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

The main findings of our study were that in fluid-responder septic shock patients (1) the ability of ∆ContCO₂/∆ContO₂ and ∆PCO₂/∆ContO₂ ratios to predict the presence of global anaerobic metabolism was excellent and higher than lactate; (2) ∆ContCO₂/∆ContO₂ ratio was not a better marker of global anaerobic metabolism than ∆PCO₂/∆ContO₂ ratio; (3) ScvO₂ failed to detect the presence of global tissue hypoxia, except for values ≥80 %.

When DO₂ is acutely reduced, VO₂ remains stable (oxygen supply independency) because the tissues adapt their OE proportionally. When DO₂ falls below a critical low value, a proportionate increase in OE cannot be maintained and the VO₂ starts to fall (oxygen supply dependency) and tissue hypoxia occurs as reflected by an abrupt increase in blood lactate concentration [13–15]. Thus, VO₂/DO₂ dependence has been considered to be a hallmark of tissue hypoxia and the activation of anaerobic metabolism [14–16], although it has been challenged because of the methodological limitations (mathematical coupling) in the VO₂/DO₂ relationship assessment [17, 18].

We defined an increase in VO₂ ≥ 15 % as a clinically significant augmentation by similarity to the definition of the increase in cardiac index, since VO₂ is proportional to this variable. This cutoff value was chosen by the fact that the least significant change in CI measured by transpulmonary thermodilution is 11.0 % when 20 mL is used to perform iced saline injections in triplicate (unpublished data). On the other hand, this definition of “VO₂ response” allows us comparing our findings with those of a previous study [8]. We confirm the results of Monnet et al. [8] that calculating VO₂ from the central instead of the mixed venous blood also allows to detect the presence of anaerobic metabolism through VO₂/DO₂ dependence. Indeed, in our study, the baseline lactate concentration was elevated in patients with VO₂/DO₂ dependency phenomenon and higher than in patients with VO₂/DO₂ independency (Table 2). Moreover, it is hard to believe that mathematical coupling of measurement errors was responsible for the VO₂/DO₂ dependency in our study. Indeed, we observed that VO₂/DO₂ dependency occurred in one subgroup of patients but not in others, despite similar changes in DO₂ (Table 2). Such a methodological problem can hardly account for the existence of VO₂/DO₂ dependency only in one subgroup. If that were an issue, one would expect it to influence results uniformly. Finally, the increase in VO₂ could have resulted from an additional non-mitochondrial non-oxidative oxygen uptake when dysoxia has resolved [19]. However, this mechanism is less likely to have occurred in our study because the observed mean slope of the VO₂/DO₂ relationship in the subgroup of VO₂-responders was 47.8 ± 10 %, suggesting VO₂/DO₂ dependency and activation of anaerobic metabolism (Table 2) [20].

In experimental conditions of tissue hypoxia, a smaller reduction in VCO₂ than VO₂ has been observed, suggesting a non-aerobic production of CO₂ [21–23]. Therefore, the occurrence of a high RQ may be considered as a sign of anaerobic metabolism. Recently, Monnet et al. [8] have used the ∆PCO₂/∆ContO₂ ratio as a surrogate of RQ and found that a ∆PCO₂/∆ContO₂ ratio at baseline ≥ 1.8 mmHg/mL predicted accurately VO₂/DO₂ dependence among patients whose DO₂ increased after fluid administration. Our results agree with those findings, and interestingly, the observed cutoff value of this ratio, in our septic shock patients, was almost similar to what was found in the Monnet et al. report [8].

The use of ∆PCO₂/∆ContO₂ ratio as a surrogate of VCO₂/VO₂ assumes that the PCO₂/CO₂ content relationship is quasi-linear, which may be true over the physiologic range of PCO₂ [24]. However, this relationship can be affected by the degree of metabolic acidosis, hematocrit, and oxygen saturation (Haldane effect), and it becomes nonlinear if these factors change [25]. In this regard, it has been shown that venous-to-arterial PCO₂ differences and venous-to-arterial CO₂ content differences might change in opposite direction in splanchnic region under conditions of very low venous oxygen saturation [26]. Recently, Ospina-Tascon et al. found a significant association with mortality, in septic shock patients, for the mixed ∆ContCO₂/mixed ∆ContO₂ ratio but not for the mixed ∆PCO₂/mixed ∆ContO₂ ratio [27]. Thus, ∆ContCO₂/∆ContO₂ ratio could be a more reliable marker of tissue hypoxia than ∆PCO₂/∆ContO₂. However, we found that ∆ContCO₂/∆ContO₂ was not better predictor of tissue hypoxia than the ∆PCO₂/∆ContO₂ in septic shock patients (Fig. 2). It does not seem that Haldane effect has played an important role in our study. Furthermore, the degree of metabolic acidosis, as reflected by base excess, was not severe enough to significantly affect the PCO₂/CO₂ content relationship in our septic shock patients. Even though the ∆ContCO₂/∆ContO₂ ratio more physiologically mirrors RQ compared with ∆PCO₂/∆ContO₂, we found that both ratios can be used accurately to predict fluid responsiveness at tissue level. However, the computation of ∆PCO₂/∆ContO₂ ratio is less cumbersome and less subject to the risk of errors, and therefore, it is much easier to be used at the bedside.

