In this study, our analyses demonstrated a U-shaped relationship between ICU admission SpO2 levels and all-cause in-hospital mortality of patients with APE. Furthermore, our study also presented the lowest mortality for the mean of SpO2 within 95–98%, which could be the optimal oxygen saturation targets and benefit oxygen therapy for patients with APE. These results were consistent for demographics, treatment information, scoring system, comorbidity subgroups, and when ICU mortality was used in place of hospital mortality.
Pulse oximetry is universally used for monitoring respiratory status of patients in ICU, which assess SaO2 based on Beer-Lambert law, and the correlation between SaO2 and SpO2 is generally high which makes SpO2 significant in the continuous monitoring and titration of oxygen supplement in ICU[25, 26]. In addition, arterial oxygen tension (PaO2) is commonly used to guide oxygen therapy in ICU as well. Compared to PaO2, SpO2 has the advantages of low cost, noninvasive, and repetitive measurement of oxygenation. Furthermore, SpO2 is also clinically more relevant, for which the ventilator and inspired oxygen fraction settings are based on SpO2 changes rather than on intermittent arterial blood gas assays[27]. Additionally, using SpO2 to titrate supplemental oxygen is better than fixed inspired oxygen fractions, which risk over-oxygenation in patients with narrow alveolar-arterial oxygen gradients and under-oxygenation in those with wide gradients. Because of the sigmoid shape of the oxyhemoglobin dissociation curve, oximetry may not detect hypoxaemia in patients with high PaO2 levels[28]. However, for the SpO2 range of 95–98%, the correlation between SpO2 and PaO2 would be fair, with little risk of underestimation of either hypoxaemia or hyperoxaemia[29].
Risk stratification of patients with APE is mandatory for determining the appropriate therapeutic management approach. Blood oxygen saturation has been used as one of the important prognostic indicators of several APE risk scores such as PESI and sPESI[30, 31]. However, few studies have explored the prognostic value of SpO2 level as a continuous variable of APE patients. In our study, the assessment of SpO2 level within the first day after ICU admission could serve as a preliminary prognostic marker for short-term mortality among all APE patients, which could help stratify the risk of APE patients and personalize their treatment. Similar to our results, Kline et al. found that a room-air pulse oximetry reading < 95% at diagnosis was associated with a significantly higher probability of in-hospital complications (death, cardiogenic shock, or respiratory failure) from pulmonary embolism[32]. However, this study was composed of emergency department patients, the proportion of patients with SpO2 within 98–100% was less, which may not fully reflect the harm of hyperoxaemia in APE patients. Considering the U-shaped relationship between SpO2 and mortality, perhaps at least three groups of SpO2 level groups are required to explore its impact on the prognosis of APE patients.
Although oxygen therapy is recommended in patients with APE and SaO2 < 90%, there is still lack of strong evidence on the optimal oxygenation target for guiding the oxygen therapy in the current APE guidelines[3, 16]. Our study presented the lowest mortality at a SpO2 within 95–98%. However, for the group with 98%<SpO2, the univariate logistic regression showed 100% SpO2 was associated with higher increased risk of all-cause in-hospital mortality compared to 95%-98% SpO2 (OR: 2.455; P = 0.01), but there was no significant difference between 99% SpO2 and 95%-98% SpO2 (OR: 1.033; P > 0.05), and then multivariate logistic regression analyses further presented that there was no significant difference between 99% SpO2 and the reference group (OR: 0.611; P > 0.05). This indicates that 99% SpO2 is not a risk indicator for APE patients which could serve as a buffer range for oxygen targets. Additionally, the SpO2 range with the lowest mortality in the mechanical ventilation subgroup was 97–99%, which also indicated 99% SpO2 was less risk and was consistent with the findings by Zhou et al. that time spent oxygen saturation 95–99% is associated with reduced mortality in critically ill patients with mechanical ventilation[33]. However, considering that patients with 99% SpO2 still have a relatively high risk of hyperoxaemia, we cautiously set the upper limit of the optimal SpO2 target at 98%[29, 34]. Besides, an upper level of 98% may reduce excessive use of high concentration oxygen therapy and avoid the potential risks of hyperoxia.
Notably, the British Thoracic Society (BTS) guideline recommends oxygen should be prescribed to achieve a target saturation of 94%-98% in patients with pulmonary embolism except for in those at risk of hypercapnic respiratory failure[5]. However, the recommendations about the use of oxygen in pulmonary embolism are based on expert opinion in BTS guideline and the evidence level is relatively low, lacking strong evidence support. Our findings are consistent with the recommendations of BTS guideline and could provide it with a higher level of evidence support. Additionally, the Oxygen-ICU trial showed that patients who received conservative oxygen therapy with SpO2 levels between 94% and 98% had lower in-hospital mortality and in-ICU mortality than those received conventional therapy with SpO2 levels between 97% and 100% (hospital mortality, 24.2% vs. 33.9%, P = 0.03; ICU mortality, 11.6% vs. 20.2%, P = 0.01), which also supports our optimal range of 95–98% for APE patients although this trial may overestimate the true treatment effect of conservative group[35, 36]. Furthermore, a retrospective study involving ICU patients with at least 48 hours of oxygen therapy showed that the optimal range of SpO2 was 94–98%, which is also consistent with our findings[37]. Our results are potentially impactful and targeting SpO2 between 95% and 98% might optimize survival for all APE patients in ICU. Since pulse oximetry is widespread and affordable, implementation of the 95–98% target would be feasible, even in resource-limited environments.
Several studies showed that overuse of oxygen therapy in ICU is common and is associated with adverse outcomes, including higher mortality, longer duration of mechanical ventilation and longer hospitalization[10, 38, 39]. Furthermore, from a dose-response relationship between arterial oxygen levels and outcomes, severe hyperoxia was more consistently associated with poor outcomes (hospital and ICU mortality) than mild hyperoxia[9]. On the other side, the hypoxaemia could be induced by APE, which contributes to the increase in pulmonary artery pressure and in severe cases it aggravates the hemodynamic impairment[40]. Thus, optimal oxygen targets are required to minimize and balance the competing risks of hypoxaemia and hyperoxaemia in APE patients. From a physiological standpoint, it is necessary to avoid hypoxaemia to maintain sufficient oxygen delivery to important tissues, while avoiding hyperoxaemia is also necessary to avoid the formation and toxic effects of reactive oxygen species (ROS)[5, 41]. Since our study included all APE patients, the results were applicable to APE patients with or without oxygen therapy. Our findings could provide a more solid foundation for the selection of SpO2 targets in the treatment groups for future treatment and research on APE patients.
Several limitations of our study should be acknowledged. Firstly, the data were from the United States, and the results may not be fully applicable to other ICUs with different practices or resources. Second, even though we performed multiple subgroup and multivariate regression analyses, residual confounding could exist. Particularly, confounding by comorbidities would mean overestimation of the association between hyperoxaemia or hypoxaemia and mortality. Finally, the study is a retrospective study based on large ICU databases and shared the same flaws as other observational studies. Thus, prospective cohorts were needed for further validation.