Hypoxemia in the ICU: prevalence, treatment, and outcome

Hypoxemia is frequent and potentially life-threatening in critically ill patients. However, the prevalence, management, and outcomes of hypoxemia in non-selected intensive care unit (ICU) patients are poorly known. Most epidemiological studies have specifically focused on patients under mechanical ventilation [1‐3] or those with criteria for acute respiratory distress syndrome (ARDS) [4‐9], and none covered the entire spectrum of the whole hypoxemic patients. Whereas mechanical ventilation may be needed in non-hypoxemic patients, a number of hypoxemic patients are treated with oxygen while breathing spontaneously. The proportion of hypoxemic patients treated with standard or high-flow oxygen therapy and without need for mechanical ventilation is unknown among the whole patients in the ICU. Moreover, whereas the severity of hypoxemia was directly associated with mortality in patients with ARDS [10], this relation is not demonstrated among the other hypoxemic patients, especially in non-intubated patients. Finally, the relationship between respiratory support, hypoxemia severity, and outcome is not straightforward. It appears then important to provide epidemiological data regarding these gaps of knowledge that could help to design future trials on acute respiratory failure.

Therefore, we designed a large, multicenter, 1-day point prevalence study to measure the prevalence of hypoxemia (defined as a PaO₂/FiO₂ ratio ≤ 300 mmHg) among all ICU patients regardless of their oxygenation device and to stratify them according to the severity of hypoxemia (PaO₂/FiO₂ between 300 and 201 in mild, between 200 and 101 in moderate, and below or equal to 100 mmHg in severe). We also analyzed the potential impact of hypoxemia and its severity on outcome.

This large, multicenter study gives for the first time data on the prevalence of hypoxemia in non-selected ICU-hospitalized patients. Strikingly, though more than half of the patients hospitalized in ICUs the day of the study were hypoxemic, 79% did not fulfill the criteria of ARDS according to the Berlin definition [10]. The prevalence of ARDS, albeit greater in the most hypoxemic patients, was still less than half (42%). Our results highlight also that hypoxemia is frequent among non-ventilated patients. The other main result of our study is that among hypoxemic patients, moderate and severe hypoxemia compared to mild hypoxemia was independently associated with higher ICU mortality.

Data concerning hypoxemia in unselected ICU patients, regardless of the presence of ARDS or the use of mechanical ventilation, are rather scarce, and we think this is strength of the SPECTRUM study to have included patients with all types of oxygenation devices. In the LUNG-SAFE study, hypoxemia was less frequent (35%), but all the patients considered in the analysis received ventilatory support [4], unlike those analyzed in our study. In another study focusing on ARDS [5], the incidence of hypoxemia was 50% among ventilated patients, but no data on non-invasively ventilated patients were given.

The prevalence of ARDS in the SPECTRUM study was 21% in hypoxemic patients, leading to an overall prevalence of 11% of included patients. This prevalence rate is close to the incidence found in the LUNG-SAFE study, in which 10.4% of the patients admitted in the ICU (23% of the mechanically ventilated patients) met the criteria for ARDS. Other studies, using the 1994 ALI/ARDS definition, reported similar results [5] or higher incidence [7, 8].

The presence of hypoxemia was associated with higher mortality and ICU length of stay, and the association with mortality was even stronger in the group of patients with severe hypoxemia. Severe hypoxemia was still associated with mortality after adjustment on respiratory support and in several sensitivity analyses, strengthening this result. This association is not so straightforward as several interventions known to improve PaO₂/FiO₂ ratio failed to reduce mortality [14] or were even detrimental [15, 16], suggesting that improving PaO₂/FiO₂ ratio cannot be an isolated therapeutic goal. Interestingly, ICU mortality among patients with mild-to-moderate hypoxemia was lower than that reported in patients with mild-to-moderate ARDS [4]. Conversely, mortality in our severely hypoxemic patients was close to that of severe ARDS patients described in other large studies. This result may be due to the fact that ARDS accounted for almost half of the severely hypoxemic patients in our cohort but also to the fact that similar pathophysiological mechanisms may be involved in severe hypoxemic patients with or without ARDS. For instance, pneumonia and aspiration as a cause of hypoxemia were more frequent in the most severe patients compared to other frequent causes of hypoxemia (see Table 2). Further studies should try to decipher the respective roles of ARDS and hypoxemia in the prognosis.

Invasiveness of respiratory support was also associated with mortality in univariate analysis, but time-dependent multivariate analysis did not confirm this association. Indeed, roles of respiratory support and severity of hypoxemia in mortality have a complex interplay as the most severe patients received the more invasive support and as respiratory support is not fixed across disease course. Our data suggest that severity of hypoxemia assessed by the P/F ratio a given day is associated with mortality whatever the ventilator support needed in line with other study [17]. This finding may be useful in clinical practice to assess even roughly the severity of hypoxemia and the potential impact on outcomes.

