxygenation.

How is CO₂ eliminated?

The three forms of CO₂ are carried by the blood flow to pulmonary circulation and eliminated by ventilation. Passive diffusion from the capillaries to the alveoli eliminates CO₂, depending on the difference in the gas tension between both spaces.

What is the relationship between CCO₂ and PCO₂?

Since CCO₂ results from the combination of the three forms by which CO₂ is transported, the formula to calculate it is complex and not practical for clinical purposes (15). In this regard, the possibility to derive CCO₂ from one single component, notably the PCO₂, is useful:

PCO₂= k × CCO₂ [3]

The k value is influenced by the degree of blood pH, haematocrit and the arterial oxygen saturation (16-18) (Figure 1). As a matter of fact, the relationship between CCO₂ and PCO₂ is almost linear over the physiological range (Figure 1). Then, in clinical practice, the PCO₂ gap is an estimate of the difference between venous and arterial CO₂ content (C_v-aCO₂).

Figure 1 Relationship between content (CCO₂) and partial pressure (PCO₂) of carbon dioxide.

What are the determinants of the PCO₂ gap?

According to the Fick equation applied to CO₂, the CO₂ excretion (which equals CO₂ production—VCO₂—in steady state) equals the product of cardiac output by the difference between mixed venous CCO₂ (C_vCO₂) and arterial CCO₂ (C_aCO₂):

VCO₂ = cardiac output × (C_vCO₂ − C_aCO₂) [4]

As mentioned above, under physiological conditions, CCO₂ can be substituted by PCO₂ (PCO₂= k × CCO₂) so that:

∆PCO₂ = k × (C_vCO₂ − C_aCO₂) [5]

and

VCO₂ = cardiac output × ∆PCO₂/k [6]

Thus, ∆PCO₂ can be calculated from a modified Fick equation:

∆PCO₂ = (k × VCO₂)/cardiac output [7]

where k is the factor cited above in the relationship between PCO₂ and CCO₂.

This relationship between ∆PCO₂ and cardiac output expresses the fact that, if cardiac output is low, the CO₂ clearance decreases, CO₂ stagnates at the venous side and P_vCO₂ increases relatively to P_aCO₂ at the venous level: this leads to an increase in the PCO₂ gap.

In other words, for a given VCO₂, a decrease in cardiac output results in an increased PCO₂ gap and vice versa. This was found by experimental studies in which, when cardiac output was gradually reduced under conditions of stable VO₂, the PCO₂ gap was observed to concomitantly increase (9,19). Conversely, in a clinical study performed in normolactatemic patients with cardiac failure, the increase in cardiac index induced by dobutamine was associated with a decrease in the PCO₂ gap, while VO₂ was unchanged (20).

How to use the PCO₂ gap in clinical practice?

Can ∆PCO₂ be used as a marker of tissue hypoxia? No!

During cardiac arrest large increases in ∆PCO₂ were reported suggesting that ∆PCO₂ can increase during tissue hypoxia (21,22). However, because of the physiologic facts explained above, ∆PCO₂ is not a straightforward indicator of anaerobic metabolism.

Indeed, in case of tissue hypoxia, ∆PCO₂ can increase, decrease or remain unchanged, since the determinants of ∆PCO₂ can change in opposite directions.

First, as mentioned above, the k factor (defining the relationship between PCO₂ and CCO₂) increases in case of tissue hypoxia, increasing the PCO₂ gap even if the venoarterial difference in CCO₂ does not change (artefactual increase of ∆PCO₂).

Second, during tissue hypoxia, CO₂ production should decrease as a result of the decrease in VO₂: the less O₂ is consumed, the less CO₂ is produced. In an animal study where cardiac output was experimentally decreased by tamponade, Zhang and Vincent observed that, below a critical level of O₂ delivery, the further decrease in both cardiac output and O₂ delivery resulted in a progressive decrease in VCO₂ along with the decrease in VO₂ (9).

Since during tissue hypoxia, k must increase (tending to increase ∆PCO₂) and VCO₂ must decrease (tending to decrease ∆PCO₂), the resultant effect on ∆PCO₂ will mainly depend on cardiac output [∆PCO₂ = (k × VCO₂)/cardiac output] (23).

Therefore, two situations should be distinguished: tissue hypoxia with reduced blood flow and tissue hypoxia with preserved or high blood flow (Figure 2).