Lactate value was not good to detect the presence of anaerobic metabolism in our septic shock patients. Our results are in discrepancy with previous findings [7, 8, 28]. However, hyperlactatemia does not necessarily reflect anaerobic metabolism secondary to tissue hypoxia, especially in septic states [3, 4, 29]. Other non-hypoxic mechanisms such as accelerated aerobic glycolysis induced by sepsis-associated inflammation [30], inhibition of pyruvate dehydrogenase [31], and impaired lactate clearance [32] may contribute to hyperlactatemia found in septic patients. In endotoxic states, lactate levels failed to discriminate between hypoxia and aerobiosis [33]. Furthermore, Rimachi et al. [34] found the presence of hyperlactatemia in 65 % of septic shock patients, but only 76 % of these patients also had a high lactate/pyruvate ratio confirming the non-hypoxic cause of hyperlactatemia in septic states. Moreover, in fluid-responder patients, we found no significant relationship between changes in VO₂ induced by VE and changes in lactate levels, whereas changes in ∆PCO₂/∆ContO₂ and ∆ContCO₂/∆ContO₂ ratios were correlated well with changes in VO₂. This finding suggests that these ratios respond to changes in global tissue oxygenation faster than blood lactate concentration likely due to the alteration of lactate clearance.

The majority (71 %) of our septic shock patients had a ScvO₂ value ≤70 % at their inclusion in the study. This finding is due to the fact that patients, in our study, were recruited in the very early period of acute circulatory failure; the time between the start of care and enrollment was only 102 min. Within this period, septic shock patients are not fully resuscitated yet, and as a consequence, low values of ScvO₂ are observed more frequently [35–37]. Even though our population seems to be different from that in the study of Monnet et al. [8], we confirm that ScvO₂ is a poor predictor of the presence of anaerobic metabolism. This can be explained by the fact that ScvO₂ is not a regulated parameter but an adaptive one that depends on four regulated constituents: oxygen consumption, hemoglobin, SaO₂, and cardiac output. Therefore, ScvO₂ is widely fluctuating. However, these results should not dissuade us from monitoring ScvO₂ but encourage us to include it in a multimodal approach. Indeed, a low ScvO₂ value reflects the inadequacy of oxygen supply, and fluid administration can be helpful in order to correct oxygen supply/demand imbalance, even in situations of VO₂/DO₂ independency, to avoid further decreases in DO₂ below a critical value leading to tissue hypoxia. On the other hand, only ScvO₂ values ≥80 % were able to predict the presence of global tissue hypoxia with a high specificity. All these patients also had higher lactate levels and higher ∆PCO₂/∆ContO₂ and ∆ContCO₂/∆ContO₂ ratios. This suggests that these patients had a greater alteration of their microcirculation due to sepsis than the other fluid-responder patients. However, this finding should be interpreted with caution, since only six patients had a baseline ScvO₂ value ≥80 % in fluid-responders’ group, and our study was not designed for testing this hypothesis.

Contrary to what was found previously [8], DO₂ did not decrease during VE, in fluid-non-responder patients, even though arterial hemoglobin significantly decreased by 5.6 ± 4.6 % (Additional file 2: Table S1), which was lower than that in the Monnet et al. study (8 ± 4 %) [8]. The discrepancy between the two studies may be due to dissimilar populations of patients and to the differences in the time to inclusion, which was longer in the study by Monnet et al. [8] than that in our study (6.1 vs. 1.7 h) explaining the more pronounced hemodilution effect in their study.

We believe our findings add significant values to the Monnet et al. study [8]. Indeed, we have demonstrated that the ∆PCO₂/∆ContO₂ ratio is a reliable marker of global anaerobic metabolism in the very early period of septic shock where patients are still not fully resuscitated and that ∆ContCO₂/∆ContO₂ is not superior to ∆PCO₂/∆ContO₂ for predicting the presence of global tissue hypoxia in these patients. Furthermore, our study shed the light on the fact that hyperlactatemia should not always be regarded as reflecting the presence of global tissue hypoxia, especially in septic shock patients. This finding is of clinical importance since elevated lactate values could incite the clinician to undertake unnecessary interventions, with their potentially harmful effects, such as tissue edema and positive fluid balance, which have constantly been associated with poorer outcome [38].

Our study presents several limitations. First, we used central venous blood instead of mixed venous to assess VO₂- and CO₂-derived variables, and thus, we might have missed the evaluation of the splanchnic oxygenation. However, our study is the second one that confirms that calculating oxygen-derived variables from the central venous blood is able to detect the presence of tissue hypoxia through VO₂/DO₂ dependence. Second, regional or local tissue hypoxia might not be detected by the assessment of the changes in global oxygen consumption. Finally, it is a single-center study, which may limit its external validity.