Scheduled nebulization with acetylcysteine didn't help ventilated patients
by Salynn Boyles, Contributing Writer, MedPage Today
Regular nebulization proved to be no more effective than nebulization on demand in a randomized trial involving critically ill patients receiving invasive ventilation, researchers reported.
Among ICU patients expected to need invasive ventilation for at least 24 hours, scheduled nebulization four times a day involving acetylcysteine with salbutamol did not result in fewer ventilator-free days, compared with a nebulization schedule based on clinical indications.
The study findings were presented at the Society for Critical Care Medicine's annual meeting, and published simultaneously in JAMA.
The study's principal researcher, Frederique Paulus, PhD, of the University of Amsterdam, told MedPage Today that the study did not address whether nebulization is the most effective therapeutic strategy for clearing mucus and clear secretions from the airway of patients who are on mechanical ventilation.
"It is possible that other treatments, including less-invasive interventions such as moving the patient, are just as effective," she said. "That hasn't really been looked at."
She said routine nebulization, given four times a day, has been the standard of care for patients on mechanical ventilation for decades.
"We thought this may not be necessary, and that is why we did this study," Paulus explained. "The thinking has been that routine nebulization may benefit the patient, and that there is no harm. But it is not clear that there is no harm."
The study included 471 patients on mechanical ventilation randomized to on-demand nebulization and 473 patients randomized to routine nebulization every 6 hours until ventilation ended.
All patients included in the trial were expected to not be extubated within 24 hours of randomization, and the exclusion criteria included age younger than 18, pregnancy, ventilation lasting more than 24 hours before randomization, previous ventilation in another intensive care unit, known allergy to acetylcysteine or salbutamol, medial history mandating use of mucolytics, and bronchodilators.
Patients assigned to the on-demand nebulization group received nebulization of 5-mL solutions containing acetylcysteine (300 mg) when thick or tenacious secretions were noted or nebulization of 5-mL solutions containing salbutamol (2.5 mg) when wheezing was clinically suspected or observed or when typical abnormalities of ventilator waves or end-tidal CO2 curves suggested obstruction of the lower airways.
These patients averaged two nebulizations over a 24-hour period, Paulus said. Ventilator-free days at day 28 was the main study outcome, with a non-inferiority margin for a difference between groups of −0.5 days.
Secondary outcomes included length of stay, mortality rates, occurrence of pulmonary complications, and adverse events.
At 28 days, patients in the on-demand group had a median 21 (IQR, 0-26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0-26) ventilator-free days (1-sided 95% CI, −0.00003 to ∞).
No significant difference in length of stay or mortality was seen, and there was no significant difference in the proportion of patients developing pulmonary complications, between the two groups.
Adverse events (13.8% versus 29.3%, difference, −15.5%; 95% CI, −20.7% to −10.3%: P<0.001) were more frequent with routine nebulization and mainly involved tachyarrhythmia (12.5% versus 25.9%, difference, −13.4% ; 95% CI, −18.4% to −8.4%: P<0.001) and agitation (0.2% versus 4.3%, difference -4.1%; 95% CI, -5.9% to -2.2%: P<0.001).
"The proportion of patients with nebulization-related agitation was higher in the routine group as compared with the on-demand group," the researchers noted in the JAMA article. "Self-extubation, reported in four patients receiving routine nebulization and possibly related to agitation, may be considered potentially life-threatening."
In addition to the observed reduction in adverse events, nebulization on demand also resulted in cost savings, Paulus said.
She acknowledged that the findings may not be generalizable to the general hospital practice setting. "One could argue that given the research setting, these nurses were on top of it. That is fair, but we think on-demand is a reasonable strategy. Of course, we have to implement this to confirm the findings."
Other study limitations cited by the researchers included the fact that nurses and physicians were not blinded, by necessity, to which intervention was being given and the exclusion of other drugs used in nebulization procedures. "The results of this trial cannot be extrapolated to other mucolytic and bronchodilating drugs," the researchers wrote.
Funding for the research was provided by the Netherlands Organization for Health Research and Development and ZonMW.