Figure 2 Illustration of the influence of cardiac output on the amplitude of the venoarterial difference of carbon dioxide partial pressure. P_aCO₂, arterial partial pressure in carbon dioxide; P_vCO₂, venous partial pressure in carbon dioxide; Qc, cardiac output; ∆PCO₂, venoarterial difference of carbon dioxide partial pressure.

In cases of tissue hypoxia with reduced systemic blood flow, P_vCO₂ increases relatively to P_aCO₂ due to the venous stagnation phenomenon, which increases ∆PCO₂. In this regard, in experimental studies where tissue hypoxia was induced by reducing blood flow, high values of ∆PCO₂ were found (19,24).

On the other hand, in cases of tissue hypoxia with preserved or high systemic blood flow ΔPCO₂ should be normal or even reduced. The high efferent venous blood flow should be sufficient to wash out the CO₂ produced by the tissues, preventing stagnation and ∆PCO₂ increase.

Results from several clinical studies have supported this hypothesis. Bakker et al. (25) found that most patients with septic shock had a ∆PCO₂ ≤6 mmHg. Cardiac index obtained in this subgroup of patients was significantly higher than that obtained in the subgroup of patients with a ∆PCO₂ >6 mmHg. Interestingly, the two subgroups did not differ in terms of blood lactate. Although VCO₂ and VO₂ were not directly measured, these data suggest that differences in CO₂ production did not account for differences in ∆PCO₂. In other words, many patients had a normal ∆PCO₂ despite tissue hypoxia, probably because their high blood flow had easily removed CO₂ produced by the tissues. Similar findings were reported by Mecher et al. (26). Clearly, these latter studies (25,26) underline the poor sensitivity of ∆PCO₂ to detect tissue hypoxia.

Normal or low ∆PCO₂ values were also reported in hypotensive patients with fulminant hepatic failure with tissue hypoxia, as strongly suggested by the increase in VO₂ after prostacyclin infusion (27). At baseline ∆PCO₂ was very low, which was probably due to the fact that VCO₂ was low—as suggested by the low VO₂—and that cardiac output was very high. These findings strongly support the fact that high flow states shock should result in a decrease, rather than an increase, of the PCO₂ gap.

The major role of cardiac output in the value of ∆PCO₂ was demonstrated in animal studies that compared ∆PCO₂ changes between models of ischemic hypoxia and models of hypoxic hypoxia (28,29). Ischemic hypoxia was created by reducing blood flow using progressive bleeding in pigs (28) or in sheep (29). Hypoxic hypoxia was created either by a progressive reduction of inspired oxygen concentration (28) or by progressive intratracheal instillation of hydrochloric acid (29). In both studies, cardiac output remained unchanged in the hypoxic hypoxia group. Significantly, ∆PCO₂ increased in the ischemic hypoxia group whereas it remained unchanged in the hypoxic hypoxia group (28,29). Similar results were reported by Vallet et al. in a model of vascular isolated dog hind limb (30). Indeed, ∆PCO₂ significantly increased when limb hypoxia was induced by ischemia while it remained unchanged when hypoxia was induced by hypoxemia with maintained limb blood flow (30).

All these experimental (28-30) and clinical (25-27) studies have confirmed that during tissue hypoxia, ∆PCO₂ can be either high or normal depending on cardiac output. Thus, a normal ∆PCO₂ cannot exclude the absence of tissue hypoxia in high blood flow states. On the other hand, ∆PCO₂ can be elevated in cases of low cardiac output, even in the absence of tissue hypoxia.

In summary, how to interpret the PCO₂ gap in practice?

An increased PCO₂ gap (>6 mmHg) suggests that cardiac output is not high enough with respect to the global metabolic conditions:

• In cases of shock (e.g., increased blood lactate), a high PCO₂ gap could prompt clinicians to increase cardiac output with the aim of reducing tissue hypoxia (Figure 3);
• In the absence of shock, a high PCO₂ gap can be associated with an increased oxygen demand.

Figure 3 Interpretation of indices of tissue oxygenation. Hb, haemoglobin; S_vO₂, venous oxygen saturation; S_aO₂, arterial oxygen saturation; C_a-vO₂, arteriovenous difference in oxygen content; ∆PCO₂, venoarterial difference in carbon dioxide partial pressure.

