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Two drugs used to help airway clearance in critically ill patients on mechanical ventilators do not reduce the time patients spend on ventilation and cause harm, researchers have found.
Publishing the findings of the MARCH trial in the New England Journal of Medicine on 10 June 2026, researchers from Queen’s University Belfast (QUB) examined the data of 1,956 patients from 71 sites across the UK to determine the effectiveness of carbocisteine and hypertonic saline in critically ill patients with acute respiratory failure and thick secretions receiving mechanical ventilation.
Both drugs are used in ICUs and are thought to help reduce the amount of time patients require mechanical ventilation.
Invasive mechanical ventilation used to treat respiratory failure can cause airway secretions to build up because it disrupts the lungs’ natural clearing system and changes the amount and thickness of secretions.
Participants were randomised to receive either usual care along with carbocisteine (750mg three times daily enterally), 6% or 7% nebulised hypertonic saline (4mL four times daily), both interventions, or usual care alone for up to 28 days.
Both drugs did not reduce the time patients spent on ventilation, the researchers observed. They also found that carbocisteine increased the risk of gastrointestinal (GI) bleeding, while hypertonic saline was associated with an increased risk of nebulisation-related harms.
The median duration of mechanical ventilation was 186.1 hours with carbocisteine and 172.7 hours with no carbocisteine, while for patients given hypertonic saline, the median duration was 184.5 hours and 174.3 hours without, the researchers noted.
The trial findings also revealed that upper GI bleeding occurred more often with carbocisteine than with no carbocisteine (13 of 965 [1.4%] vs. 2 of 966).
Bronchoconstriction leading to bronchodilator use occurred significantly more often with hypertonic saline than without (23 of 967 [2.4%] vs. 4 of 964 [0.4%]), as did hypoxemia during nebulisation (40 of 967 [4.1%] vs. 3 of 964 [0.3%]), the trial results showed.
Study co-author Mark Borthwick, consultant pharmacist in critical care at Oxford University Hospitals NHS Foundation Trust, told The Pharmaceutical Journal: “This was a fantastic trial conducted by a truly multi-professional team of physiotherapists, nurses, doctors and pharmacists to seek answers about the utility of commonly prescribed medications used for difficult-to-clear secretions in critically ill patients.
“We found that carbocisteine and hypertonic saline had no beneficial effect on duration of ventilation in these patients and, worryingly, we actually saw harm.
“We know these interventions are widely used — this is why we did the trial, and these results show that we should stop using them. Learning from the whole process, we should not now simply substitute other non-tested mucoactive agents in the hope that they work. Instead, we should do clinical trials to get results that inform practice.”
Study co-chief investigator Danny McAuley, professor of intensive care medicine at the Wellcome-Wolfson Institute for Experimental Medicine at QUB, said: “Acute respiratory failure is one of biggest killers in critically ill patients in ICU. Moving forwards, we will need to make sure we only use treatments which are effective and safe, based on evidence from trials such as this.
“Translating these findings into clinical guidelines and relevant policy will help to achieve this and improve the outcomes for our critically ill patients.”
Anthony Gordon, director for the National Institute for Health and Care Research Health Technology Assessment Programme — which funded the study — commented: “Sometimes there can be a temptation to simply ‘do everything’ for critically ill patients. Studies like the MARCH trial are crucial to properly evaluate treatments, building knowledge and evidence to ensure seriously ill patients who visit ICU receive the safest and most suitable treatments.”
