Introduction
There is increasing evidence that individually optimized hemodynamic therapy oriented on goals to maintain and improve tissue perfusion and/or oxygenation improves patient outcome [
1]. The development of tissue hypoxia is a leading cause of postoperative organ failure and mortality following major surgery [
2,
3]. Early recognition and correction of warning signals of persistent inadequacy of tissue perfusion is therefore of particular importance, especially in patients with a reduced physiological reserve [
1,
4].
The inability to meet an increase in oxygen (O
2) demand with surgical trauma either by an increase in O
2 delivery or an increase in O
2 extraction can lead to tissue hypoxia [
5,
6]. Several markers of impaired tissue oxygenation have been explored to help identify patients at increased risk of complications. Postoperative organ failure has been shown to be associated with reduced central venous O
2 saturation (ScvO
2), which explores the balance of O
2 delivery and tissue O
2 consumption [
7]. However, there is evidence that O
2-derived variables are poorly correlated with anaerobic metabolism [
8-
11]. Indeed, both normal and high values (that is, ≥75%) for ScvO
2 do not preclude the presence of tissue hypoxia in case of impaired O
2 extraction capabilities, which may therefore limit the usefulness of ScvO
2 monitoring [
12,
13]. In contrast, it has also been shown that strategies aimed at reducing high serum lactate levels, as a warning signal of a persistent tissue hypoxia at ICU admission, could reduce length of stay and mortality [
14,
15]. However, a rise in lactate level may be delayed compared with markers of tissue oxygenation adequacy, such as oxygen extraction [
16], and could be not sensitive enough to reflect tissue hypoperfusion [
14].
Previous relatively small studies have proposed central venous-to-arterial carbon dioxide gradient (PCO
2 gap), a global index of tissue perfusion, as a useful measurement to characterize the insufficient flow state in spite of apparently normal macrocirculatory parameters [
17,
18]. Tissue partial pressure of carbon dioxide (PCO
2) reflects metabolic alterations due to inadequate perfusion in actively metabolized tissues [
19]. The PCO
2 gap, which has been shown to be inversely related to cardiac output (CO) [
20], is considered as a marker of the ability of the venous blood flow to remove the CO
2 excess produced in tissues [
21]. Thus, an impaired tissue perfusion during a reduced blood flow is the main determinant of a rise of the PCO
2 gap [
22]. However, despite promising findings from both experimental and clinical data, the prognostic significance of the PCO
2 gap has only been examined to a small extent in the context of major surgical trauma. The purpose of this study was to evaluate the clinical relevance of high values of the PCO
2 gap, and their relationships to other markers of impaired tissue perfusion and oxygenation (that is, blood lactate and ScvO
2). We hypothesized that the PCO
2 gap could serve as a useful tool to help identify patients at high risk of postoperative complications at ICU admission following major surgery.
Discussion
The main finding of our study is that a PCO2 gap >6 mmHg at ICU admission following major surgery is predictive of postoperative complications in high-risk surgical patients. Patients with an enlarged PCO2 gap had more organ failure, increased durations of mechanical ventilation as well as length of hospital stay, and a trend towards higher mortality rates, although the latter did not reach statistical significance.
To the best our knowledge, this study is the first to evidence the prognostic significance of an enlarged PCO
2 gap at ICU admission in high-risk surgical patients. In patients who developed postoperative complications, the increase in PCO
2 gap was maximal immediately after ICU admission and gradually decreased thereafter as a result of medical support. The diagnostic performance of the PCO
2 gap is quite similar to the SOFA score with the huge advantage of being measurable at patient admission. In addition, the measurement of the PCO
2 gap is much more responsive than the SOFA score and easy to implement at the bedside. These results are supported by the results of a previous study by our group in which an enlarged PCO
2 gap was associated with an increased rate of postoperative complications in patients who remained inadequately managed by volume loading during an individualized goal-directed therapy [
17]. These results also echo those of previous studies in patients with severe sepsis or septic shock in which a large PCO
2 gap was associated with higher rates of organ failure and greater mortality [
18,
21,
27]. In all these studies, the thresholds for PCO
2 gap values were around 5 to 6 mmHg, as in our study.
The increase in venous PCO
2 would reflect a state of insufficient flow relative to CO
2 production [
28,
29]. Indeed, in an
in situ, vascularly isolated, innervated dog hindlimb model, Vallet and colleagues evidenced that the PCO
2 gap increased during low blood flow-induced tissue hypoxia (ischemic hypoxia) while it remained unchanged during hypoxemia-induced hypoxia (hypoxic hypoxia) [
22]. These results were confirmed in a mathematical analysis model [
30] and in
in vivo conditions in pig [
31] and in sheep [
9]. These results are also in agreement with those of Bakker and colleagues [
21] who showed that, in patients with septic shock, the PCO
2 gap was smaller in survivors than in non-survivors, despite quite similar CO, O
2 delivery (DO
2) and O
2 consumption (VO
2) values. In septic shock patients, characterized by an increased PCO
2 gap and a low flow state, fluid challenge was found to lower the PCO
2 gap while increasing CO [
32]. In contrast, no significant changes in CO and PCO
2 gap were found in patients with normal PCO
2, thus confirming the relationship between an increased PCO
2 gap and insufficient flow [
32].