In a patient with a high initial value of ∆PCO₂, following the time-course of ∆PCO₂ can also be helpful to assess the global metabolic effects of a therapy aiming at increasing cardiac output. Under conditions of oxygen supply-dependency, when cardiac output increases, the decrease in anaerobic metabolism tends to decrease ∆PCO₂ but the increase in VO₂ tends to increase ∆PCO₂. As a result, ∆PCO₂ is expected to decrease to a lesser extent than in the case of oxygen supply independence. Consequently, unchanged ∆PCO₂ with therapy should not mean that the therapy has failed but rather that the treatment should be intensified until obtaining a frank decrease in ∆PCO₂, indicating that the critical level of O₂ delivery has been actually overcome.

On the other hand, a normal PCO₂ gap (≤6 mmHg) suggests that cardiac output is high enough to wash out the amount of the CO₂ produced from the peripheral tissues (Figure 2). Thus, increasing cardiac output has little chance to improve global oxygenation and such a strategy should not be a priority.

Combined analysis of ∆PCO₂ and oxygen-derived variables

Even though ΔPCO₂ cannot directly identify the presence of anaerobic metabolism, its combination with oxygen-derived variables has been suggested to overcome this issue (31). Indeed, as mentioned above, in case of anaerobic metabolism, VCO₂ tends to increase because of the buffering of excessively produced protons, but also tends to decrease because of the decrease in VO₂. Then, indexing VCO₂ by VO₂ should help detect the excess in CO₂ produced due to the occurrence of anaerobic metabolism. In other words, dividing VCO₂ by VO₂ may help detect the production of CO₂ which is not due to VO₂.

The issue is then to estimate the ratio VCO₂/VO₂ at the bedside. As shown on Figure 4, using the Fick equation, and substituting CCO₂ by PCO₂, as suggested above, this ratio can be estimated by the ΔPCO₂/C_a-vO₂ ratio, where C_a-vO₂ stands for the arteriovenous difference in O₂ content.

Figure 4 Estimation of the respiratory quotient from the ratio between venoarterial difference in carbon dioxide partial pressure and arteriovenous difference in oxygen content. C_a-vO₂, arteriovenous difference in oxygen content; CO₂, carbon dioxide; C_v-aCO₂, venoarterial difference in carbon dioxide content; P_v-aCO₂, venoarterial difference in carbon dioxide partial pressure.

In a series of 89 critically ill patients (148 measurements) where the mixed venous blood was sampled through a pulmonary catheter, a close correlation was found between blood lactate concentration and the ∆PCO₂/C_a-vO₂ ratio, while no correlation was found between blood lactate concentration and ∆PCO₂ alone and between blood lactate concentration and C_a-vO₂ alone (31). Similarly, in 51 septic shock patients, Monnet et al. showed a significant correlation between blood lactate and the ∆PCO₂/C_a-vO₂ ratio when the venous blood gas analysis was performed on the central, not the mixed venous blood (8). Similar results were found by Mesquida et al. who also demonstrated an increased mortality among patients with higher ∆PCO₂/C_a-vO₂ ratios, whereas no difference was observed for ∆PCO₂ and S_cvO₂ (32).

In summary, an increase in the ∆PCO₂/C_a-vO₂ ratio above 1.4 mmHg/mL (31,32) should be considered as a marker of global anaerobic metabolism. Its normalization during resuscitation has been suggested as a therapeutic target (33). In the latter study, only lactate and ∆PCO₂/C_a-vO₂ resulted to be independently associated to mortality at multivariate analysis, among a series of haemodynamic variables in septic shock. Furthermore, mortality was significantly higher among patients with increase in both lactate and ∆PCO₂/C_a-vO_2, compared to the one of those with only elevated lactate levels and a normal ∆PCO₂/C_a-vO_2.

S_cvO₂vs. PCO₂-derived indices

An advantage of the PCO₂ gap over S_cvO₂ is that it remains a valid marker of the adequacy of cardiac output to the metabolic conditions even if the microcirculation is injured and the oxygen extraction is impaired. This could be due to the fact that CO₂ is about 20 times more soluble than O₂ (34). The microcirculatory impairment, with large venoarterial shunts, impedes the diffusion of O₂ between cells and red blood cells, while the diffusion of CO₂ remains unaltered (34). A confirmation comes from the study performed by Ospina-Tascón et al., where, in the early phases of septic shock, ∆PCO₂ was actually able to detect the adequacy of microvascular blood flow (35).

