Albuterol Found Ineffective in Acute Lung Injury

SAN FRANCISCO — A placebo-controlled clinical trial of albuterol in acute lung injury was terminated after the first interim analysis showed that the beta-2 agonist was no better than placebo.

The data and safety monitoring board (DSMB) found that patients given aerosolized albuterol had no improvement in ventilator-free days or 60-day mortality, Dr. Michael A. Matthay reported at a meeting on critical care medicine sponsored by the University of California, San Francisco.

Dr. Matthay of UCSF said there were good reasons to suspect that beta-2 agonist therapy would be beneficial in acute lung injury (ALI). In preclinical studies, the therapy increased the resolution of alveolar edema by promoting sodium and chloride transport, and reduced lung vascular permeability. In a clinical trial, ALI patients treated intravenously with salbutamol had lower lung water levels.

The ALTA (Albuterol for the Treatment of ALI) trial used aerosolized albuterol because observational studies suggested that therapeutic levels of albuterol could be achieved in the pulmonary edema fluid of ALI patients. The drug does not simply deposit in the airways.

All patients had a P/F (arterial oxygen pressure to fraction of inspired oxygen ratio, or PaO2 to FiO2 ratio) below 300 mm Hg, bilateral infiltrates, and no clinical evidence of left atrial hypertension. The patients were receiving positive pressure ventilation via endotracheal tube. Patients were excluded if they had moderate to severe liver disease, moderate to severe chronic obstructive pulmonary disease, chronic or acute need for beta agonists, or acute myocardial infarction within 30 days. Patients were given aerosolized albuterol at 5 mg/2.5 mL, or 2.5 mL of normal saline, every 4 hours until day 10 or until 24 hours after extubation. The albuterol dose was reduced to 2.5 mg/2.5 mL if the patient developed tachycardia or arrhythmia.

At the time the DSMB terminated the trial, 282 patients had been enrolled. There were no significant differences between albuterol and placebo groups on any baseline demographic or laboratory measurement, including Acute Physiology and Chronic Health Evaluation (APACHE) III score, number of organ failures, tidal volume, type of primary lung injury, electrolytes, blood pressure, and central venous pressure.

The investigators found that plasma albuterol levels were in the expected range in virtually all patients who were assessed.

The study's primary outcome was the number of ventilator-free days within 28 days after admission. Patients receiving albuterol had a mean of 14.5 ventilator-free days versus 16.5 days for control patients. A secondary outcome was 60-day mortality, which was 23% among patients taking albuterol and 17.7% among control patients. Neither of those differences was statistically significant.

The investigators found no evidence of albuterol's effectiveness in any subgroup analysis, including analyses limited by gender, in patients with P/F below 200 mm Hg, and in patients with or without shock.

Dr. Matthay, who was the principal investigator of the ALTA trial, suggested three possible reasons that albuterol did not perform as expected.

It could be that the alveolar epithelium may have been too injured to respond to beta agonist therapy. The aerosol route could have delivered inadequate levels of albuterol to the injured alveoli. Or conservative fluid management and lower tidal volume ventilation might have reduced lung injury and lung water to the extent that any additional fluid clearance with albuterol therapy had no beneficial effect.

Dr. Matthay said that he had no conflicts of interest to disclose. The ALTA study was supported by the National Heart, Lung, and Blood Institute.

SAN FRANCISCO — A placebo-controlled clinical trial of albuterol in acute lung injury was terminated after the first interim analysis showed that the beta-2 agonist was no better than placebo.

The data and safety monitoring board (DSMB) found that patients given aerosolized albuterol had no improvement in ventilator-free days or 60-day mortality, Dr. Michael A. Matthay reported at a meeting on critical care medicine sponsored by the University of California, San Francisco.

Dr. Matthay of UCSF said there were good reasons to suspect that beta-2 agonist therapy would be beneficial in acute lung injury (ALI). In preclinical studies, the therapy increased the resolution of alveolar edema by promoting sodium and chloride transport, and reduced lung vascular permeability. In a clinical trial, ALI patients treated intravenously with salbutamol had lower lung water levels.

The ALTA (Albuterol for the Treatment of ALI) trial used aerosolized albuterol because observational studies suggested that therapeutic levels of albuterol could be achieved in the pulmonary edema fluid of ALI patients. The drug does not simply deposit in the airways.

All patients had a P/F (arterial oxygen pressure to fraction of inspired oxygen ratio, or PaO2 to FiO2 ratio) below 300 mm Hg, bilateral infiltrates, and no clinical evidence of left atrial hypertension. The patients were receiving positive pressure ventilation via endotracheal tube. Patients were excluded if they had moderate to severe liver disease, moderate to severe chronic obstructive pulmonary disease, chronic or acute need for beta agonists, or acute myocardial infarction within 30 days. Patients were given aerosolized albuterol at 5 mg/2.5 mL, or 2.5 mL of normal saline, every 4 hours until day 10 or until 24 hours after extubation. The albuterol dose was reduced to 2.5 mg/2.5 mL if the patient developed tachycardia or arrhythmia.