In our study, ScvO
2 did not allow us to discriminate between patients with and without postoperative complications. These results seem to contradict previous studies. Indeed, recently published data clearly demonstrate that low ScvO
2 during and after major abdominal surgery is associated with an increased risk of postoperative complications [
7,
16,
33]. In addition, ScvO
2 was part of early goal-directed therapy protocol algorithms that have proven their effectiveness in improving the prognosis of patients [
16,
34]. As the use of ScvO
2 has become increasingly popular in the management of high-risk surgical patients, one part of our patients (at the convenience of the anesthetist in charge of the patient) had already been treated using ScvO
2 during surgery before inclusion in the study. The hemodynamics of our patients were in part optimized, as evidenced by ScvO
2 values above 70% in both groups. Another point to consider is that sepsis was the main cause of postoperative complications in our study (47%). In this situation where microcirculation failure is frequent, a normal or high ScvO
2 value does not preclude tissue hypoperfusion [
12,
13,
35]. According to the modified Fick equation applied to CO
2, the PCO
2 gap is linearly related to CO
2 production (VCO
2) and inversely related to CO [
29]. In situations where the VO
2/DO
2 relationship is satisfied, the flow is sufficient to wash out the CO
2 produced by the tissue even if there is an additional anaerobic VCO
2 [
22]. Conversely, when blood flow is low, the PCO
2 gap may increase even if there is no increase in VCO
2 [
31]. Taken together, these factors may explain why, in some of our patients, the PCO
2 gap was increased while ScvO
2 was normal and ScvO
2 failed to predict postoperative complications [
36].
Similarly, lactate levels were not an independent factor associated with postoperative complications, unlike the PCO2 gap. This difference is not entirely a surprise since our surgical patients benefited from immediate hemodynamic support in the operating room and intensive care. Therefore, these patients were not necessarily in a decompensated state as evidenced by the small increase in lactate levels (<2.5 mmol/l on average) and ScvO2 > 70% including patients who present with postoperative complications. The increase in PCO2 gap seems only to suggest that there is a hemodynamic optimization margin for these patients. Moreover, the PCO2 gap and lactate levels may reflect different events since lactate clearance is slower than the dynamic and rapid change in PCO2 gap; the lactate level could reflect the hemodynamic state in the last hours of surgery. If there was a significant relationship between the rate of lactate at H0 and intraoperative variables, such as intravenous fluids, blood loss, episodes of low mean blood pressure ≤60 mmHg for more than 10 minutes, and duration of surgery (data not shown), the strength of this association is quite relative, since the correlation coefficients ranged from 0.273 to 0.359. If intraoperative events influenced the lactate levels at postoperative ICU admission, they were not the only explanation.
In this context, when early goal-directed therapy has reached its objectives including ScvO
2 > 70%, the PCO
2 gap could be a useful additional tool to continue processing hemodynamic optimization. In several studies using a goal-directed therapy in sepsis, it was demonstrated that either lactate clearance or PCO
2 gap could be useful for identifying a persistent tissue hypoperfusion even when ScvO
2 goals had been achieved [
15,
18]. In surgical patients, it has been shown that an individualized preload-targeted fluid loading to maintain tissue perfusion was not sufficient to prevent significant differences in outcome [
37]. Interestingly, the mean PCO
2 gap was larger in patients with complications with a “normalized” DO
2/VO
2 ratio (ScvO
2 ≥ 71%) than in patients without complications, with 5 mmHg as the best threshold value. Associated with these previous studies, our results confirm that the PCO
2 gap is a useful and additional tool to detect persistent tissue hypoperfusion. Moreover, the increase in lactate level, another marker of inadequate VO
2/DO
2 relationship, is often delayed compared to other markers such as ScvO
2 [
16]. In our study the elevation of the PCO
2 gap was very early, starting at patient inclusion. Part of this increase was probably secondary to the intraoperative hemodynamic situation. The PCO
2 gap at H0 was significantly higher in patients undergoing intraoperative catecholamine (6.88 ± 3.16 versus 3.02 ± 8.7,
P = 0.006), but this effect appears to be limited to the most seriously ill patients (those receiving catecholamines) since there was no correlation between PCO
2 gap at H0 and other intraoperative macrocirculatory variables (mean arterial pressure, heart rate, blood loss, fluid loading, blood transfusions, dieresis; data not shown).
Our study has several limitations. First, this was a single-center study involving patients undergoing major abdominal surgery. It is therefore uncertain whether our findings can be extrapolated to other non-abdominal surgery. Second, we are aware that the number of patients was relatively small which could limit the external validity of the study, and that complementary data are needed to confirm the result. Nevertheless, when we considered that one measurement of PCO
2 ≥ 6 mmHg at inclusion was associated with the occurrence of postoperative complications, we found a
post-hoc power >90%. Third, the use of central venous-to-arterial PCO
2 difference as a surrogate for mixed venous PCO
2 gap might be a further limitation. Nevertheless, it has been found that central venous PCO
2, obtained from a simple central blood sample instead of a pulmonary arterial blood sample, is a valuable alternative to mixed PCO
2 and that correlation with CO still exists in this context [
38].
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ER was one of the designers of this study, the largest contributor to the manuscript and performed the statistical analysis. EF was one of the designers of this study and was involved in drafting the manuscript. OP participated in the design of this study, inclusion of patients and developed the database. MF was involved in the inclusion of patients, and the design and development of the database. BT was one of the designers of this study and was involved in drafting the manuscript. GL is the head of the department in which patients were included and was involved in drafting and revising the manuscript. BV was the main designer of this study and has contributed to the manuscript. All authors read and approved the manuscript.