Aiming at illustrating the superiority of the PCO₂ gap over S_vO₂, Vallée et al. included 50 septic shock patients where a S_cvO₂ higher than 70% had been achieved (36). The central venous PCO₂-arterial PCO₂ difference (PCO₂ gap) was abnormally high (>6 mmHg) in half of the patients (36). In that subgroup, blood lactate level tended to be higher and cardiac output to be lower compared to patients with a central PCO₂ gap ≤6 mmHg. The authors concluded that S_cvO₂ may not be sufficient to guide therapy and that, when the 70% S_cvO₂ value is reached, the presence of a central PCO₂ gap >6 mmHg might be useful to identify patients who still remain inadequately resuscitated (36). Another study showed that the combination of S_cvO₂ and central PCO₂ gap predicted outcome in 172 critically ill patients resuscitated from septic shock better than S_cvO₂ alone (37). Patients who met both targets appeared to clear lactate more efficiently (37). Similar results were reported in a series of septic shock patients (38).

Regarding the comparison of S_cvO₂ with the central ∆PCO₂/C_a-vO₂ ratio, our team performed a study where 51 critically ill patients received fluid (8). In patients in whom volume expansion increased cardiac output, central PCO₂ gap was able to follow the changes in cardiac output. Among patients in whom cardiac output increased, VO₂ increased in around half of the cases (indicating dependency between VO₂ and O₂ delivery) while VO₂ remained stable in the other ones (indicating independence between VO₂ and O₂ delivery). The increase of VO₂ was detected by changes in the ∆PCO₂/C_a-vO₂ ratio but not by the changes in ∆PCO₂ (8). Interestingly, in our cohort, S_cvO₂ could not detect changes in VO₂, because it included a large proportion of septic shock patients in whom S_cvO₂ was in the normal range due to oxygen extraction impairment. This confirmed the superiority of the ∆PCO₂/C_a-vO₂ ratio over ScvO₂ to detect tissue hypoxia in septic shock patients. Finally, the changes in lactate were also able to detect changes in VO₂. However, lactate was measured three hours after fluid administration while the ∆PCO₂/C_a-vO₂ ratio was measured immediately after its end (8). This suggests that one advantage of the ∆PCO₂/C_a-vO₂ ratio over lactate is that it changes immediately after changes in VO₂. However, Mallat et al. observed in septic shock patients that the increase in VO₂ after volume expansion was detected much better by both the ∆PCO₂/C_a-vO₂ and the C_v-aCO₂/C_a-vO₂ ratio than by blood lactate (39).

In summary, all these arguments suggest that, in case of septic shock with O₂ extraction impairment, in contrast with S_vO₂ or S_cvO₂, ∆PCO₂remains a reliable marker of the adequacy of cardiac output with the metabolic condition and that the ∆PCO₂/C_a-vO₂ ratio remains a valid indicator of the adequacy between O₂ delivery and VO₂. Moreover, compared to lactate, the CO₂-derived variables have the advantage to change without delay and to follow the metabolic condition in real time.

Errors and pitfalls of the PCO₂ gap

Although many studies confirmed the association between an elevation in both ∆PCO₂ and ∆PCO₂/C_a-vO₂ ratio and poor outcome in terms of lactate clearance, changes in VO₂ and mortality (40-42), some other ones showed a limited or even a negative correlation between elevated ∆PCO₂ and increase in blood lactate or mortality (43-45). Part of the discrepancy might be related to the fact that the latter studies were performed in post-cardiac surgery patients.

Haemodilution was recently investigated by Dubin et al. in an experimental model (46): the reliability of the ∆PCO₂/C_a-vO₂ ratio was compared between sheep with progressive haemorrhage and sheep with progressive haemodilution. Interestingly, the authors observed that in the haemodilution group, the ∆PCO₂/C_a-vO₂ ratio increased despite the absence of anaerobic metabolism. These findings, together with the high correlation with haemoglobin changes (R²=0.79; P<0.001), suggest that changes were explained by a rightward shift of the relationship between PCO₂ and CCO₂ (46).

In this regard, conflicting results have been reported also in terms of prognostic value of ∆PCO₂/C_a-vO₂ and ∆CCO₂/C_a-vO₂: while some authors observed that the ∆CCO₂/C_a-vO₂ ratio was an independent predictor of mortality, contrary to the ∆PCO₂/C_a-vO₂ ratio (33), others observed that the ∆PCO₂/C_a-vO₂ ratio but not the ∆CCO₂/C_a-vO₂ was associated with increased mortality (42).

