What literature is available that compares acetylcysteine nebulization and sodium chloride 7% nebulization for respiratory secretions? Are there situations where one is preferred over the other?

Comment by InpharmD Researcher

There is limited and inconsistent evidence directly comparing nebulized acetylcysteine and 7% sodium chloride for the management of respiratory secretions. Most available literature compares each agent to either normal saline or 3% sodium chloride, with mixed results regarding lung function, mucus clearance, and hospitalization rates. One study in patients with stable COPD found that both agents improved cough symptoms, with sodium chloride showing greater nighttime relief and acetylcysteine leading to a significant improvement in FEV1. However, neither agent was shown to consistently improve mucus properties or clearance across all studies. Overall, current literature is insufficient to establish superiority of one agent over the other.

Background

A 2017 meta-analysis was conducted to determine the benefit and safety of inhaled mucoactive agents outside of cystic fibrosis (CF). It included 11 parallel randomized clinical trials and 19 crossover trials. Diagnoses included non-CF bronchiectasis, chronic obstructive pulmonary disease (COPD), and asthma. Hypertonic saline (HS) was investigated in 5 studies. Three trials with 23 to 40 participants tested HS in bronchiectasis. Results favored hypertonic saline over active cycle of breathing technique (ACBT) after one dose and HS over normal saline (NS) after 3 months (standard mean difference [SMD] in FEV1 0.34; 95% CI -0.06 to 0.75); however, the effects were not significant at 12 months. Results of improvement in lung function in patients treated with N-acetylcysteine were inconsistent. In conclusion, HS was not consistently more effective than NS for lung function and hospitalization in bronchiectasis. [1]

A 2019 review and meta-analysis evaluated mucoactive agents (e.g. N-acetylcysteine [NAC], hypertonic saline [HS], dornase alfa, heparin, and mannitol) to enhance airway clearance in adults with various lung conditions. Overall, mucus benefits were inconsistent among mucoactive agents. After two days of use following thoracic or abdominal surgery, NAC increased mean mucus weight from 2.65 ± 3.47 g to 7.50 ± 6.29 g. Hypertonic saline and NAC did not affect mucus characteristics during invasive ventilation. Overall, the data suggests that hypertonic saline and NAC are ineffective for atelectasis/mucus plugging while intubated. However, direct comparisons between acetylcysteine and hypertonic saline is limited. [2]

A 2009 consensus report reviews inhaled therapies for CF, including both hypertonic saline and NAC as mucolytics/mucous mobilizers. Hypertonic saline (3% to 7%) improves mucociliary clearance by hydrating airway secretions and has demonstrated benefits in lung function and reduction of exacerbations. A Cochrane review notes that the article supports its efficacy in short-term trials, but a placebo-controlled study showed the forced expiratory volume in one second (FEV1) improvement of 3.2% over 48 weeks and a 56% reduction in exacerbations. While NAC is mentioned in this article, it is not discussed in the same context as hypertonic saline. Instead, NAC is discussed for its ability to inactivate oxygen and is commonly stabilized with ethylenediaminetetraacetic acid (EDTA), which has no influence on pulmonary function but is capable of chelating metal ions. The chemical compatibility data indicate that NAC is miscible with several agents, including salbutamol and budesonide. Dornase alfa, which is another mucolytic, was shown to produce modest improvements in FEV1 (16%) compared to hypertonic saline (3%). Although NAC was not widely used in this article as a comparison to hypertonic saline, it does highlight that hypertonic saline is more widely used and effective for enhancing mucous clearance in cystic fibrosis patients. [3]

A 2015 randomized controlled trial evaluated the changes in secretion density, airway pressures, and oxygen saturation in patients nebulized by NAC in comparison to normal saline. A total of 40 mechanically ventilated patients were randomized to either receive 2 ml of 20% NAC in 8ml NS (n= 20) or 10 ml NS (n= 20), both three times daily for one day. Patient baseline characteristics in each group were similar. Data was collected at baseline, at 12 hours, and at 24 hours. Results showed that while NAC significantly lowered the overall average secretion density compared to NS (p= 0.006), the change in density between baseline and each time of administration was not statistically significant (p= 0.087). NAC also significantly increased oxygen saturation over time (p= 0.014) but plateaued at the end of the 12-hour mark (p= 0.902). There were no significant changes in plateau/peak airway pressures in either group. The authors concluded that nebulization with NAC in mechanically ventilated patients was not more effective than NS in reducing the density of mucous secretions. Some major limitations of this study were the short intervention period and small sample size. Notably, this study also only compared NAC to 0.9% NS rather than 0.7% NS, but still provides preliminary information on NAC’s potential effectiveness in this setting. More direct comparative studies are needed to better evaluate the benefits and risks of NAC compared to 0.7% sodium chloride. [4]

