Two common drugs for ventilated patients did not help — and caused harm

Drugs meant to loosen or clear mucus are given routinely to critically ill patients on ventilators, on the reasonable-sounding theory that thinner, more mobile secretions are easier to cough or suction out and so let a patient come off the machine sooner. The MARCH trial put two of the most widely used such agents to a proper test, and both failed it — while each turned out to carry a harm of its own [s1].

The result matters precisely because these are not exotic drugs. Carbocisteine is a cheap oral mucolytic, and nebulised hypertonic saline is a saltwater mist, both used across intensive care units "despite limited evidence of their effectiveness or safety," as the investigators put it [s1]. When a treatment is that entrenched, a large, neutral trial is the only thing that can dislodge it.

What the trial did

MARCH was a multicentre, open-label, randomised trial with a two-by-two factorial design — a structure that lets one trial test two treatments at once [s1]. It enrolled critically ill, mechanically ventilated participants aged 16 or older who had acute respiratory failure and difficult-to-clear secretions [s1]. Every participant received usual care and was then assigned to carbocisteine (750 mg three times daily, given enterally), 6% or 7% nebulised hypertonic saline (4 ml four times daily), both interventions, or usual care alone, for up to 28 days [s1].

The two questions were kept separate: any carbocisteine versus no carbocisteine, and any hypertonic saline versus no hypertonic saline [s1]. The primary outcome was the duration of mechanical ventilation, measured from randomisation to the first episode of successful unassisted breathing [s1]. In all, 1,956 participants were randomised — 486 to carbocisteine, 485 to hypertonic saline, 492 to both, and 493 to usual care alone [s1]. The trial was funded by the UK's National Institute for Health and Care Research and a Belfast hospital charitable fund, and registered as MARCH [s1][s2].

What it found

Neither drug shortened the time patients spent on a ventilator. There was no evidence that the two treatments interacted (hazard ratio 1.01; 95% confidence interval 0.83 to 1.22; P = 0.91), so each could be read on its own [s1].

For carbocisteine, the median duration of mechanical ventilation was 186.1 hours (95% CI 168.3 to 196.6) with the drug and 172.7 hours (95% CI 165.2 to 190.4) without it — a difference that pointed, if anything, the wrong way, with an adjusted hazard ratio of 0.96 (95% CI 0.87 to 1.05, P = 0.34) [s1]. For hypertonic saline, the medians were 184.5 hours (95% CI 165.6 to 194.1) with and 174.3 hours (95% CI 166.9 to 192.7) without, an adjusted hazard ratio of 1.00 (95% CI 0.91 to 1.10, P = 0.98) [s1]. In plain terms: no benefit, from either.

The harms are the part to read twice

A neutral efficacy result would, on its own, be an argument to stop using the drugs. MARCH went further and found active harm.

Clinically important upper gastrointestinal bleeding occurred significantly more often with carbocisteine than without it — in 13 of 965 patients (1.4%) versus 2 of 966 (0.2%), a risk ratio of 6.51 (95% CI 1.47 to 28.76, P = 0.01) [s1]. Hypertonic saline produced two respiratory harms: bronchoconstriction leading to bronchodilator use, in 23 of 967 patients (2.4%) versus 4 of 964 (0.4%), a risk ratio of 5.73 (95% CI 1.99 to 16.52, P = 0.001); and hypoxaemia during nebulisation, in 40 of 967 (4.1%) versus 3 of 964 (0.3%), a risk ratio of 13.29 (95% CI 4.12 to 42.83, P<0.001) [s1]. The absolute numbers are small, but they run in one direction — toward harm — in a setting where the drugs were supposed to help.

How to read it

The authors' conclusion is blunt: among critically ill patients with acute respiratory failure, neither carbocisteine nor hypertonic saline significantly reduced the duration of mechanical ventilation, "and each was associated with harm" [s1]. That is close to the strongest verdict a trial can deliver against an established practice — not merely "no proven benefit," but "no benefit plus a measurable downside."

Two caveats keep it honest. The trial was open-label, so clinicians knew who received what, which can colour bedside decisions [s1]. And the primary outcome was time on the ventilator, a marker of recovery rather than survival itself; the abstract does not frame this as a mortality trial [s1]. But those limitations cut against the drugs, not for them: an open-label design that still fails to show benefit is not being flattered by its own bias.

The wider lesson is one this site has met before — that widely used treatments can persist for years on plausibility rather than evidence, and sometimes evaporate when finally tested. Related coverage has examined a null trial of sodium bicarbonate in in-hospital cardiac arrest, bicarbonate tested again in shock with acidosis, and how sepsis is recognised early.

What to watch

The immediate question is whether guidelines and unit-level protocols drop these agents from routine use in ventilated patients, and how quickly. The harder one is how many other bedside habits in critical care would survive the same kind of test [s1].

This article describes trial results and is not medical advice. Decisions about treatment in intensive care are for the clinicians responsible for a patient.

Sources

• Carbocisteine or Hypertonic Saline for Acute Respiratory Failure — New England Journal of Medicine, 10 June 2026
• MARCH trial registration, ISRCTN17683568 — ISRCTN Registry