Other authors investigated possible causes of misleading interpretation of both ∆PCO₂ and the ∆PCO₂/C_a-vO₂ ratio. Mallat et al. showed that hyperventilation creates an increase in ∆PCO₂ in healthy volunteers (47). Saludes et al. tested the effects of a hyperoxygenation trial on ∆PCO₂ (48), and observed that, even though oxygen parameters increased both on the arterial and venous side, PCO₂ augmented only in the venous blood, leading to an increase in both ∆PCO₂ and ∆PCO₂/C_a-vO₂ ratio which was probably not related to changes in blood flow (48).

In addition, some technical aspects should be kept in mind when these indices are used in clinical practice. First, some errors in the PCO₂ gap measurements may occur when sampling the venous blood: incorrect sample container, contaminated sample by air or venous blood or catheter fluid (49). Second, a too long delay of transport of blood sampling may significantly change the blood gas content at the venous and the arterial site (50).

Third, it is important to remind that variations in both ∆PCO₂ and the ∆PCO₂/C_a-vO₂ ratio are submitted to a certain degree of variability. In this regard, in a series of 192 patients, Mallat et al. showed that the smallest detectable difference of ∆PCO₂ was ±1.8 mmHg, corresponding to a least significant change of 32%. For the ∆PCO₂/C_a-vO₂ ratio, the smallest detectable difference was ±0.57 mmHg/mL, corresponding to a least significant change of 38% (51).

Conclusions

A proper analysis of the physiology of CO₂ metabolism reveals that the PCO₂ gap indicates the adequacy of cardiac output with the metabolic condition while the adequacy between O₂ delivery and O₂ consumption is better indicated by the ∆PCO₂/C_a-vO₂ ratio in critically ill patients. The CO₂-derived indices seem to be quite reliable when measured in the central venous blood. In contrast to S_vO₂ or S_cvO₂, they remain useful in septic shock patients with an impaired O₂ extraction.

Acknowledgments

None.

Footnote

Conflicts of Interest: JL Teboul and X Monnet are members of the Medical Advisory Board of Pulsion Medical Systems, Getinge. F Gavelli has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

