From Pages to Practice
On March 11, 2020 the director-general of the World Health Organization declared Covid-19 -- caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV 2) -- as a global pandemic. Early experience with Covid-19 has clearly demonstrated a wide spectrum of clinical presentations. As with Middle East respiratory syndrome (MERS) and the original SARS before it, a proportion of patients develop hypoxemic respiratory failure due to acute respiratory distress syndrome (ARDS). In the absence of a vaccine or definitive therapy, optimization of supportive care is critical in the management of these patients.
Unified guidelines do not exist for oxygen saturation in mechanically ventilated patients, possibly reflecting the fact that optimal saturation is disease dependent. In studies of nonhypoxemic patients with acute myocardial infarction or stroke, higher oxygen targets were not beneficial. Furthermore, an early clinical trial and subsequent systematic review demonstrated potential harm in over-oxygenation of acutely ill adults. Finally, the risks of supplemental oxygen in patients prone to hypercapnic respiratory failure are well known.
In contrast with these studies, the LOCO2 trial, published recently in NEJM, only enrolled patients with ARDS, a disease characterized by impaired gas exchange at the alveolar level. Patients were randomized to receive liberal oxygenation (PaO2 90-105 mmHg; SpO2≥96%) or conservative oxygenation (PaO2 55-70 mmHg; SpO288-92%) with a primary outcome of all-cause death at 28 days. The trial was stopped early due to futility and safety concerns as 34.3% of patents in the conservative group met the primary outcome compared to 26.5% in the liberal group.
LOCO2 contrasts the concurrently published ICU-ROX trial in its restriction to patients with ARDS where the pathophysiological process is impaired oxygenation. In ICU-ROX, the use of conservative oxygen therapy, as compared with usual oxygen therapy, in adults undergoing mechanical ventilation in the ICU did not significantly affect the primary outcome of ventilator-free days or a secondary mortality outcome. These divergent results raise the possibility that ARDS patients may be more susceptible to hypoxemic insults as suggested by a higher number of mesenteric ischemic events in the conservative oxygenation group.
The following NEJM Journal Watch summary explains the study and results in more detail:
Patricia Kritek, MD reviewing Barrot L et al. N Engl J Med 2020 Mar 12
A recent study showed no benefit or harm from a conservative oxygen strategy that maintained oxygen saturation at <97% (NEJM JW Gen Med Dec 15 2019 and N Engl J Med 2019 Oct 14; [e-pub]). However, this target did not seem particularly conservative to many clinicians.
Investigators in France randomized patients with acute respiratory distress syndrome (ARDS) to either a target partial pressure of oxygen (PaO2) of 55 to 70 mm Hg (conservative group; saturation, 88%–92%) or a PaO2 of 90 to 105 mm Hg (liberal group; saturation, ≥96%), for the first 7 days of treatment; three quarters of patients had moderately severe ARDS. The trial was stopped early due to safety concerns after 205 patients were enrolled. Although higher mortality in the conservative group did not reach statistical significance at 28 days (34% vs. 26%), mortality at 3 months was significantly higher in the conservative group (44% vs. 30%). Five mesenteric ischemic events occurred in the conservative group and none in the liberal group; most other measures did not differ.
COMMENT: At the “conservative” titration goal, some patients likely had episodes of severe hypoxemia. This might be the reason for the signal for harm, even though previous studies have suggested that lower oxygenation targets are safe. Avoiding an oxygen saturation of 100% still seems prudent, but titrating down to a saturation of 90% or lower might put patients — at least, those with ARDS — at risk. A target in the mid-90s seems reasonable for most patients who receive mechanical ventilation; this target is supported by a recent large observational study in which the optimal range for intensive-care patients was 94% to 98% (Chest 2020; 157:566).