Two of the most commonly used mucoactive therapies in ICUs—carbocisteine and nebulized hypertonic saline—failed to improve outcomes in patients with acute respiratory failure who were mechanically ventilated, and they were associated with important adverse events, according to findings from the MARCH trial recently published in The New England Journal of Medicine.1
The multicenter study, led by Bronwen Connolly, PhD, Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, enrolled 1,956 critically ill patients across 71 hospitals in the United Kingdom. The findings challenge a long-standing practice that has largely been supported by physiologic rationale rather than robust clinical evidence.
Jesse Hall, MD, Professor Emeritus in the Department of Medicine and Section of Pulmonary and Critical Care Medicine at the University of Chicago, said the trial was “a reasonably powered study with a good design.” He added that the findings “strongly counsel against the use of these agents singly or in combination” when trying to facilitate liberation from mechanical ventilation.
Retained airway secretions are a common challenge in patients who are mechanically ventilated. Impaired mucociliary clearance can make secretion management difficult and may delay ventilator liberation. As a result, mucoactive therapies are frequently prescribed in ICUs despite limited evidence demonstrating meaningful clinical benefit. Investigators noted that such agents are used in more than 80% of ICUs and in roughly 20% to 30% of patients who are mechanically ventilated.
The phase 3, open-label trial was designed to address this evidence gap. Patients 16 years of age or older with acute respiratory failure requiring invasive mechanical ventilation and difficult-to-clear secretions were randomly assigned to receive carbocisteine, hypertonic saline, both therapies, or usual care. Treatment continued for up to 28 days. The primary end point was duration of mechanical ventilation, measured from randomization until successful unassisted breathing for at least 48 hours or death.
Neither intervention improved the primary outcome. Patients receiving carbocisteine had a median ventilation duration of 186.1 hours compared with 172.7 hours among those who did not receive the drug (adjusted HR, 0.96; 95% CI, 0.87-1.05). Similarly, patients treated with hypertonic saline remained on ventilation for a median of 184.5 hours compared with 174.3 hours among those not receiving the therapy (adjusted HR, 1.00; 95% CI, 0.91-1.10). Investigators also found no evidence that combining the two treatments provided any advantage.
Safety findings were among the most notable aspects of the trial. Clinically significant upper gastrointestinal bleeding occurred in 1.4% of patients receiving carbocisteine compared with 0.2% of controls. Hypertonic saline was associated with bronchoconstriction requiring bronchodilator therapy in 2.4% of treated patients vs 0.4% of controls, while hypoxemia during nebulization occurred in 4.1% and 0.3% of patients, respectively.
Dr. Hall said these adverse events were more than statistical observations.
“They are clinically significant events and tip the balance from ‘no benefit’ to ‘no benefit and likely harms,’” he said.
The findings also serve as a reminder of the limits of biologic plausibility in critical care. “Biologic plausibility is just that—plausibility and, importantly, not probability,” Dr. Hall said.
While physiologic rationale may generate hypotheses, therapies must ultimately be validated in clinical trials before being adopted into practice, he said.
The investigators said the trial helps resolve long-standing uncertainty surrounding two of the most widely prescribed mucoactive therapies in critical care and supports concerns that routine use may represent low-value care.
Although the trial did not identify a subgroup that benefited, Dr. Hall said selected populations could still be explored in future research.
“That would be reasonable to explore but would require carefully collected pilot data showing safety and some signal of benefit,” he said.
For now, Dr. Hall said, clinicians should focus on standard secretion-management strategies. Any approach beyond usual care, including suctioning tailored to secretion burden, remains largely anecdotal and should itself be evaluated in prospective trials, he said.
References
1. Connolly B, Dickson N, Campbell C, et al. Carbocisteine or hypertonic saline for acute respiratory failure. N Engl J Med. Published online June 10, 2026. doi:10.1056/NEJMoa2603406
