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SAN FRANCISCO -- Starting high-flow oxygen right away for young children with acute hypoxemic respiratory failure didn't help them leave the hospital sooner than standard oxygen therapy, the PARIS-2 trial showed.

In fact, hospital stays were actually significantly longer in patients, ages 1-4 years, randomized to high-flow oxygen as the initial primary therapy than for those initially assigned nasal cannula oxygen (median 1.77 vs 1.50 days; adjusted HR 0.83, 95% CI 0.75-0.92, P<0.001), reported Andreas Schibler, MD, of St. Andrew's War Memorial Hospital in Brisbane, Australia.

Findings were consistent both with and without obstructive airways disease (wheeze), Schibler said in a presentation at the Society of Critical Care Medicine (SCCM) Critical Care Congress. The findings were simultaneously published online in .

Early high-flow oxygen also nearly doubled ICU admission rates (12.5% vs 6.9%; aOR 1.93, 95% CI 1.35-2.75), which Schibler called surprising, albeit in keeping with the pilot PARIS trial of the same interventions but in a broader age category of children up to age 16 years.

Just why high-flow oxygen had those effects wasn't clear, Schibler and colleagues noted.

Tolerability of high-flow oxygen was an issue, with more crossovers from that group to standard oxygen therapy than vice versa. While that "change to a second form of oxygen therapy may have prolonged time receiving oxygen therapy and thus a longer stay in the hospital...it seems unlikely that this factor accounts for these findings because the significant between-group differences in length of oxygen therapy and hospital stay were still apparent in the per-protocol analysis, which excluded all participants who switched oxygen therapies," they wrote.

Another possibility is that the care team perceived children on high-flow oxygen as sicker, the researchers noted. "This may have influenced the clinical team to be less aggressive with regard to weaning and thus artificially prolonging oxygen therapy, and ultimately length of stay.

Slow weaning of oxygen therapy in pediatric patients is well documented, they said, which prolongs the length of the hospital stay. "Although the weaning protocol of oxygen therapy targeting an SpO2 of 92% to 98% was the same for both intervention groups, it is possible that greater familiarity with the weaning of standard oxygen resulted in the differences demonstrated."

Similar reasons might have been behind lowering the threshold for escalation of care to ICU admission, the group suggested.

Regardless, there was no benefit to starting high-flow oxygen therapy early during hospital management, they emphasized, noting the "emerging trend to support respiration with methods other than standard oxygen therapy, particularly initially during the course of hospitalization with the aim of reducing the work of breathing and to potentially prevent progression of disease."

And that's important given how many centers are using high-flow oxygen in this setting, commented SCCM president Vinay Nadkarni, MD, of Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine in Philadelphia.

"Everybody is searching for good, cheap, inexpensive, noninvasive measures for early intervention to prevent that progression" from acute respiratory distress to respiratory failure, he said in an interview.

"It's disappointing," said Nadkarni, who was not involved in the study. "But on the one hand, it reinforces that our current therapy for this age-group child ... the current usual care therapy of nasal cannula oxygen is as effective as this high flow nasal cannula therapy. What it doesn't address is if this therapy could be effective for the under 1-year-old infant, where one might speculate that there's an opportunity for improvement."

The trial's 1- to 4-year-olds might have had a harder time tolerating the high-flow oxygen compared with either infants or older children, he added. "It is a difficult age group to use a noninvasive therapy that has to be on their face, especially if they're sick and irritable and just want to be held."

The pilot study with a wider range of ages (albeit excluding those under age 12 months with viral bronchiolitis) had shown significantly greater treatment failure in the standard oxygen group, unlike in PARIS-2. "The reason for this difference between the 2 studies is uncertain," the researchers stated, pointing out that 82% of the children in the pilot study were in the same age range as the children in the current trial. "Even though there were no significant differences in mean parental or staff comfort scores (as measured on a 100-mm visual analog scale, which this trial assessed at 1 hour and between 4 hours and 48 hours after starting the trial interventions), intolerance of treatment was more frequently cited for treatment failure in the high-flow oxygen group."

Study Details

PARIS-2 included 1,567 children (median 1.9 years, 46.7% female) admitted to 14 metropolitan and tertiary care hospitals in Australia and New Zealand due to acute hypoxemic respiratory failure.

The trial randomized children 1:1 to high-flow oxygen therapy or standard oxygen therapy between Dec. 18, 2017, and March 18, 2020, with all follow-up completed by March 22, 2020 -- which was just in time from the perspective of how COVID-19 might have challenged the study conduct and interpretation, Schibler said at the SCCM session.

Intervention was open-label, as the type of oxygen therapy could not be masked, the researchers noted, but the investigators were blinded to assignment.

Among the secondary outcomes, median length of oxygen therapy came out lower in the standard oxygen therapy group compared with high-flow oxygen therapy-treated patients (0.75 vs 1.07 days; aHR 0.78, 95% CI 0.70-0.86). The sole death occurred in the high-flow oxygen group.

Schibler also highlighted the slightly lower incidence of transfer to a tertiary care hospital with onsite PICU in the standard oxygen group, albeit based on small numbers (2.2% vs 2.3%; aOR 0.92, 95% CI 0.13-6.75). "The PICU admission trend is driven by the availability of PICU onsite," he stated.

In addition to the open-label design, the lack of clinical data during the weaning process was a limitation, the researchers acknowledged, although they pointed out that "the staff working at the participating hospitals were familiar with the weaning process as per the previous randomized clinical trial and hence, it is unlikely that a learning curve with the high-flow oxygen therapy contributed to an increased length of hospital stay."

Another limitation was the relatively short average length of stay, which would have been hard to improve upon, Nadkarni pointed out.

He suggested that further studies are still warranted, particularly in infants, and perhaps in a slightly later phase of illness. Also, he cautioned against extrapolation of the results to COVID-19 cases, which were not included in the study and might have different characteristics and outcomes.

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