Acute hyperventilation increases the central venous-to-arterial PCO₂ difference in stable septic shock patients

Awareness that tissue hypoperfusion is a key factor in the pathogenesis of the multiple organ failures has focused the attention on surrogate indicators of tissue perfusion in the critically ill patient [1, 2]. In this context, venous-to-arterial carbon dioxide tension difference (∆PCO₂) has been proposed as a marker of tissue hypoperfusion in patients with septic shock [3–9]. In fact, the increase in ∆PCO₂ that has been observed in low-flow states is mainly related to venous hypercapnia, rather than a decrease in arterial CO₂ partial pressure (PaCO₂), which can be explained by the tissue CO₂ stagnation phenomenon. Indeed, due to the decrease in transit time, there is a higher than usual addition of CO₂ per unit of blood passing the efferent microvessels, which leads to a rise in CO₂ partial pressure in the venous blood (PvCO₂) [10–12].

The reason for the preferred use of ∆PCO₂ over PvCO₂ as a marker of global tissue perfusion is that ∆PCO₂ was found to be less influenced by changes in PaCO₂ than PvCO₂ [13–15]. However, acute changes in PaCO₂ or arterial pH might have direct effects on microvascular tone and/or might induce variations in systemic oxygen consumption [15–18], and could then affect ∆PCO₂. Recently, in healthy volunteers, acute hyperventilation was shown to be associated with an increase in the peripheral venous-to-arterial CO₂ difference due to a reduction in peripheral blood flow induced by acute hypocapnia [19, 20]. Furthermore, Morel et al. [21] found, in a small study that included mechanically ventilated postoperative patients, that acute decreases in PaCO₂ resulted in significant increases in ∆PCO₂ without any change in cardiac output. Therefore, it is not clear so far what the impact of the rapid decrease in PaCO₂ on ∆PCO₂ is. This question is important because if PaCO₂ or arterial pH fluctuations could influence ∆PCO₂, this effect will have to be taken into account by the physician when interpreting ∆PCO₂ at the bedside. The aim of this study was to investigate the impact of acute hyperventilation on ∆PCO₂ in mechanically ventilated and hemodynamically stable septic shock patients.

This prospective and observational study was conducted in a single general adult intensive care unit (ICU). The study was approved by our local institutional ethics committee (Comité d’éthique du Centre Hospitalier du Dr. Shaffner de Lens, France). Informed consent was obtained from each subject’s next of kin.

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.

In stable septic shock patients, acute hyperventilation leads to a significant increase in ∆PCO₂, which is associated with an increase in VO₂, also induced by hyperventilation. Microcirculatory dysfunction is a key pathological mechanism involved in septic shock patients and could, also, be exacerbated by acute changes in alveolar ventilation. This finding should be taken into account when interpreting ∆PCO₂ at the bedside. Further studies are needed to investigate the effects of acute hyperventilation on systemic oxygen consumption and local vascular tone.