Bhavani Shankar Kodali MD

Can Negative (a-ET)CO₂ differences occur?

Where can they occur?

What are the reasons for negative values?

Four physiological reasons

Increase in the slope of phase III

Negative (a-ET)PC02 values were observed more than 30 yr ago by Nunn et al. during anesthesia although no explanation was offered.1 Fletcher et al. observed negative or zero (a-ET)PCO₂ values in 12% of normal subjects during anesthesia and IPPV with large tidal volumes and low frequencies.2 Negative values were also observed during anesthesia in 50% of pregnant subjects,3 in 8.1% of patients after post-cardiac bypass (PCB)4 and in 50% of infants.5

Piper reviewed several studies with negative arterial to end-tidal CO₂ differences in 1986 and concluded that the reasons for the remarkably pronounced disagreement between the experimental data of different studies cannot be definitely identified and suggested that it is desirable that more observational and experimental data become available in future to review this subject.6 Since then several studies have reported negative differences as stated above. The following possible mechanism have been postulated to explain observed (a-ET)PCO₂ differences under various circumstances.

Large tidal volume and low frequency ventilation result in (i) better ventilation of dependent well-perfused alveoli which improves V/Q matching (small area of alveolar dead space as above in figure I). (ii) Gas emptying from slow alveoli to reach the mouth, whereas it would have remained in the airways with small frequent breaths. Under these circumstances the low V/Q areas (alveoli with higher PC02) make a more substantial contribution to the gas exchange. The net effect of these factors is to enable the terminal part of phase III to exceed mean PaC02, resulting in negative (a-ET)PC02.2

Alveolar PCO₂ varies cyclically, being lowest at end-inspiration and highest at end-expiration. However, because of mixing in the heart and syringe, PaCO₂ sampled at the radial artery is the spatial and temporal mean of alveolar PCO₂ (Riley’s physiological integrator) and therefore it is quite possible for PETCO₂ to exceed the sampled PaCO₂. The increased cardiac output and increased C02 production, reduced FRC and low compliance associated with pregnancy may result in greater cyclical variations in alveolar PCO₂ during a respiratory cycle and also in more alveoli with long time constants. During expiration, PACO₂ increases towards PVC02 (partial pressure of mixed venous C02) more rapidly in pregnant subjects because a larger amount of C02 is evolved into a lung which becomes smaller as expiration continues. Further, pregnant subjects resemble the obese in some features namely reduced FRC and low total compliance and hence may exhibit a biphasic slope reminiscent of phase IV of the nitrogen closing volume test. The PC02 of most alveolar gas is less than PaC02 but, in the terminal part of the expirate, PC02 rises rapidly and may exceed PaC02. The combined effect of these two mechanisms increases the slope of phase III (Figure 4) and the likelihood of sampling a PETCO₂ greater than PaC02.3,7-12 The presence of a wide range of V/Q mismatching and reduced FRC may result in negative (a-ET)PC02 values in patients after cardiopulmonary bypass.4,7 Increased C02 production and reduced FRC may be responsible for the negative (a-ET)PCO₂ values observed in infants.5