At the time the DSMB terminated the trial, 282 patients had been enrolled. There were no significant differences between albuterol and placebo groups on any baseline demographic or laboratory measurement, including Acute Physiology and Chronic Health Evaluation (APACHE) III score, number of organ failures, tidal volume, type of primary lung injury, electrolytes, blood pressure, and central venous pressure.

The investigators found that plasma albuterol levels were in the expected range in virtually all patients who were assessed.

The study's primary outcome was the number of ventilator-free days within 28 days after admission. Patients receiving albuterol had a mean of 14.5 ventilator-free days versus 16.5 days for control patients. A secondary outcome was 60-day mortality, which was 23% among patients taking albuterol and 17.7% among control patients. Neither of those differences was statistically significant.

The investigators found no evidence of albuterol's effectiveness in any subgroup analysis, including analyses limited by gender, in patients with P/F below 200 mm Hg, and in patients with or without shock.

Dr. Matthay, who was the principal investigator of the ALTA trial, suggested three possible reasons that albuterol did not perform as expected.

It could be that the alveolar epithelium may have been too injured to respond to beta agonist therapy. The aerosol route could have delivered inadequate levels of albuterol to the injured alveoli. Or conservative fluid management and lower tidal volume ventilation might have reduced lung injury and lung water to the extent that any additional fluid clearance with albuterol therapy had no beneficial effect.

Dr. Matthay said that he had no conflicts of interest to disclose. The ALTA study was supported by the National Heart, Lung, and Blood Institute.

SAN FRANCISCO — A placebo-controlled clinical trial of albuterol in acute lung injury was terminated after the first interim analysis showed that the beta-2 agonist was no better than placebo.

The data and safety monitoring board (DSMB) found that patients given aerosolized albuterol had no improvement in ventilator-free days or 60-day mortality, Dr. Michael A. Matthay reported at a meeting on critical care medicine sponsored by the University of California, San Francisco.

Dr. Matthay of UCSF said there were good reasons to suspect that beta-2 agonist therapy would be beneficial in acute lung injury (ALI). In preclinical studies, the therapy increased the resolution of alveolar edema by promoting sodium and chloride transport, and reduced lung vascular permeability. In a clinical trial, ALI patients treated intravenously with salbutamol had lower lung water levels.

The ALTA (Albuterol for the Treatment of ALI) trial used aerosolized albuterol because observational studies suggested that therapeutic levels of albuterol could be achieved in the pulmonary edema fluid of ALI patients. The drug does not simply deposit in the airways.

All patients had a P/F (arterial oxygen pressure to fraction of inspired oxygen ratio, or PaO2 to FiO2 ratio) below 300 mm Hg, bilateral infiltrates, and no clinical evidence of left atrial hypertension. The patients were receiving positive pressure ventilation via endotracheal tube. Patients were excluded if they had moderate to severe liver disease, moderate to severe chronic obstructive pulmonary disease, chronic or acute need for beta agonists, or acute myocardial infarction within 30 days. Patients were given aerosolized albuterol at 5 mg/2.5 mL, or 2.5 mL of normal saline, every 4 hours until day 10 or until 24 hours after extubation. The albuterol dose was reduced to 2.5 mg/2.5 mL if the patient developed tachycardia or arrhythmia.

At the time the DSMB terminated the trial, 282 patients had been enrolled. There were no significant differences between albuterol and placebo groups on any baseline demographic or laboratory measurement, including Acute Physiology and Chronic Health Evaluation (APACHE) III score, number of organ failures, tidal volume, type of primary lung injury, electrolytes, blood pressure, and central venous pressure.

The investigators found that plasma albuterol levels were in the expected range in virtually all patients who were assessed.

The study's primary outcome was the number of ventilator-free days within 28 days after admission. Patients receiving albuterol had a mean of 14.5 ventilator-free days versus 16.5 days for control patients. A secondary outcome was 60-day mortality, which was 23% among patients taking albuterol and 17.7% among control patients. Neither of those differences was statistically significant.

The investigators found no evidence of albuterol's effectiveness in any subgroup analysis, including analyses limited by gender, in patients with P/F below 200 mm Hg, and in patients with or without shock.

Dr. Matthay, who was the principal investigator of the ALTA trial, suggested three possible reasons that albuterol did not perform as expected.

It could be that the alveolar epithelium may have been too injured to respond to beta agonist therapy. The aerosol route could have delivered inadequate levels of albuterol to the injured alveoli. Or conservative fluid management and lower tidal volume ventilation might have reduced lung injury and lung water to the extent that any additional fluid clearance with albuterol therapy had no beneficial effect.

Dr. Matthay said that he had no conflicts of interest to disclose. The ALTA study was supported by the National Heart, Lung, and Blood Institute.