Combo May Help Stave Off Acute Respiratory Distress Syndrome

Damian McNamara

May 19, 2016

SAN FRANCISCO — For hypoxemic patients, early intervention with an inhaled corticosteroid plus a long-acting beta₂ agonist significantly improves outcomes, according to results from LIPS-B — the Lung Injury Prevention Study With Budesonide and Formoterol (NCT01783821).

"Hypoxemia is really the main predictor of acute respiratory distress syndrome," said Emir Festic, MD, from the Mayo Clinic Jacksonville in Florida.

Inhaled corticosteroids and long-acting beta₂ agonists could play a role in the prevention of lung injury because they are known to decrease inflammation, preserve barrier function, and decrease extravascular lung water, he explained.

He and his colleagues hypothesized that delivering these medications directly to the lung shortly after hospital admission would maximize drug delivery and minimize any systemic adverse effects.

Their double-blind randomized phase 2a study involved patients who presented to the emergency department with acute hypoxemia who required supplemental oxygen to maintain saturation at 92% to 96% and who were admitted to the hospital.

Dr Festic presented the study results here at the American Thoracic Society 2016 International Conference.

The investigators screened 1633 patients but excluded the majority because they were already taking inhaled steroids, chronic steroids, or beta agonists. Ultimately, the team randomly assigned 29 patients to treatment with the combination of an inhaled corticosteroid and a long-acting beta₂ agonist and 30 patients to placebo. All participants had a lung injury prediction score of at least 4.

At baseline, the groups were similar except for two notable differences: those treated with the combination were older than those treated with placebo (70 vs 57 years) and were less likely to have experienced shock (10% vs 47%).

To evaluate early intervention, researchers at five sites enrolled patients within 12 hours of presentation to the emergency department (mean, 8.8 hours). Patients received aerosolized budesonide 0.5 mg/2 mL and formoterol 20 µg/2 mL or placebo within 4 hours of study entry and every 12 hours thereafter for 5 days, or until hospital discharge or death.

The primary efficacy outcome was change in the ratio of oxygen saturation to fraction of inspired oxygen from baseline to day 5. The investigators also looked at this ratio by treatment day. A categorical change in the ratio was a "more clinically relevant" and significant primary end point, Dr Festic said.

For the primary outcome, more patients in the treatment group than in the placebo group experienced an increase in the ratio of oxygen saturation to fraction of inspired oxygen (62% vs 43%) or an unchanged ratio (38% vs 30%), and fewer patients in the treatment group experienced a decrease in the ratio (0% vs 27%; P > .01).

Table. Secondary Outcomes

Outcomes Treatment (n = 29) Placebo (n = 30) P Value
Absolute change 100 35 .20
Mechanical ventilation 21% 53% .01
Acute respiratory distress syndrome 0% 23% .01
Admission to the ICU 41% 73% .01
Days in the ICU 4 6 .02
Days in the hospital 4 8 .02


"Early treatment with inhaled budesonide and formoterol is feasible in high-risk patients," said Dr Festic.

Treatment was also associated with lower rates of mechanical ventilation and acute respiratory distress syndrome, and shorter stays in the intensive care unit and the hospital, but "we had a small sample size and some baseline differences," he added.

"We are very enthused. To me, despite the imbalance of baseline characteristics, we established the feasibility and efficacy for these protective therapies," he told Medscape Medical News. "Clearly, we think this supports a larger clinical trial."

This study, along with LIPS-A, which looked at the effect of aspirin on the development of acute respiratory distress syndrome (JAMA. Published online May 15, 2016), "is absolutely crucial in our field," said session moderator Ivor Douglas, MD, from the University of Colorado Denver.

He praised Dr Festic's team for the impressive feat of enrolling patients within 12 hours of presentation and initiating therapy within 4 hours. "It's a huge challenge in acute respiratory distress syndrome to do studies in a timely fashion. It's been very frustrating to us in this field; we end up giving therapeutics late in the course of disease.

After the presentation, Dr Douglas asked if delivering therapy directly to the lungs is effective in these very sick patients.

"We did not examine that," Dr Festic explained. "We used the same nebulizer, and the respiratory therapist made sure it was empty. But we didn't measure levels in the blood to make sure."

"I asked about the pharmaceutical effects," Dr Douglas told Medscape Medical News, because "you cannot extrapolate from asthma and other studies to critically ill patients breathing like a train and about to go on a ventilator."

"I personally wonder if there are sufficient data to progress from phase 2 to phase 3," Dr Douglas said. "Clearly, more work needs to be done before we get there."

The LIP-B investigators are now seeking funding for a phase 2b study, with an enrollment target of 500 patients from the Mayo Clinic Rochester, the Mayo Clinic Jacksonville, the Beth Israel Deaconess Medical Center, the University of Arizona, and Stanford University.

This use of budesonide and formoterol is off-label. Dr Festic and Dr Douglas have disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2016 International Conference: Abstract 7851. Presented May 16, 2016.

Follow Damian McNamara on Twitter: @MedReporter



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