In this study, we investigated the relationship between intraoperative oxygen tension and mortality after OPCAB. A mildly hyperoxic level of intraoperative arterial oxygen tension was associated with improved outcomes after OPCAB when compared to normoxic, near-normoxic, and severely hyperoxic levels. Patients with intraoperative time-weighted average PaO2 levels between 150 mmHg and 250 mmHg had a significantly lower risk of in-hospital mortality than those with time-weighted average PaO2 levels 150 mmHg and 250 mmHg. Furthermore, intraoperative PaO2 exhibited a U-shaped relationship with in-hospital mortality in the non-hypoxic range.
Perioperative DO2 management is associated with complications after cardiac surgery, including neurologic injury (Hogue et al. 1999; Bahrainwala et al. 2011; Magruder et al. 2018; Murphy et al. 2009) and renal impairment (de Somer et al. 2011; Ranucci et al. 2005; Magruder et al. 2015).To optimise perioperative DO2, physicians have focused only on CO, haemoglobin (Hb) concentration, and SaO2. In contrast, PaO2 has been of less interest because its theoretical contribution to DO2 and arterial oxygen content (CaO2) is limited according to the following equation (Shepherd and Pearse 2009):
$${DO}_{2}=CO \times {CaO}_{2}$$
$$=CO\times (1.34\times Hb\times {SaO}_{2}+0.0034\times {PaO}_{2})$$.
In addition, most previous studies have emphasised the importance of CO and Hb concentrations rather than PaO2 (Hogue et al. 1999; Bahrainwala et al. 2011; Ranucci et al. 2005). In this study, we demonstrated that postoperative mortality may differ according to intraoperative PaO2 strata given similar Hb concentrations and CO. From our analysis of the causes of death, we could not identify any clues to the mechanism underlying this finding. Nonetheless, higher SvO2 (indicating a higher DO2) may explain in part the improved postoperative mortality observed in the mild hyperoxia group. Similar results were reported by Legrand and colleagues (2014). In their study, median central venous oxygen saturation increased from 71–84% after increasing FiO2 from 0.4 to 1.0 in critically ill patients (Legrand et al. 2014). The increase in central venous oxygen saturation was not fully explained by CO, Hb level, or SaO2, rather it was considerably accounted for by PaO2 (Legrand et al. 2014). Likewise, Yu and colleagues (2006) observed a significant increase in tissue oxygen partial pressure after increasing FiO2 in critically ill patients. Taken together, these findings indicate that dissolved oxygen (or PaO2) may contribute to DO2 more than expected in real-world practice. According to the aforementioned equation, in a hypothetical patient with Hb concentration of 10 g/dL and an SaO2 of 100%, an isolated change of 0.5 g/dL in Hb concentration or 5% in SaO2 is equivalent to a PaO2 change of 197 mmHg. This calculation implies that a large increase in PaO2 is required to obtain a clinically meaningful increase in DO2. However, in our study, we observed that even a mild increase in intraoperative PaO2 may result in improved survival after OPCAB. Considering that transfusion may be associated with poor postoperative outcomes (Nam et al. 2020; Rohde et al. 2014; Vlaar et al. 2011) and that SaO2 remains 100% or nearly 100% during intraoperative mechanical ventilation, increasing FiO2 (thereby increasing PaO2) may be a simple and efficient alternative method for physicians to improve DO2 during cardiac surgery.
In our study, severe intraoperative hyperoxia (PaO2 >250 mmHg) was associated with an increased risk of mortality compared to mild hyperoxia (PaO2 150–250 mmHg). Moreover, on the spline curves, the risk of in-hospital mortality exhibited a U-shaped pattern. The risk declined as intraoperative PaO2 increased from the normoxic level to approximately 200 mmHg, following which it began to increase. Similar results were reported by Helmerhorst and colleagues (2017). In their multicentre observational cohort study of more than 14,000 ICU patients, various PaO2 metrics used to define hyperoxia during ICU admission exhibited a U-shaped relationship with in-hospital mortality. However, their PaO2 inflexion point appeared earlier, at approximately 150 mmHg. Given the absence of a clear definition of hyperoxia (Heinrichs et al. 2018), future studies seeking a hyperoxic threshold beyond which clinical outcomes worsen are warranted.
In this study, CO levels were comparable between the normoxia/near-normoxia and mild hyperoxia groups, whereas the CO level in the severe hyperoxia group (PaO2 >250 mmHg) was significantly lower than that in the other groups (pairwise comparisons, not shown in the Results section). This may be important given that previous studies have reported that significant hyperoxia (PaO2 450–550 mmHg) increases systemic vascular resistance, thus decreasing CO (Harten et al. 2005; Inoue et al. 2002). In another study, Smit and colleagues (2016) compared a PaO2 target of 200–220 mmHg during cardiopulmonary bypass and 130–150 mmHg during ICU admission (similar to the mild hyperoxia group in our study) to a lower target of 130–150 mmHg during cardiopulmonary bypass and 80–100 mmHg in the ICU (similar to the normoxia/near-normoxia group in our study). The resultant systemic vascular resistance and CO did not differ between the two targets. These results are concordant with our finding that mild hyperoxia (PaO2 of 150–250 mmHg) increased SvO2 without a decrease in CO. To date, the PaO2 threshold beyond which CO begins to decrease remains unknown.
Our results should be interpreted with caution for several reasons. First, this study was retrospective in nature, and the results may indicate merely an association, not a cause-effect relationship between intraoperative hyperoxia and mortality after OPCAB. Although we adjusted for a large set of clinical covariates to offset this drawback, potential confounders may still be in play. Indeed, we could not address some of the EuroSCORE II variables. Randomised controlled trials should therefore be conducted. An ongoing study aims to compare the length of hospital stay after OPCAB between patients receiving two different levels of intraoperative FiO2 (ClinicalTrials.gov identifier, NCT03945565). Second, since FiO2 was usually set to 0.4–0.5 in this study, the difference in PaO2 may have stemmed from individual lung conditions, such as diffusion capacity or ventilation/perfusion ratio, which may have confounded our results. Third, we only compared SvO2 among the study groups and could not calculate DO2. Although DO2 is reflected as SvO2, it is accurate to say that SvO2 indicates a balance between oxygen supply and demand (Shepherd and Pearse 2009).