Regional hypoxia and partial pressure of carbon dioxide gradients: what is the link?

Gut hypoperfusion is often suspected in critically ill patients but identifying it can be difficult. The usual diagnostic tools, such as echography or CT scan, are not sensitive enough and can only detect extreme situations. Global hemodynamic measurements are commonly performed in critically ill patients and provide essential information. Nevertheless, gut hypoperfusion is still often unrecognized, either because of the development of regional blood flow alterations, even when cardiac output is maintained, or because gut blood flow may paradoxically be preserved when cardiac output is decreased. The measurement of hepatic venous oxygen saturation may be useful to evaluate the adequacy of splanchnic blood flow [1]. In addition, an elevated gradient between mixed-venous and hepatic venous oxygen saturation is suggestive of hepato-splanchnic VO₂/DO₂ dependency [2]. Unfortunately, this measurement reflects total hepato-splanchnic blood flow, including not only portal, but also hepatic, arterial blood flow. Hence, gut hypoperfusion can still occur even when hepatic venous oxygen saturation is maintained [3]. Ideally portal blood should be sampled, but this is not feasible in clinical practice. Hepatic vein lactate measurements [4] can also be used to detect splanchnic hypoxia, but similar limitations apply to these measurements. In addition, lactate measurements can be influenced by other factors than tissue hypoxia [5].

Measurements of CO₂ gradients may thus provide an excellent alternative. These can be estimated not only in mixed-venous blood, reflecting the adequacy of cardiac output to whole body metabolism [6] or locally in venous beds [7], but also in various tissues, mainly the subcutaneous tissue, tongue and the stomach, to assess the adequacy of regional blood flow to regional metabolism. Tissue to arterial PCO₂ gradients are thought to be more reliable markers of tissue hypoxia than veno-arterial CO₂ gradients [8]. Tissue hypercarbia occurs in various experimental models of tissue hypoxia [9]. Similarly, increases in gastric mucosal CO₂ are commonly observed in critically ill patients. Several studies have demonstrated that an increase in gastric mucosal PCO₂ is associated with a poor outcome in critically ill patients, including patients with septic shock [10] and postoperative patients [11]. Increased gastric to arterial CO₂ gradients (PCO₂gap), which are independent of systemic acidosis and hypercarbia, are also associated with a worse outcome in septic patients [12].

Several investigators have questioned the ability of gastric mucosal PCO₂ to detect tissue hypoperfusion [13, 14]. In this issue Knuesel et al. [15] specifically address the problem of the potential redistribution of blood flow within the splanchnic bed during an acute decrease in splanchnic blood flow, and its impact on regional CO₂ measurements. They investigated the effects of an isolated decrease in splanchnic blood flow on regional blood flow distribution within the splanchnic region as well as on splanchnic metabolism and mucosal PCO₂. The authors designed a complex surgical model in pigs in which a shunt between the proximal and the distal abdominal aorta generated a specific decrease in splanchnic blood flow with minor changes in cardiac output or arterial pressure. Blood flow to the hepatic, splenic, celiac trunk and superior mesenteric arteries, and portal vein was measured by flow probes. Catheters in the hepatic, portal, mesenteric and splenic veins allowed blood sampling for blood gas analysis and lactate determination. In addition, tonometry catheters were inserted in the jejunum and in the stomach.

Knuesel et al. [15] first observed that regional redistribution between the various splanchnic organs did not occur. Accordingly, jejunal and gastric tonometric values increased similarly. This is of particular importance as some authors have reported that gastric tonometry may be less sensitive than jejunal tonometry [16]. The physiological basis for this limitation would be the hepatic arterial buffer response, which would favor celiac trunk vasodilatation and, hence, preservation of gastric perfusion. However, this compensatory response cannot be maintained and is lost in sepsis. Hence, differences between gastric and jejunal PCO₂ are probably more related to specific technical problems, such as gastro-esophageal reflux, than to blood flow redistribution inside the splanchnic area.

The second, and also very important, finding was that gastric tonometry can detect isolated gut hypoperfusion. This study nicely confirms that the principal determinant of PCO₂ gradients is flow and that these gradients can be used to track changes in flow. Indeed the authors addressed the very important issue of the interpretation of tissue CO₂ measurements. The regional PCO₂ gradient represents the balance between regional CO₂ production and clearance. CO₂ can be produced either aerobically, thus independent of tissue hypoxia, or by buffering H+ anions by tissue bicarbonate in the context of tissue hypoxia. Of note, the same amount of CO₂ will be generated for a similar degree of tissue hypoxia, whatever the type of hypoxia (hypoxic, anemic, stagnant or cytopathic) but CO₂ will be cleared if blood flow is maintained. For gastric or ileal tonometry, the main determinants will be mucosal blood flow. Tugtekin et al. [17] demonstrated, in septic pigs, that an increased PCO₂gap was related to the heterogeneity of gut mucosal blood flow even though cardiac output and mesenteric blood flow were maintained. Of course, gut hypoperfusion is more likely to occur when total splanchnic blood flow is decreased or when cardiac output is low.

We previously reported that the decrease in PCO₂gap in response to dobutamine was suggestive of a low fractional splanchnic blood flow [18]. An important question is whether an increased PCO₂ gradient can also be observed in other types of hypoxia, when blood flow is preserved? Recent data suggest that this may not be true. Neviere et al. [19] reported that the increase in PCO₂gap in pigs was less pronounced in hypoxic hypoxia than in ischemic hypoxia. Similarly, the increase in PCO₂gap was blunted in anemic hypoxia in sheep [20]. This suggests that maintenance of flow limits the increase in PCO₂gap. Similar results would be expected in cytopathic hypoxia in which, by definition, blood flow is maintained.

Finally, Knuesel et al. [15] tried to evaluate the role of the Haldane effect on PCO₂ gradients. Changes in arterial oxygen saturation induce similar changes in PCO₂ for a given CO₂ content. Calculating CO₂ content, Jakob et al. [14] suggested that the Haldane effect may explain the paradoxical increase in PCO₂gap together with an increase in splanchnic blood flow in patients after cardiac surgery. Unfortunately, the calculation of CO₂ content difference is complex, necessitating multiple calculations, so that small errors in measurements can lead to large errors in CO₂ content differences. Simplified formulas provide an easy way to calculate the relative contribution of the Haldane effect, but these cannot be applied when there are large differences in the venous and arterial blood acid-base status, which is the case in ischemic hypoxia. Hence, Knuesel et al. [15] could only calculate the contribution of the Haldane effect in control animals in which minor changes in flow and PCO₂ were observed. Nevertheless, they observed that the Haldane effect played a minor role in their results as, in most cases, PCO₂ gradients and CO₂ content differences evolved similarly.

In conclusion, gastric tonometry is a minimally invasive technique that can be used to assess the adequacy of gastric mucosal blood flow to metabolism. Although an increased gradient may suggest gut hypoxia, especially when the PCO₂gap is greater than 20 mmHg [8], a normal PCO₂gap does not rule out gut hypoxia as long as gut mucosal blood flow is maintained.