Tang W, Zhu D, Wu F, et al. Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion. Eur Rev Med Pharmacol Sci. 2023;27(11):5119-5127.
To assess whether intravenous (IV) N-acetylcysteine (NAC) is superior to placebo and noninferior to ambroxol in improving sputum viscosity and expectoration difficulty
Key Take Away
This is the first large, robust study of the efficacy of IV NAC in respiratory diseases with abnormal mucus secretion. It provides new evidence for IV NAC administration in this indication in clinical situations where the IV route is preferred.
Multicenter, randomized, controlled, subject, and rater-blinded study examining whether IV NAC is superior to placebo and noninferior to ambroxol (known agent) in improving sputum viscosity and expectoration difficulty
The study included 333 hospitalized subjects from 28 centers in China with respiratory disease (eg, acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis, bronchiectasis) and abnormal mucus secretion who were randomly allocated in a 1:1:1 ratio of either NAC (n=111), ambroxol hydrochloride (n=111), or placebo (n=111). A total of 286 participants completed the study (96 in NAC group; 95 in ambroxol HCl group; 95 in placebo group). Participants were approximately two-thirds male and one-third female, with about 50% identifying as never-smokers, and the other half reporting they are current or former smokers. Smoking status did not appear different between groups.
Exclusion criteria included subjects with active tuberculosis, lung cancer, pulmonary fibrosis, acute pulmonary thromboembolism, markedly abnormal hepatic enzymes, or markedly elevated creatinine.
Participants were randomized to receive NAC (600 mg), ambroxol hydrochloride (30 mg), or placebo as an IV infusion twice daily for 7 days. Assessments were done at baseline, day 3, and after 7 days of IV infusion with the participant’s randomly chosen agent.
Study Parameters Assessed
Mucolytic and expectorant efficacy was assessed by ordinal categorical 4-point scales and analyzed by stratified and modified Mann-Whitney U statistics. At each time point, sputum viscosity and color, expectoration difficulty, and cough were recorded using the 4-point scale, with higher numbers indicating worse symptomology.
Primary Outcome Measure
The primary outcome measure was the change from baseline to day 7 in sputum viscosity score or expectoration difficulty score between the NAC and placebo groups.
Secondary outcomes included the comparison of the viscosity and expectoration effects of NAC to ambroxol hydrochloride, and ambroxol hydrochloride to placebo.
NAC showed consistent and statistically significant superiority to placebo and noninferiority to ambroxol in change from baseline to day 7 in both sputum viscosity scores [mean (SD) difference: 0.24 (0.763), P<0.001 vs placebo] and expectoration difficulty score [mean (SD) difference: 0.29 (0.783), P=0.002 vs placebo]. Safety findings confirm the good tolerability profile of IV NAC reported from previous small studies, and no new safety concerns were identified.
The full funding for this clinical trial was not disclosed. One author has several relationships with pharmaceutical companies, but there were no reported conflicts of interest by the authors.
NAC has been used as an oral, respiratory, and parenteral drug in the United States since its approval by the Food and Drug Administration (FDA) in the early 1960s. In respiratory medicine, it has generally been employed as a mucolytic via nebulizer treatments. It is also used parenterally as an antidote for acetaminophen toxicity and is seeing more use in research in the neuro-psychiatry world.
NAC has an extensive history as a mucolytic for acute and chronic lung conditions.
Ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine), is an over-the-counter mucoactive agent and has been a widely used oral medication to treat both acute and chronic respiratory diseases since 1978 in various countries. It is not approved for any use by the FDA and is not available in the United States or Canada. Ambroxol is an effective mucokinetic and secretagogue, promoting mucous clearance, facilitating expectoration, and easing productive cough.1
In contrast, NAC has an extensive history as a mucolytic for acute and chronic lung conditions. It directly splits sulfur linkages of mucoproteins, reducing viscosity of bronchial and lung secretions. NAC improves bronchial and lung function, reduces cough, and improves oxygen saturation in the blood.2
I have personally recommended NAC as an IV, oral, nebulized, and nasal spray drug or supplement. The study conclusions showing statistical significance that “NAC showed consistent and statistically significant superiority to placebo and non-inferiority to ambroxol in change from baseline to day 7” are not surprising, given its reliable effects from a clinical perspective.
This study reinforces the safety, utility, and efficacy of a very old respiratory medication we all should not only stay aware of but also use more frequently in all its forms.