The main findings of our study were as follows: (1) acute increase in alveolar ventilation resulted in a significant increase in ∆PCO2 accompanied with a significant decrease in ScvO2; (2) these changes were linked to a significant increase in oxygen consumption induced by acute hyperventilation.
Early identification and treatment of tissue hypoperfusion are critical factors in the management of septic shock patients. In this regard, ∆PCO2 has been considered as a marker that reflects the adequacy of tissue perfusion in septic shock states [3–9]. Increased ∆PCO2 is associated with venous hypercapnia, which is explained by the low-flow-induced CO2 stagnation phenomenon [11, 12]. Venous hypercapnia results from insufficient elimination of the CO2 produced by peripheral tissues, secondary to reductions in systemic and microcirculatory blood flow. However, under spontaneous breathing, hyperventilation may decrease PaCO2 and thus may preclude the CO2 stagnation-induced increase in PvCO2 [24]. Because alveolar hyperventilation would decrease both arterial and venous PCO2 without eliminating the increased venous-to-arterial PCO2 gap, it is recommended to assess ∆PCO2 rather than only monitor PvCO2 as a global marker of tissue perfusion [25].
However, a few studies have assessed the effects of acute hyperventilation on ∆PCO2 in critically ill patients [13, 14, 21]. We found that the acute increase in alveolar ventilation led to a significant increase in ∆PCO2 with an amplitude (2.2 mmHg) that was larger than its smallest detectable difference (2.0 mmHg) [23]. In addition, when the changes in ∆PCO2 are expressed as relative changes, acute hyperventilation induced a significant increase in ∆PCO2 with a magnitude (48.5%) that was also greater than its least significant change (32.4%) [23], which is the minimum change that needs to be measured by a laboratory analyzer in order to recognize a real change in measurement. In other words, the observed increase in ∆PCO2 can be considered as a true change and was not due to a random variation. Our findings are in agreement with the results of Morel et al. [21]. Indeed, these authors studied the effects of an acute decrease in PaCO2, obtained by increasing the respiratory rate, on ∆PCO2 in mechanically ventilated post-cardiac surgery patients. They found that acute hyperventilation provoked a significant increase in ∆PCO2 (from 4.2 ± 1.8 to 7.6 ± 1.7 mmHg), while the cardiac index was unaffected. In that study [21], ScvO2 also decreased in parallel with the increase in alveolar ventilation. Furthermore, in an animal study [16], the gradient between gastric mucosal PCO2 and PaCO2 (indicator of gut perfusion), obtained with gastric tonometry, increased significantly after hyperventilation. However, our results disagree with those of a previous study [13] that found no impact of hyperventilation on mixed venous-to-arterial PCO2 difference in mechanically ventilated patients. In that study, the increase in alveolar ventilation was obtained very progressively by increasing the tidal volume from 7 to 10 mL/kg over a period of 3 h, which might explain the absence of changes in mixed venous-to-arterial PCO2 difference. Also, the mean cardiac index at baseline was high (4.55 ± 0.90 mL/min/m2), which would have prevented any increase in mixed venous-to-arterial PCO2 difference by washing out any addition of CO2 from the peripheral circulation.
Several mechanisms can be suggested to explain the increase in ∆PCO2 observed in our study. A first potential explanation is that acute hyperventilation provoked the increase in systemic oxygen consumption and therefore CO2 production. Thus, for a given venous blood flow, the increase in tissue CO2 production should lessen the decrease in PcvCO2 (induced by hyperventilation) relatively to the decrease in PaCO2, leading to a rise in ∆PCO2. We believe that such a mechanism may have contributed to the increase in ∆PCO2 after acute hyperventilation in our study. Indeed, we observed a strong correlation between the increases in VO2 between before and after hyperventilation and the increases in ∆PCO2 (Fig. 2a). Also, the magnitude of the decrease in PcvCO2 after hyperventilation was significantly less than the decrease in PaCO2 (−16.5 ± 4.8 vs. −22.7 ± 5.5%, p < 0.001, respectively), explaining the observed increase in ∆PCO2. Similarly, the reduction in ScvO2 found after hyperventilation can be explained by the increase in VO2. It is unlikely that the increase in VO2 with hyperventilation was a result of an unstable state because of the lack of hemodynamic and temperature differences (Table 2), and the absence of changes in vasopressor and sedation drugs during the study period. We think that the observed increase in VO2 was induced by acute hyperventilation since we found a good association between changes in pH and changes in VO2 (Fig. 1). Acute respiratory alkalosis has been found, in some experiments in animals and humans, to increase VO2 and CO2 production independently of any significant hemodynamic changes [17, 18, 26, 27]. Indeed, hyperventilation alkalosis, in mechanically ventilated dogs, increased VO2 by 10–25% [17, 18]. In anesthetized paralyzed patients, contradictory findings were observed with some authors reporting a significant increase in whole-body VO2 [27], whereas others failed to demonstrate any significant variation [14]. Recently, Morel et al. [20], reported a twofold increase in VO2 in healthy volunteers with hypocapnic condition compared to hypercapnic condition for the same minute volume, suggesting a possible contribution of this mechanism to the observed increase in peripheral venous-to-arterial CO2 difference after induced acute respiratory alkalosis. The mechanism by which an acute respiratory alkalosis stimulates oxygen consumption is unclear and may involve many intracellular processes. A decrease in intracellular hydrogen ion concentration may stimulate the activity of phosphofructokinase, a key enzyme in the glycolytic cycle, which could result in increased intracellular adenosine triphosphate (ATP) hydrolysis and increased VO2 [28, 29]. Interestingly, we found a significant increase in lactate level induced by acute hyperventilation (Table 2). This finding could be an indirect marker supporting the activation of the phosphofructokinase enzyme and the increased rate of glycolysis in our study. Indeed, several studies reported increased lactate production with alkalosis [30, 31], reflecting increased glycolysis.
