The main result of our study is that, in a population of septic shock patients, once MAP and ScvO2 values were normalized, high PcvaCO2/CavO2 ratio values were associated with the lack of lactate clearance within the following hours, and this condition was associated with patient mortality. In our population, the ability of the PcvaCO2/CavO2 ratio to predict lactate evolution was stronger than that of the PcvaCO2 gap. To our knowledge this is the first study exploring this issue, and our data validate that integration of the PcvaCO2/CavO2 ratio within the resuscitation process of septic shock might have relevant clinical utility.
The present study aimed to add some information for a daily clinical question, such as whether to stop or continue resuscitating those patients suffering from septic shock once MAP and S
cvO
2 endpoints have been reached but lactate values are still elevated. According to current international guidelines [
1], normalization of S
cvO
2 as a global marker for the adequacy of tissue oxygenation would be sufficient. On the other hand, using lactate clearance as guidance for the resuscitation process has been demonstrated to be as effective as S
cvO
2 guidance [
3]. However, the real-time nature of S
cvO
2 monitoring has been decisive for its widespread use above lactate monitoring. In clinical practice, an adequate knowledge of the value and limitations of both variables would be desirable in order to understand each scenario, and take decisions accordingly. In recent years, some studies have corroborated the prognostic value of the P
cvaCO
2 gap in several clinical conditions [
11-
14], and this parameter has been proposed as an additional marker of tissue perfusion adequacy [
10]. Importantly, its value seems to persist even when S
cvO
2 has been normalized [
11,
13,
14]. According to these observations, it has been suggested that adding the P
cvaCO
2 gap as a supplementary endpoint in the resuscitation process of septic shock might prove beneficial [
10], but to date prospective interventional studies exploring this issue are still lacking. Moreover, some authors have suggested that correcting the P
cvaCO
2 gap by the C
avO
2 (P
cvaCO
2/C
avO
2 ratio) might enhance its value as a marker of anaerobic metabolism [
15,
18]. The P
cvaCO
2/C
avO
2 ratio has been proposed as an approximation of the respiratory quotient, the relationship between global carbon dioxide production and global oxygen consumption (VO
2). According to Fick’s equation, VO
2 is equal to the product of cardiac output and the C
avO
2. Similarly, global carbon dioxide production is equal to the product of cardiac output and the central venous-to-arterial carbon dioxide content difference. The respiratory quotient is therefore equal to the central venous-to-arterial carbon dioxide content difference/C
avO
2 ratio. Increased carbon dioxide production, relative to oxygen consumption, occurs under conditions of tissue hypoxia, and the presence of anaerobic metabolism may be inferred when the respiratory quotient rises above 1. Since over the physiological range of carbon dioxide contents the partial pressure of carbon dioxide is linearly related to carbon dioxide content, using the P
cvaCO
2 as a surrogate for the carbon dioxide content difference has been previously accepted [
15,
18]. In the present study, we aimed at exploring whether an increased P
cvaCO
2 gap and its combination with the C
avO
2 at the end of early goal-directed therapy would be predictive of an inadequate lactate clearance, and thus a ready-to-use tool for the decision-making process.
The PcvaCO2/CavO2 ratio as a marker of anaerobic metabolism
Mekontso-Dessap and coworkers suggested that the P
cvaCO
2/C
avO
2 ratio might be a reflection of anaerobic metabolism, demonstrating a positive correlation between this parameter and lactate [
15]. Indeed, in their study the P
cvaCO
2/C
avO
2 ratio was superior to S
cvO
2 and the P
cvaCO
2 gap for predicting elevated lactate values. Our study was designed to go one step further, and we explored the ability of the P
cvaCO
2/C
avO
2 ratio to predict the adequacy of lactate clearance. Again, our results support the hypothesis that the P
cvaCO
2/C
avO
2 ratio is a better predictor of anaerobic metabolism than the P
cvaCO
2 gap. Of note, lactate values at inclusion were not associated with lactate evolution, strengthening the concept that an elevated lactate value at a given time point does not infer the presence of anaerobic metabolism. In a recent study, Monnet and coworkers nicely showed that, after performing a volume expansion, among those patients who were considered to be responders (increase in cardiac output) only patients with an elevated P
cvaCO
2/C
avO
2 ratio at baseline increased their VO
2 [
18]. In other words, the ability to increase the metabolic rate, after increasing oxygen availability, was only observed in those patients with an altered P
cvaCO
2/C
avO
2 ratio. According to their results, the authors introduced the idea that VO
2 might only increase in response to an increase in global oxygen delivery when VO
2 is limited (global oxygen delivery dependency), as suggested by an elevated P
cvaCO
2/C
avO
2 ratio. Regrettably, we did not calculate VO
2 or global oxygen delivery in our patients. However, on the whole our data are in accordance with these previous observations, and we might hypothesize that those patients whose P
cvaCO
2/C
avO
2 ratio was high might have a limited VO
2, causing anaerobic metabolism, and consequently were not able to decrease their lactate values within the following hours.
