Previous investigators reported that gas exchange consistently worsened when cardiac output (Qt) was increased under normal and pathological conditions. This blog discusses about an alternative explanation, besides the one previously proposed that was based on some attenuation of hypoxic pulmonary vasoconstriction. The new concept emphases the inherent heterogeneity of regional blood flow (Q), as well as the skewed relationship between ventilation perfusion ratio (V/Q) and arterial oxygen tension (PaO2). Namely, PaO2 is exquisitely sensitive to any change of V/Q ratio from 0 to 1, which is many times more than that from 1 to 100. As Qt is increased, the additional pulmonary flow is by no means uniformly distributed. Thus, either ventilation (V) remains stable or even becomes more variable, V/Q heterogeneity increases at increased Qt. The higher Q in most regions reduces their corresponding V/Q ratios from the previously normal value of about 0.8 to 1, precipitously into the hypoxic range towards true shunt (V/Q = 0) and increases the V/Q mismatch. In contrary, the simultaneously created higher V/Q units cannot mitigate these adverse changes because of the sigmoid shape of hemoglobin oxygen dissociation curve. By this mechanism, diseased lungs are more susceptible to hypoxemia when Qt is increased due to their pre-existing V/Q abnormalities.