For patients struggling to breathe because of acute respiratory failure, clearing mucus from the airways is a routine part of treatment. Mucoactive agents are widely used for this purpose. But after years of clinical use, one question remains: Do mucoactive agents actually help?
To figure this out, researchers designed a large study called the MARCH (Mucoactives in Acute Respiratory Failure: Carbocisteine and Hypertonic Saline) randomized trial, which included nearly 2,000 adults across 71 hospitals in the United Kingdom who were on ventilators and having trouble clearing mucus. The focus of the study was to determine the effectiveness of two widely used mucoactive agents: carbocisteine and hypertonic saline (HTS).
The drugs did not deliver the hoped-for benefits. Those who were on carbocisteine spent about the same amount of time on the ventilator as those who didn’t get any treatment, and the same was true for HTS. Instead, the medications appeared to do more harm than good. Patients treated with these mucoactive agents had side effects like bleeding in the stomach, tightened airways and a drop in blood oxygen levels.
The findings are published in the New England Journal of Medicine.
More harm than good?
We can’t live without breathing, and acute respiratory diseases make that essential function extremely difficult, sometimes impossible. Doctors often have to place such patients in intensive care on a ventilator, which breathes for them. However, being on a ventilator makes it harder for the body to clear mucus from the airways naturally. The mucus also becomes thicker and stickier, so it builds up instead of clearing out.
To overcome this, patients are often given mucoactive agents to loosen or clear mucus. More than 80% of ICUs around the world use these drugs, giving them to roughly 1 in 4 or 5 ventilated patients. However, most doctors administer them based on observation and experience, as there is insufficient evidence to show they actually work. Safety also remained unclear, particularly for routine use in critically ill patients on ventilators.
In this trial, the researchers set out to settle both sides of that question: Do these treatments help patients, or could they actually be causing harm?
They selected participants age 16 or older in intensive care units (ICUs) who were on a breathing machine because of sudden lung failure and had difficulty clearing mucus from their lungs, as determined by their doctors.
They used a 2-by-2 factorial design, splitting participants into four groups to test two treatments simultaneously. The groups included the carbocisteine group, the HTS group, those who received both and those who received neither.
They continued this open-label study, in which doctors and researchers knew who was receiving what, for up to 28 days or until the patient was able to breathe on their own. The team noted how long it took patients to be taken off the ventilator and whether they experienced any complications during the study period.
No gain, clearer risks
Neither carbocisteine nor hypertonic saline made any difference in how long patients stayed on ventilators compared with usual care. In all groups, patients came off ventilation and were holding steady at around 7–8 days.
Patients who received carbocisteine were about seven times more likely to develop serious bleeding in the upper stomach or gut than those who did not (1.4 vs. 0.2%). Patients treated with HTS experienced more breathing-related complications than those in other groups.
They were more likely to develop bronchoconstriction requiring urgent rescue medication, as well as more frequent dangerous drops in blood oxygen levels during treatment. Neither of the mucoactive therapies led to meaningful improvements in survival or other major outcomes, like how long patients stayed in the ICU or hospital.
ICU practice may need revisiting
The researchers noted that the findings point to potential harm from both mucoactive agents, suggesting their routine use in clinical practice should be approached with caution.
Health care systems and hospitals may need to rethink ICU protocols, especially the routine use of carbocisteine and hypertonic saline in ventilated patients, to reduce avoidable side effects. The results call for better monitoring of side effects when mucoactive agents are included in treatment.