Our analysis shows that Pv-aCO2 from peripheral venous blood correlates with Pv-aCO2 from mixed venous blood, showing a bias of about 55%. In particular, although the bias shows a linear increase, this increase in the bias between the two measures is theoretically not relevant from the clinical point of view, provided that the agreement on the cut-off value is maintained. For the clinical use of the Pv-aCO2 value adopted so far, this bias would not seem to affect the applicability of the Pv-aCO2p index. Bakker et al. have shown that 6 mmHg is the value above, and a net reduction in cardiac output compared to tissue metabolic needs occurs [4]. Ospina-Tascón et al. showed that beyond that cut-off value, the mortality of patients in septic shock increases exponentially [12]. Guo et al. found that this cut-off value has a sensitivity of 86% and a specificity of 67% for a Cardiac Index value lower than 2.2 L/(min x m^2) [13]. Given these premises, the cut-off of Pv-aCO2 from peripheral venous blood, identified as corresponding to Pv-aCO2, does not lose clinical significance.
Pv-aCO2 is determined by cardiac output and metabolic status, and in the literature, it has been taken as an indicator of the adequacy of venous blood flow in removing CO2 produced by peripheral tissues. The meta-analysis of Al Duhailib et al., summarizing the results of 21 studies (2,155 patients), finds that a Pv-aCO2 generically "high" (> 6 mmHg in most included studies) is a predictive factor of mortality in ICU (OR 2.22; 95%CI 1.30–3.82) [14].
While the predictive role of poor outcomes seems relatively established (at least in certain populations of patients hospitalized in intensive care, such as, for example, patients in the condition of septic shock) and despite the sum of the studies agree on the subsistence of the correlation of Pv-aCO2 with the cardiac output, several studies have shown the inconsistency of the Pv-aCO2/Ca-vO2 ratio in evidencing a condition of anaerobiosis [15]. Dubin et al. (on an animal model in which a hemodilution condition was experimentally induced compared to hemorrhagic loss) found that this ratio increases considerably in the first condition, regardless of oxygen consumption [16]. Similar results, through an experimental study on an animal model, comparing two conditions of artificially induced ischemic and hypoxic hypoxia (by arterial ligation and by reduction of the inspiratory fraction of oxygen), have shown that, in the first situation, the Pv-aCO2 shows an incremental trend. In contrast, in the second condition, it remains stable [17]. The Authors concluded that Pv-aCO2 is not a good marker for anaerobiosis. Due to the Haldane effect, the reduction in oxygen delivery is not followed proportionally by a similar increase in Pv-aCO2.
As for the concordance between Pv-aCO2 from mixed venous and central venous blood (from the superior vena cava), studies conducted so far have shown an excellent agreement: the bias is between a minimum of 3.0 mmHg and a maximum of 9.0 mmHg with a correlation value above 90% [8–10]. Some studies have been conducted to verify the agreement between PvCO2 values from arterial and peripheral venous blood [18]. Not unexpectedly, these studies showed poor agreement. The discrepancy found in these studies supports the role of Pv-aCO2 in discriminating between patients with adequate and inadequate cardiac output. The PCO2 along the venous sector strongly undergo the effect of "washing" of the blood flow brought by the cardiac output when the latter is inadequate; PCO2 increases disproportionately, especially in the venous sector, rather than in the arterial one.
A study conducted by Shastri et al. on an animal model in which hyper- and hypoventilation conditions were produced (Pv-aCO2 data compared on blood samples collected within the first 60 seconds after the introduction of the ventilator modification) found that, during hyperventilation, Pv-aCO2 increased rapidly while, conversely, during hypoventilation, Pv-aCO2 decreased [19]. These variations were due to a rapid reduction of PaCO2 (therefore in the arterial sector) during the increase in respiratory rate and, similarly but in the opposite direction, to a rapid increase of PaCO2 during hypoventilation. The Authors conclude that changes in the ventilator arrangement could change the Pv-aCO2 values and, therefore, the prognostic significance of this variable, at least within a certain time of blood sampling.
In the literature, to our knowledge, only one other study has evaluated the correlation between Pv-aCO2 and Pv-aCO2p. Gao et al. found a significantly higher correlation than our value (r-value 0.90 vs 0.69) over a larger population than ours [20]. However, beyond the methodological differences between the two studies, the correlation we found undergoes a great divergence, especially for values above the equivalent cut-off (about 10 mmHg according to the bias we found), beyond which the Pv-aCO2p values show a divergent trend for Pv-aCO2, probably linked to factors depending on the local blood circulation [21, 22]. In addition to the degree of correlation, evaluating the agreement between the two measures is crucial to apply this measure to clinical practice.
Several clinical settings deal with the management of the septic patient, at least in the early stages of the syndrome, such as pre-hospital medicine, emergency medicine, and hospital medicine. Our study indicates a good correlation between Pv-aCO2 and Pv-aCO2p. The correlation, however, is limited to patients in septic shock, subjected to an invasive mechanical ventilation regime, and within the first 24 hours of admission to the ICU (and therefore from the establishment of a condition of frank hemodynamic shock). The implications of this result, if confirmed on larger populations and externally validated, could develop in the direction of a less invasive and yet more accurate approach than current septic patient standards. Potentially, such results could lead to early and "tailored" management of the septic patient.
Limitations
Our study aimed to identify a clinically tolerable agreement between Pv-aCO2 and Pv-aCO2p. Before applying the Pv-aCO2p in clinical practice, our results should be validated by an RCT (i.e., ventilatory settings, administration of vasopressor or inotropic drugs, etc., have to be established within pre-defined margins by a research protocol). In addition, the correlation between Pv-aCO2/Pv-aCO2p and the cardiac index we found may not be clinically confirmed where the above experimental conditions (ventilation settings, hemodynamic management, etc.) are not controlled. Ospina-Tascòn et al., in a clinical study of 60 patients admitted to the Intensive Care, found a poor correlation (in the order of r^2 = 0.08–0.22) between Pv-aCO2 and cardiac index [23]. The concordance between low cardiac output values and Pv-aCO2 is greater for low flow values and, therefore, for the increased venous-arterial difference. However, as cardiac output increases, other factors may come into play, such as increased tissue metabolism induced by a condition of systemic inflammation response syndrome (e.g. SIRS), which could influence the microcirculation conditions and tissue oxygen extraction capability [21, 22]. Moreover, there is no reference standard for determining the adequacy of cardiac output. The cardiac index is insufficient to determine the adequacy of cardiac output concerning the metabolic needs of the body's tissues.