TOPLINE

In patients with critical illness and acute respiratory failure, adding carbocisteine or hypertonic saline (HTS) to usual care did not shorten the duration of mechanical ventilation. The use of these agents was associated with harm: Carbocisteine increased the risk for upper gastrointestinal bleeding, and HTS increased the risk for bronchoconstriction and hypoxemia during nebulization.

METHODOLOGY

• Researchers conducted a phase 3 trial to compare the clinical effectiveness and safety of adding carbocisteine or HTS to usual care vs usual care alone in patients with acute respiratory failure.
• They enrolled 1956 patients aged 16 years or older across 71 UK sites; all were receiving invasive mechanical ventilation for acute respiratory failure and had difficult-to-clear secretions. The mean ages across study groups ranged from 56.6 to 57.7 years, and 69.1%-70.6% were men.
• Patients were randomly assigned to receive carbocisteine alone (750 mg three times daily, enterally, for up to 28 days), nebulized 6% or 7% HTS alone (4 mL four times daily for up to 28 days), both agents, or usual care alone.
• The primary outcome was between-group difference in the duration of mechanical ventilation, defined as the number of hours from randomization to the first successful unassisted breathing (maintained for 48 hours) or death, with follow-up conducted up to 60 days.
• Primary comparisons were any carbocisteine (carbocisteine alone or in combination with HTS) vs no carbocisteine (HTS or usual care alone) interventions and any HTS (HTS alone or in combination with carbocisteine) vs no HTS (carbocisteine or usual care alone) interventions.

TAKEAWAY

• The median duration of mechanical ventilation was 186.1 hours with any carbocisteine intervention compared with 172.7 hours with no carbocisteine intervention; the difference was not statistically significant.
• The median duration of mechanical ventilation was 184.5 hours with any HTS intervention compared with 174.3 hours with no HTS intervention; no statistically significant benefit was observed.
• Clinically important upper gastrointestinal bleeding was significantly more frequent with any carbocisteine than with no carbocisteine intervention (risk ratio [RR], 6.51; P = .01). Bronchoconstriction requiring bronchodilator therapy and hypoxemia during nebulization were more frequent with any HTS than with no HTS intervention (RRs, 5.73 and 13.29, respectively; P ≤ .001 for both).
• Serious adverse events were rare. One serious adverse reaction was reported in the combination group (0.2% of patients) and was deemed related to carbocisteine.

IN PRACTICE

“Among critically ill patients with acute respiratory failure, neither carbocisteine nor HTS significantly reduced the duration of mechanical ventilation, and each was associated with harm,” the authors wrote.

SOURCE

The study was led by Bronwen Connolly, PhD, Queen’s University Belfast, Belfast, Northern Ireland. It was published online on June 10, 2026, in The New England Journal of Medicine.

LIMITATIONS

The trial was open label. Some patients assigned to groups without mucoactive agents received off‑protocol treatment, which may limit interpretation of the findings. Moreover, the trial was not formally powered to detect interactions between the two mucoactive agents.

DISCLOSURES

This trial was supported by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme and the Belfast Health and Social Care Trust Charitable Trust Fund. Two authors reported being employees of the NIHR. Several other authors disclosed receiving grants or contracts, speaker fees, consulting fees, participation on clinical advisory boards, and other relationships with multiple organizations, including the NIHR.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.