References

1. Vincent JL, De Backer D. Oxygen transport-the oxygen delivery controversy. Intensive Care Med 2004;30:1990-6. [Crossref] [PubMed]
2. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 1995;333:1025-32. [Crossref] [PubMed]
3. Monnet X, Teboul JL. My patient has received fluid. How to assess its efficacy and side effects? Ann Intensive Care 2018;8:54. [Crossref] [PubMed]
4. Londoño J, Niño C, Díaz J, et al. Association of Clinical Hypoperfusion Variables With Lactate Clearance and Hospital Mortality. Shock 2018;50:286-92. [Crossref] [PubMed]
5. Legrand M, Payen D. Understanding urine output in critically ill patients. Ann Intensive Care 2011;1:13. [Crossref] [PubMed]
6. Hernandez G, Bellomo R, Bakker J. The ten pitfalls of lactate clearance in sepsis. Intensive Care Med 2019;45:82-5. [Crossref] [PubMed]
7. Vincent JL, Quintairos E, Silva A, et al. The value of blood lactate kinetics in critically ill patients: a systematic review. Crit Care 2016;20:257. [Crossref] [PubMed]
8. Monnet X, Julien F, Ait-Hamou N, et al. Lactate and venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders. Crit Care Med 2013;41:1412-20. [Crossref] [PubMed]
9. Zhang H, Vincent JL. Arteriovenous differences in PCO2 and pH are good indicators of critical hypoperfusion. Am Rev Respir Dis 1993;148:867-71. [Crossref] [PubMed]
10. Randall HM, Cohen JJ. Anaerobic CO2 production by dog kidney in vitro. Am J Physiol 1966;211:493-505. [Crossref] [PubMed]
11. Jensen FB. Red blood cell pH, the Bohr effect, and other oxygenation-linked phenomena in blood O2 and CO2 transport. Acta Physiol Scand 2004;182:215-27. [Crossref] [PubMed]
12. Geers C, Gros G. Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol Rev 2000;80:681-715. [Crossref] [PubMed]
13. West J. Gas transport to the periphery: how gases are moved to the peripheral tissues. In: Respiratory physiology: the essentials. 4th edition. Baltimore: Williams and Wilkins, 1990:69-85.
14. Teboul JL, Scheeren T. Understanding the Haldane effect. Intensive Care Med 2017;43:91-3. [Crossref] [PubMed]
15. Douglas AR, Jones NL, Reed JW. Calculation of whole blood CO2 content. J Appl Physiol (1985) 1988;65:473-7. [Crossref] [PubMed]
16. Cavaliere F, Giovannini I, Chiarla C, et al. Comparison of two methods to assess blood CO2 equilibration curve in mechanically ventilated patients. Respir Physiol Neurobiol 2005;146:77-83. [Crossref] [PubMed]
17. Jensen FB. Comparative analysis of autoxidation of haemoglobin. J Exp Biol 2001;204:2029-33. [PubMed]
18. McHardy GJ. The relationship between the differences in pressure and content of carbon dioxide in arterial and venous blood. Clin Sci 1967;32:299-309. [PubMed]
19. Groeneveld AB, Vermeij CG, Thijs LG. Arterial and mixed venous blood acid-base balance during hypoperfusion with incremental positive end-expiratory pressure in the pig. Anesth Analg 1991;73:576-82. [PubMed]
20. Teboul JL, Mercat A, Lenique F, et al. Value of the venous-arterial PCO2 gradient to reflect the oxygen supply to demand in humans: effects of dobutamine. Crit Care Med 1998;26:1007-10. [Crossref] [PubMed]
21. Grundler W, Weil MH, Rackow EC. Arteriovenous carbon dioxide and pH gradients during cardiac arrest. Circulation 1986;74:1071-4. [Crossref] [PubMed]
22. Weil MH, Rackow EC, Trevino R, et al. Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N Engl J Med 1986;315:153-6. [Crossref] [PubMed]
23. Dres M, Monnet X, Teboul JL. Hemodynamic management of cardiovascular failure by using PCO(2) venous-arterial difference. J Clin Monit Comput 2012;26:367-74. [Crossref] [PubMed]
24. Van der Linden P, Rausin I, Deltell A, et al. Detection of tissue hypoxia by arteriovenous gradient for PCO2 and pH in anesthetized dogs during progressive hemorrhage. Anesth Analg 1995;80:269-75. [PubMed]
25. Bakker J, Vincent JL, Gris P, et al. Veno-arterial carbon dioxide gradient in human septic shock. Chest 1992;101:509-15. [Crossref] [PubMed]
26. Mecher CE, Rackow EC, Astiz ME, et al. Venous hypercarbia associated with severe sepsis and systemic hypoperfusion. Crit Care Med 1990;18:585-9. [Crossref] [PubMed]
27. Wendon JA, Harrison PM, Keays R, et al. Arterial-venous pH differences and tissue hypoxia in patients with fulminant hepatic failure. Crit Care Med 1991;19:1362-4. [Crossref] [PubMed]
28. Nevière R, Chagnon JL, Teboul JL, et al. Small intestine intramucosal PCO(2) and microvascular blood flow during hypoxic and ischemic hypoxia. Crit Care Med 2002;30:379-84. [Crossref] [PubMed]
29. Dubin A, Murias G, Estenssoro E, et al. Intramucosal-arterial PCO2 gap fails to reflect intestinal dysoxia in hypoxic hypoxia. Crit Care 2002;6:514-20. [Crossref] [PubMed]
30. Vallet B, Teboul JL, Cain S, et al. Venoarterial CO(2) difference during regional ischemic or hypoxic hypoxia. J Appl Physiol (1985) 2000;89:1317-21. [Crossref] [PubMed]
