Common ICU mucus therapies may do more harm than good

Clinical Takeaway: Don’t routinely add carbocisteine or nebulized hypertonic saline for mechanically ventilated ICU patients with acute respiratory failure and difficult-to-clear secretions; neither shortened ventilation, and each was linked to specific harms.

Mucoactive agents are widely used for difficult-to-clear secretions in mechanically ventilated ICU patients, but this large randomized trial challenges routine use and supports de-implementation when benefit is uncertain.

In the phase 3, open-label MARCH trial, 1,956 critically ill patients at 71 UK sites were randomized in a 2-by-2 factorial design to usual care plus carbocisteine, 6% or 7% nebulized hypertonic saline, both treatments, or usual care alone for up to 28 days.

The primary endpoint, duration of mechanical ventilation from randomization to successful unassisted breathing, was not improved with either intervention. Median ventilation time was 186.1 hours with carbocisteine versus 172.7 hours without it (adjusted hazard ratio [aHR], 0.96; 95% confidence interval [CI], 0.87-1.05; P=0.34). With hypertonic saline, median ventilation time was 184.5 hours versus 174.3 hours without hypertonic saline (aHR, 1.00; 95% CI, 0.91-1.10; P=0.98). There was no evidence of treatment interaction.

Secondary outcomes were similarly neutral, including extubation time, ICU and hospital length of stay, antibiotic duration, and mortality. By day 28, mortality was 22.8% with carbocisteine versus 23.7% without it, and 22.3% with hypertonic saline versus 24.2% without it.

Safety signals favored caution. Clinically important upper GI bleeding occurred more often with carbocisteine than without it (1.4% vs 0.2%; risk ratio [RR], 6.51). Hypertonic saline increased bronchoconstriction requiring bronchodilators (2.4% vs 0.4%; RR, 5.73) and hypoxemia during nebulization (4.1% vs 0.3%; RR, 13.29).

“Our findings address previous uncertainty regarding the usefulness of two mucoactive treatments…[and] arouse concern regarding the continued use of these agents,” the authors wrote.

Source: Connolly B, et al; MARCH Trial Investigators. (2026, June 10). N Engl J Med. Carbocisteine or Hypertonic Saline for Acute Respiratory Failure