Introduction
The PaO_{2}/FIO_{2} ratio represents the pressure exerted in the blood by the unbound molecules of oxygen, normalized to the fractional volume of inspired oxygen. The PaO_{2}/FIO_{2} ratio is used to assess the lung’s capability to oxygenate the blood, primarily in ARDS, where its thresholds of 150, 200, and 300 are used/proposed to classify ARDS severity [1, 2]. Ideally, a given PaO_{2}/FIO_{2} ratio value should correspond to a definite lung severity, independently of FIO_{2}. In reality, the same severity may be associated with quite different PaO_{2}/FIO_{2} values, depending on several factors, as previously described [3].
Alveolar PO_{2}
Consequently, an identical PaO_{2}/FIO_{2} ratio of 150 measured at the barometric pressure of Mexico City (2250 m) or Göttingen (150 m) in two patients breathing 30% O_{2}, with identical PaCO_{2}/R ratios, would result in a sharply different PaO_{2}/PAO_{2} ratios: 0.32 in Göttingen, decidedly less than the 0.49 in Mexico. The impact of PaCO_{2}/R ratio on PAO_{2} is less dramatic, unless extracorporeal CO_{2} removal is in use. In this case, the R may be very low, producing a consistent decrease in the alveolar PO_{2}, if FIO_{2} is not adequately increased [4, 5, 6].
Arterial PO_{2}
 1.
CcO_{2} strictly depends on PAO_{2}, which is proportional to the FIO_{2} (Eq. 1), while the CaO_{2} is proportional to the PaO_{2} (through the oxygen dissociation curve) [8]. Therefore, the difference (CcO_{2} – CaO_{2}) and the ratio (CaO_{2}/CcO_{2}) are strictly related and hold the same physiological meaning of PaO_{2}/FIO_{2} ratio.
 2.
Because the (CcO_{2} – CaO_{2}) difference equals the product: [venous admixture × (CcO_{2} – CvO_{2})], the same (CcO_{2} – CaO_{2}), i.e., the same PaO_{2}/FIO_{2}, may derive from myriad combinations of venous admixture fraction and (CcO_{2} – CvO_{2}). These range from extremely high venous admixture fraction and low (CcO_{2} – CvO_{2}), i.e., high CvO_{2}, or vice versa.
 3.
CcO_{2} primarily depends on FIO_{2}; therefore, for a given FIO_{2} any change of (CcO_{2} – CvO_{2}) only depends upon the CvO_{2}.
 4.
CvO_{2}, for a given arterial oxygenation, strictly depends on oxygen consumption (VO_{2}) and cardiac output (Qt); indeed, CvO_{2} = CaO_{2} – VO_{2}/Qt.

PaO_{2} is lower at higher venous admixture levels and increases nonlinearly with FIO_{2} along the isovenous admixture lines.

For a given oxygen consumption and venous admixture level, cardiac output exerts a tremendous effect on PaO_{2}. It must be stressed, however, that the primary determinant is the CvO_{2} (see point 4 above).
Clinical use
Assessment of severity
Although the PaO_{2}/FIO_{2} ratio has limits as a surrogate of venous admixture, the PaO_{2}/FIO_{2} ratio offers several advantages: first, it is easy to measure; second, when tested across large populations (but not necessarily in individual patients), the PaO_{2}/FIO_{2} reflects reasonably well the severity of anatomical derangements measured by CT scanning [1]. Nonetheless, the accuracy of PaO_{2}/FIO_{2} ratio for indexing ARDS severity (e.g., Berlin ARDS definition) would improve greatly if determined at a standard PEEP value. In previous work [10], we used 5 cmH_{2}O to avoid the masking effect of higher PEEP on PaO_{2}/FIO_{2} ratio, which may be due either to decreasing venous admixture or altering hemodynamics. Standardization of FIO_{2} would further improve the accuracy and comparability of severity among patients [11].
PEEP selection
Changes in PaO_{2}/FIO_{2} ratio are frequently used to assess recruitability during ARDS, on the assumption that increases in PaO_{2}/FIO_{2} ratio are due to lung recruitment [12]. Unfortunately, increasing PEEP often decreases cardiac output. Theoretically, if the venous admixture and oxygen consumption do not change, this would reduce the PaO_{2}/FIO_{2} ratio. However, this seldom occurs, as the venous admixture usually changes in proportion to the cardiac output [12, 13, 14, 15]. Therefore, caution must be used when setting PEEP with the PaO_{2}/FIO_{2} approach, as its apparent that improvement may be due to decreased cardiac output in the absence of recruitment—a principle long known but often forgotten.
Conclusions

PaO_{2}/FIO_{2} ratio is a surrogate of venous admixture measurement for approximating ARDS severity and relates well to anatomical differences on the CT scan.

At a given venous admixture, the PaO_{2}/FIO_{2} ratio may differ, depending on oxygen consumption and cardiac output. Conversely, for the same PaO_{2}/FIO_{2}, venous admixture may vary with FIO_{2}.

To better assess severity of lung injury and follow its evolution, PaO_{2}/FIO_{2} ratio should be measured at standardized levels of PEEP and FIO_{2}. Selecting PEEP according to PaO_{2}/FIO_{2} ratio may be misleading if hemodynamics are not taken into account.
Notes
Compliance with ethical standards
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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