Outcome
Although the present study was not powered to explore the prognostic value of the P
cvaCO
2 gap and the P
cvaCO
2/C
avO
2 ratio in terms of organ failure evolution or survival, our data suggest a significant association between mortality and the presence of an elevated P
cvaCO
2/C
avO
2 ratio at the end of early goal-directed therapy. The association between the P
cvaCO
2 gap and outcome has been demonstrated consistently in several scenarios, even in the presence of a normalized S
cvO
2 [
11-
14]. Although we were not able to reproduce the prognostic value of the P
cvaCO
2 gap, our data suggest that the prognostic significance is enhanced when correcting the P
cvaCO
2 gap for the oxygen content difference. Independently of our results regarding mortality, the demonstration that the P
cvaCO
2/C
avO
2 ratio can predict the evolution of lactate strengthens its value, and brings this parameter closer to clinical practice. Since lactate clearance adequacy has already, and repeatedly, been associated with outcome [
4,
17], the ability to predict lactate evolution might prove useful in order to perform further resuscitation maneuvers, or to avoid unnecessary interventions and in doing so elude their potential deleterious effects.
Study limitations
Several limitations might be taken into account when considering our results. Firstly, this is a single-center study, so our results might have limitations when trying to generalize for other ICUs or other settings. On the other hand, the homogeneity of our resuscitation process would strengthen the value of the observed results. Secondly, we failed to demonstrate a relationship between the P
cvaCO
2 gap and lactate clearance, but the observed tendency to higher P
cvaCO
2 gap values in those patients unable to decrease their lactate might suggest that the limited number of patients studied would account for this lack of significance. An additional limitation would derive from the lack of standardization of the time points of lactate measurement. Since this is an observational study, paired blood gas analyses were performed according to the medical team, without intervention from the researchers. Although current practice in our ICU includes the verification of a persistent normalized S
cvO
2 and confirming an adequate lactate clearance, the timing of this verification is inconstant. Therefore, our second pair of measurements was associated with time variability. Nevertheless, the elapsed time between measurements was 3 ± 2 hours, which is in accordance with previous clinical works prospectively evaluating lactate clearance and outcome [
3,
4]. When exploring the prognostic value of the P
cvaCO
2/C
avO
2 ratio, we might be cautious with the observed results. As discussed above, the present study was not designed for this purpose, and the reduced sample size might limit the significance of the association with mortality, as suggested by the absence of prediction of mortality by the Simplified Acute Physiology Score II. Although the existing literature has proposed the P
cvaCO
2/C
avO
2 ratio as a surrogate of the respiratory quotient, several situations might affect the relationship between carbon dioxide content and partial pressure of carbon dioxide, such as the Haldane effect [
19]. Oxygen saturations were calculated from partial pressure of oxygen values, not measured by co-oximetry, with a potential source of error in the displayed ScvO
2 values. Finally, we analyzed the value of the P
cvaCO
2 gap and the P
cvaCO
2/C
avO
2 ratio once the recommended S
cvO
2 goal was reached. However, since the S
cvO
2 value might be limited in septic conditions, when oxygen extraction deficit occurs, whether the P
cvaCO
2 gap and the P
cvaCO
2/C
avO
2 ratio might be useful independently of S
cvO
2 deserves further study. Regrettably, this issue was not addressed in our study.