Mystery of PCO2 Gap in Sepsis.

How to cite this article: Patil VP. Mystery of PCO2 Gap in Sepsis. Indian J Crit Care Med 2019;23(10):443-444.

BACKGROUND

Exactly 2 years ago, an article was published in Indian Journal of Critical Care Medicine, which showed that high PCO2 gap after 6 hours of resuscitation of septic shock patients was associated with high mortality.[1] The study by Arajuo et al, that is being published in this issue of Indian Journal of Critical Care Medicine fails to show any such correlation.[2]

The PCO2 gap is difference between partial pressure of CO2 in venous blood (PvCO2) and arterial blood (PaCO2). PCO2 gap is considered to be a marker of relationship between cardiac output (CO) to global metabolic demand, i.e., a marker of adequacy of venous blood flow to eliminate CO2 produced by peripheral tissues. Considering physiology, CO2 is the end product of aerobic metabolism and therefore venous CO2 content and thus, PCO2 reflects the global tissue blood flow relative to metabolic demand. Under steady-state conditions, PCO2 gap is determined by several factors: difference in veno-arterial CO2 content, CO2 dissociation curve (which expresses the relationship between CO2 pressure and CO2 content), CO and alveolar ventilation. It has been shown that out of all these factors, fall in CO has maximum influence on CO2 gap.[3]

Is PCO2 Gap a Good Marker of CO?

Many studies have shown that PCO2 gap is inversely related to CO. A strong relationship between CO2 gap and cardiac output was observed by Baker et al in 64 adult patients with septic shock. They also observed that the patients with increased CO2 gap also had a higher PaCO2 and a lower P/F ratio, showing that higher CO2 gap is seen in patients with pulmonary impairment.[4] Similar relationship between CO2 gap and CO was found by Cuschieri et al. in a mixed population of critically ill patients, in which about one-third of population were patients with circulatory and cardiogenic shock.[5] However, many studies involving septic shock patients failed to show any association between CO and CO2 gap or showed a weak relationship suggesting that high CO2 gap does not necessarily reflect low cardiac output in vasodialatory shock states.[6-8]

The increase in the venous-arterial pCO2 gradient in shock states from baseline value of 2–5 mm Hg is generally due to inadequate washout of CO2 from venous system. Under low-flow conditions due to slow transit time, CO2 stagnation leads to increase in venous CO2 content, PvCO2 and PCO2 gap. Sepsis is characterized by heterogeneity of microcirculation and decrease in functional capillary density with high cardiac output. This may contribute to inadequate washout of CO2 and thus high CO2 gap.

Does CO2 Gap Predict Tissue Hypoxia?

One of the reasons for high morbidity and mortality in sepsis is tissue hypoxia. Vallet et al. showed in a canine model of isolated limb, that ischemic hypoxia (diminished DO2 due to reduced blood flow) gave rise to increased CO2 gap but hypoxic hypoxia (preserved blood flow with reduced arterial PO2) resulted in normal CO2 gap. This happened because the preserved blood flow was sufficient to clear the generated CO2 in hypoxic hypoxia.[9] Similar findings were reported by Nevière et al.[10]

Wendon et al. prospectively studied 22 hypotensive patients with fulminant hepatic failure and found normal CO2 gap with evident tissue hypoxia, suggesting that high flow states with tissue hypoxia can also have normal CO2 gap. This was explained by low VO2 with consequent low CO2 production, which was removed by high CO.[11]

CO2 produced at tissue level diffuses into vascular compartment due to pressure gradient and then removed by microcirculation. Microvascular alterations, present in sepsis and in other pathologic states involving the microcirculation, can impede the movement of CO2 from the tissues into the vascular compartment. The end result of this is increased tissue CO2 concentration without increase in vascular CO2 content. Hence, increases in tissue CO2 will go unnoticed by measurement of venous PCO2 and CO2 gap, although they may be detected by methods that measure tissue PCO2, such as gastric tonometry or sublingual capnometry. Thus increases in venous PCO2 and CO2 gap are neither sensitive nor specific markers of tissue hypoxia.[12]

Another major limitation of CO2 gap is that it reflects global status of circulation. A normal CO2 gap does not rule out regional hypoperfusion. Studies have reported splanchnic hypoperfusion in sepsis with high cardiac output,[13,14] and gut mucosal ischemia can lead to translocation of bacteria and multiorgan dysfunction.

Probably these are the reasons why studies looking at CO2 gap have been inconsistent in their findings. Bakker in their study found pH, lactate, and oxygen saturation as significant discriminators of survival. Adding CO2 gap to these factors, however, did not increase the predictability of survival, indicating that CO2 gap was a confounding variable.[4] Muller et al., in their prospective cohort study of 350 septic patients, found correlation between high PCO2 gap and 28-day mortality in patients with cardiac dysfunction but not in patients without cardiac dysfunction.[15] Retrospective analysis conducted by Troskot et al. in 71 patients with septic shock found that High P(v-a)CO2 was related to mortality in nonventilated patients but not in ventilated patients.[16] Guinot et al. failed to show any association between PCO2 gap and postoperative complications and mortality in patients undergoing cardiac surgery.[17]

In conclusion, CO2 gap alone, is not the ideal biomarker that we are looking at, for guiding resuscitation in patients with septic shock, nor it can be used for prognosticating outcomes in this group of patients. It should be used along with other clinical and laboratory parameters to chart further course of action.