We also evaluated the oxygenation devices used and the ventilator settings in hypoxemic patients. High-flow oxygen and NIV were not rare, even among severely hypoxemic patients. Almost 20% of the patients with a PaO₂/FiO₂ ratio ≤ 100 were not on invasive mechanical ventilation, despite the fact that several studies have shown that NIV for de novo hypoxemic respiratory failure is associated with a poorer outcome in patients who finally required invasive mechanical ventilation [18‐20]. We included all patients in the ICU and presenting hypoxemia (both de novo acute respiratory failure and acute on chronic respiratory failure), and it may be that those patients with severe hypoxemia on NIV had severe chronic respiratory failure or severe cardiogenic pulmonary edema. High-flow oxygen therapy was recently shown to have beneficial effects in patients with a PaO₂/FiO₂ ratio ≤ 200, as compared with standard oxygen and NIV in a randomized controlled trial [11]. However, the outcome of patients with the most severe hypoxemia receiving high-flow oxygen is unknown. Interestingly, in our study, high-flow oxygen was proportionally more frequently used in the most severely ill patients.

In mechanically ventilated patients, hypoxemia was associated with the use of “protective ventilation” in most cases with low V_t and higher PEEP, permissive hypercapnia and hypoxemia resulting in median plateau and driving pressures below the commonly admitted thresholds. Whereas reduced tidal volume appeared beneficial in observational studies among non-ARDS patients [21] and is currently the object of ongoing trials, the value of other protective strategies such as reducing driving pressure, increasing PEEP, or prone positioning may deserve evaluation in this population. The use of adjunctive therapies was correlated with the degree of hypoxemia. Neuromuscular blocking agents were the most often used in line with recent ARDS guidelines [22]: half of the patients with a PaO₂/FiO₂ ratio ≤ 100 were continuously paralyzed. More surprising is the limited use of prone positioning on the day of the study in the subgroup of severely hypoxemic patients, even if not all patients fulfilled ARDS criteria. Recourse to prone positioning was, for instance, less frequent than the use of inhaled NO, whereas the level of evidence widely favors prone positioning rather than inhaled NO during ARDS [23‐25].

Our study provides novel data about hypoxemia prevalence and management that could have implications for research and clinical practice. We provide an accurate prevalence of hypoxemia and stratification according to its severity even in those breathing spontaneously. This could help in the design of future interventional studies targeting these patients. In the clinical practice, physician should be alerted by the severity of hypoxemic non-intubated patients and the risk of mortality.

As we enrolled more than 90% of the screened patients, our observations were likely unbiased. However, our study has some limits. First, it was a point prevalence study and thus does not yield accurate data on incidence. By design, patients with prolonged stay had more chance to be included and are thus overrepresented in our study. Data on length of stay had then to be interpreted with caution and does not reflect accurately the mean length of stay of patients admitted in the ICU. Given the higher ICU length of stay of hypoxemic patients, one could hypothesize that the incidence of hypoxemia is lower than the prevalence. Conversely, some patients without hypoxemia on the day of study may have had hypoxemia before or after the study day during their ICU stay, and some hypoxemic patients may have been more severe. Likewise, our data on adjuvant therapies should be analyzed with caution as some, such as extracorporeal membrane oxygenation, cover a long period of time and so increase the chance of being present on the day of the study. Second, arterial blood gas was not analyzed in 31% of patients. In those cases, hypoxemia was assessed with an extrapolation of the PaO₂/FiO₂ ratio from the SpO₂/FiO₂ ratio. However, most patients classified as “hypoxemic” underwent arterial blood gas analysis on the day of the SPECTRUM study. Moreover, published data show that PaO₂/FiO₂ can be accurately derived from the SpO₂/FiO₂ ratio [12, 26, 27] and sensitivity analysis including only patients with arterial blood gases was consistent with our result on mortality. Third, we conducted our study in spring to avoid the inclusion during an influenza seasonal pandemic; thus, our results could have been different in other seasons. Fourth, the inclusion of patients with limitation of treatment could impact our results as invasive devices are less likely to be used and mortality is higher in these patients. However, this allows to report in an unbiased way our epidemiological data. Lastly, the difficulty of separating ARDS from non-ARDS in hypoxemic patients is well known. In our survey, the diagnosis of ARDS was based on the Berlin criteria given in the CRF, independently of the clinical judgment of the clinician. However, chest-X ray analysis was not independently assessed. Even though we found a percentage of ARDS similar to that found in other large cohorts, it has been shown that ARDS is largely underdiagnosed, especially in its mild forms [4]. Even in the era of the Berlin definition, ARDS continues to be underrecognized, especially because of concerns about the reliable interpretation of chest radiographs [28]. Finally, although we identified an independent association between hypoxemia and mortality, our study does not provide mechanistic explanations of this finding.

In this 1-day point prevalence study, more than half of the patients suffered from hypoxemia, of mostly mild-to-moderate severity. ARDS criteria were present the day of data collection in only one out of five patients and were far from capturing the spectrum of hypoxemia in the ICU setting. Non-invasive methods of oxygenation were largely used even in the most hypoxemic patients. Finally, among hypoxemic patients, moderate and severe hypoxemia were independently associated with ICU survival, as compared to mild hypoxemia.