A second possibility is that acute hypocapnia resulted in systemic vasoconstriction, thus decreasing the elimination of the total CO2 produced by the peripheral tissues, and increasing the ∆PCO2. It has been shown that acute hypocapnia induces vasoconstrictive responses in various organs [14, 32, 33]. In healthy volunteers, Umeda et al. [19] observed that acute hyperventilation decreased both the minimal and mean flow velocity in the radial artery assessed by Doppler echography. The authors concluded that the decrease in mean blood flow, which was the result of increased vascular tone induced by hyperventilation, was responsible for the rise in peripheral venous-to-arterial CO2 difference that they observed after acute hyperventilation. Similarly, Morel et al. [20] found a significant drop in the skin microcirculatory blood flow of healthy volunteers, evaluated with in vivo reflectance confocal microscopy, secondary to acute hypocapnia. In our study, we observed a significant increase in systemic vascular resistance in parallel with the elevation of alveolar ventilation (Table 2). Nevertheless, changes in systemic vascular resistance were not significantly correlated with changes in ∆PCO2 nor with changes in ScvO2, which suggests, indirectly, a minimal participation of this mechanism to the increase in ∆PCO2. However, since we did not specifically evaluate the microcirculation we cannot eliminate or confirm the contribution of the vasoconstrictive mechanism to the observed increase in ∆PCO2 secondary to acute hyperventilation.
A third possibility of the increase in ∆PCO2 is that acute hyperventilation could induce variations in the PCO2/CO2 content relationship. This mechanism is, however, unlikely to have occurred in our patients. Indeed, the relationship between CO2 content and PCO2, which is curvilinear rather than linear, is influenced by many factors such as the degree of metabolic acidosis, the hematocrit, and the oxygen saturation (Haldane effect) [12, 34]. Our patients did not have metabolic acidosis, and acute hyperventilation did not change the base excess meaningfully (Table 2). Although venous oxygen saturation decreased significantly after acute hyperventilation, it is unlikely that this change could have affected the PCO2/CO2 content relationship, because first, it was not large; in this extent as stressed by Jakob et al. [35], changes in ∆PCO2 might not parallel changes in CO2 content differences under conditions of very low values of venous oxygen saturation (<30%), which was not the case in our patients. Second, if Haldane effect had affected the PCO2/CO2 content relationship, it would have resulted in a decrease in ∆PCO2, rather than an increase in ∆PCO2 [36].
Our results are of clinical importance. Indeed, changes in ventilator settings are regularly needed in mechanically ventilated patients. Since ∆PCO2 is now widely recognized as a valuable marker to evaluate tissue perfusion in septic shock, a clinician should be aware that acute changes in pH or PaCO2 induced by hyperventilation could impact ∆PCO2 independently of changes in tissue perfusion. These findings should not dismiss the clinical value of ∆PCO2 as a marker to detect tissue perfusion derangements. On the contrary, our results highlighted the usefulness of ∆PCO2, as an index of VCO2/cardiac output ratio, to detect the imbalance between the relative increase in VCO2 and the blood flow, whatever the mechanism of this imbalance is (increases in oxygen consumption [37, 38] or tissue hypoperfusion [9]).
We acknowledge some limitations to our study. First, the number of patients studied was small, but the study was sufficiently powered to detect a real change in ∆PCO2 induced by hyperventilation. Second, the study was performed in a sample of septic shock patients from a single center, potentially limiting the generalizability of the results. However, our results confirm those of a previous study performed in a different patient population (post-cardiovascular surgery patients) [21]. Third, VO2 was calculated from central venous oxygen saturation and not from mixed venous oxygen saturation or measured by indirect calorimetry, what might limit its accuracy. However, in our study, we were interested in investigating the changes in VO2 induced by acute hyperventilation rather than by its absolute value. Furthermore, it has recently been demonstrated that calculating the oxygen-derived variables from the central venous blood allowed the detection of global tissue hypoxia in critically ill patients [39, 40]. Finally, we did not evaluate the microcirculation, and thus, we were incapable of drawing any conclusions about the effects of acute hyperventilation on the local vascular tone and its relationship to ∆PCO2.