31. Mekontso-Dessap A, Castelain V, Anguel N, et al. Combination of venoarterial PCO2 difference with arteriovenous O2 content difference to detect anaerobic metabolism in patients. Intensive Care Med 2002;28:272-7. [Crossref] [PubMed]
32. Mesquida J, Saludes P, Gruartmoner G, et al. Central venous-to-arterial carbon dioxide difference combined with arterial-to-venous oxygen content difference is associated with lactate evolution in the hemodynamic resuscitation process in early septic shock. Crit Care 2015;19:126. [Crossref] [PubMed]
33. Ospina-Tascón GA, Umaña M, Bermúdez W, et al. Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med 2015;41:796-805. [Crossref] [PubMed]
34. Vallet B, Pinsky MR, Cecconi M. Resuscitation of patients with septic shock: please “mind the gap”! Intensive Care Med 2013;39:1653-5. [Crossref] [PubMed]
35. Ospina-Tascón GA, Umaña M, Bermúdez WF, et al. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med 2016;42:211-21. [Crossref] [PubMed]
36. Vallée F, Vallet B, Mathe O, et al. Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive Care Med 2008;34:2218-25. [Crossref] [PubMed]
37. Du W, Liu DW, Wang XT, et al. Combining central venous-to-arterial partial pressure of carbon dioxide difference and central venous oxygen saturation to guide resuscitation in septic shock. J Crit Care 2013;28:1110.e1-5. [Crossref] [PubMed]
38. Mallat J, Pepy F, Lemyze M, et al. Central venous-to-arterial carbon dioxide partial pressure difference in early resuscitation from septic shock: a prospective observational study. Eur J Anaesthesiol 2014;31:371-80. [Crossref] [PubMed]
39. Mallat J, Lemyze M, Meddour M, et al. Ratios of central venous-to-arterial carbon dioxide content or tension to arteriovenous oxygen content are better markers of global anaerobic metabolism than lactate in septic shock patients. Ann Intensive Care 2016;6:10. [Crossref] [PubMed]
40. Ospina-Tascón GA, Bautista-Rincón DF, Umaña M, et al. Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock. Crit Care 2013;17:R294. [Crossref] [PubMed]
41. He HW, Liu DW, Long Y, et al. High central venous-to-arterial CO2 difference/arterial-central venous O2 difference ratio is associated with poor lactate clearance in septic patients after resuscitation. J Crit Care 2016;31:76-81. [Crossref] [PubMed]
42. Mesquida J, Saludes P, Pérez-Madrigal A, et al. Respiratory quotient estimations as additional prognostic tools in early septic shock. J Clin Monit Comput 2018;32:1065-72. [Crossref] [PubMed]
43. Morel J, Grand N, Axiotis G, et al. High veno-arterial carbon dioxide gradient is not predictive of worst outcome after an elective cardiac surgery: a retrospective cohort study. J Clin Monit Comput 2016;30:783-9. [Crossref] [PubMed]
44. Guinot PG, Badoux L, Bernard E, et al. Central Venous-to-Arterial Carbon Dioxide Partial Pressure Difference in Patients Undergoing Cardiac Surgery is Not Related to Postoperative Outcomes. J Cardiothorac Vasc Anesth 2017;31:1190-6. [Crossref] [PubMed]
45. Abou-Arab O, Braik R, Huette P, et al. The ratios of central venous to arterial carbon dioxide content and tension to arteriovenous oxygen content are not associated with overall anaerobic metabolism in postoperative cardiac surgery patients. PloS One 2018;13:e0205950. [Crossref] [PubMed]
46. Dubin A, Ferrara G, Kanoore Edul VS, et al. Venoarterial PCO2-to-arteriovenous oxygen content difference ratio is a poor surrogate for anaerobic metabolism in hemodilution: an experimental study. Ann Intensive Care 2017;7:65. [Crossref] [PubMed]
47. Mallat J, Mohammad U, Lemyze M, et al. Acute hyperventilation increases the central venous-to-arterial PCO2 difference in stable septic shock patients. Ann Intensive Care 2017;7:31. [Crossref] [PubMed]
48. Saludes P, Proença L, Gruartmoner G, et al. Central venous-to-arterial carbon dioxide difference and the effect of venous hyperoxia: A limiting factor, or an additional marker of severity in shock? J Clin Monit Comput 2017;31:1203-11. [Crossref] [PubMed]
49. d’Ortho MP, Delclaux C, Zerah F, et al. Use of glass capillaries avoids the time changes in high blood PO(2) observed with plastic syringes. Chest 2001;120:1651-4. [Crossref] [PubMed]
50. Wan XY, Wei LL, Jiang Y, et al. Effects of time delay and body temperature on measurements of central venous oxygen saturation, venous-arterial blood carbon dioxide partial pressures difference, venous-arterial blood carbon dioxide partial pressures difference/arterial-venous oxygen difference ratio and lactate. BMC Anesthesiol 2018;18:187. [Crossref] [PubMed]
51. Mallat J, Lazkani A, Lemyze M, et al. Repeatability of blood gas parameters, PCO2 gap, and PCO2 gap to arterial-to-venous oxygen content difference in critically ill adult patients. Medicine (Baltimore) 2015;94:e415. [Crossref] [PubMed]