Mucus Thinners Yield Troubling Results for Ventilated ICU Patients

Two commonly used mucoactive agents leaned toward more harm than benefit for critically ill patients with acute respiratory failure, according to the open-label randomized MARCH trial.

In people with acute respiratory failure and difficult-to-clear secretions receiving usual care, no reduction in duration of mechanical ventilation was observed with the addition of either carbocisteine (median 186.1 vs 172.7 hours with no carbocisteine, P=0.34) or nebulized hypertonic saline (HTS; 184.5 vs 174.3 hours with no HTS; P=0.98).

Meanwhile, each was associated with harm, reported researchers led by Bronwen Connolly, PhD, of Queen’s University Belfast in Northern Ireland, in the New England Journal of Medicine.

Carbocisteine recipients had an excess risk of clinically important upper gastrointestinal (GI) bleeding and HTS was linked to bronchoconstriction leading to nebulized bronchodilator use and hypoxemia during nebulization:

• Upper GI bleeds: 1.4% vs 0.2% (RR 6.51, 95% CI 1.47-28.76)
• Bronchodilator use: 2.4% vs 0.4% (RR 5.73, 95% CI 1.99-16.52)
• Hypoxemia: 4.1% vs 0.3% (RR 13.29, 95% CI 4.12-42.83)

“Our findings address previous uncertainty regarding the usefulness of two mucoactive treatments in patients with acute respiratory failure,” Connolly and colleagues wrote. “These findings arouse concern regarding the continued use of these agents.”

Acute respiratory failure is the most common cause of intensive care unit (ICU) admission. Its rapid, progressive course can require invasive mechanical ventilation, which in turn can make patients’ airway secretions difficult to clear. Up to 30% of ICU patients receiving invasive mechanical ventilation are given mucoactive agents, most commonly carbocisteine and hypertonic saline, presumably to enhance airway clearance.

However, evidence backing the use of mucoactive agents in acute respiratory failure is “limited,” Connolly and team noted.

“Of note, similar findings of clinical ineffectiveness and adverse events … have been documented in other respiratory diseases, such as bronchiectasis,” they added.

The MARCH trial enrolled 1,956 critically ill patients with acute respiratory failure at 71 sites in the U.K. from February 2022 to April 2025. Patients were 16 years or older, receiving invasive mechanical ventilation for acute respiratory failure, and had secretions that were difficult to clear based on the judgment of the clinical team.

Participants were randomized in a 1:1:1:1 ratio to usual care alone or in combination with carbocisteine (750 mg three times daily for up to 28 days), nebulized 6% or 7% hypertonic saline (4 mL four times daily for up to 28 days), or combination carbocisteine and hypertonic saline.

Usual care included airway clearance management approaches such as suctioning, heated humidification, respiratory physiotherapy airway clearance, and isotonic saline.

MARCH’s primary outcome was the duration of mechanical ventilation, defined as time from treatment randomization to first successful unassisted breathing, maintained for 48 hours, or to death.

Baseline characteristics were similar across the study’s four groups, with average ages ranging from 56.6 years to 57.7 years. Most of the groups’ patients were men (69.1% to 70.6%) and white (85.9% to 86.9%), with mean APACHE II scores ranging from 17.0 to 17.2 points, and 20.7% to 21.3% having acute respiratory distress syndrome.

Across comparison groups, the duration of treatment was approximately 12 days, and treatment adherence was around 85%.

Mortality rates at day 28 were 22.8% in those who received any carbocisteine, 23.7% in those who received no carbocisteine, 22.3% in those receiving any hypertonic saline, and 24.2% in those who received no hypertonic saline.

The investigators found no evidence of a statistical interaction between the two mucoactive agents as combination therapy.

Additionally, the study didn’t reveal characteristics that might shape patients’ underlying secretion loads or innate airway clearance mechanisms, which could identify patient subgroups that might benefit from mucoactive agents, the researchers noted.

Study limitations included the lack of a standardized definition of difficult-to-clear secretions, which could lead to variability between clinicians. There were no data on the number of patients who received mucoactive therapy before randomization. In addition, some patients assigned to usual care only did end up receiving one of the mucoactive agents.