A 2007 review article summarized the published literature on the most frequently used mucoactive agents in children with non-CF lung disease. A total of 34 articles (12 RCTs and 22 uncontrolled clinical observations) were included in the review after a MEDLINE search from 1966 to 2007. Mucoactive agents included NAC (5-20%), hypertonic saline (3%), and recombinant human deoxyribonuclease enzyme (rhDNase). NAC was evaluated in a total of 13 studies (5 RCTs, 1 historical control, and 7 observational studies). In RCTs involving adults with chronic bronchitis or COPD, NAC showed slightly fewer exacerbations and a shorter period of disability, but no significant difference in lung function. On the other hand, several observational studies reported beneficial effects of nebulized NAC in children with atelectasis, acute asthma, inhalation injury, and lower respiratory tract infections. However, due to the absence of control groups, definitive conclusions could not be made about NAC’s effectiveness. Hypertonic saline was evaluated in 3 RCTs, all involving children with RSV bronchitis. Compared to normal saline, 3% hypertonic saline (given with either terbutaline or epinephrine) showed some short-term improvements in RSV symptoms but no significant differences in chest X-ray results or hospitalization rates. Lastly, two RCTs evaluated the use of rhDNase in infants with RSV bronchiolitis but found no clinical benefits with rhDNase. This review highlights that current evidence is insufficient to support one agent over the other and more robust clinical studies are needed to determine the efficacy of these mucoactive agents. [5]

A 2024 prospective study compared the efficacy of nebulized NAC and 3% sodium chloride in patients with stable COPD. A total of 60 patients were assigned to either NAC 600 mg/day (n= 30) or 4mL of 3% sodium chloride twice daily (n= 30). Both groups demonstrated statistically significant symptom improvement, as measured by the COPD Assessment Test (CAT) and the Clinical COPD Questionnaire (CCQ), with reductions of 12.7% and 8.3% in the NAC group and 8.7% and 8.8% in the sodium chloride group (p<0.03). Daytime cough severity decreased by 14% and nighttime cough by 33.9% in the NAC group, compared to 12.1% and 44% in the sodium chloride group. Only the NAC group showed a significant improvement in FEV1 (9.3%; p<0.02). Changes in dyspnea severity were not statistically significant in either group. The authors concluded that both NAC and 3% sodium chloride are beneficial for symptom relief in COPD patients without exacerbation, while NAC may confer additional benefit in FEV1. Although this study compared NAC to 3% sodium chloride rather than 7%, it can provide clinically relevant insight into the relative efficacy of NAC versus hypertonic saline formulations. [6]

References:

[1] Tarrant BJ, Le Maitre C, Romero L, et al. Mucoactive agents for chronic, non-cystic fibrosis lung disease: A systematic review and meta-analysis. Respirology. 2017;22(6):1084-1092. doi:10.1111/resp.13047
[2] Tarrant BJ, Maitre CL, Romero L, et al. Mucoactive agents for adults with acute lung conditions: A systematic review. Heart Lung. 2019;48(2):141-147. doi:10.1016/j.hrtlng.2018.09.010
[3] Heijerman H, Westerman E, Conway S, Touw D, Döring G; for the consensus working group. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus. J Cyst Fibros. 2009;8(5):295-315. doi:10.1016/j.jcf.2009.04.005.
[4] Masoompour SM, Anushiravani A, Tafaroj Norouz A. Evaluation of the Effect of Nebulized N-Acetylcysteine on Respiratory Secretions in Mechanically Ventilated Patients: Randomized Clinical Trial. Iran J Med Sci. 2015;40(4):309-315.
[5] Boogaard R, de Jongste JC, Merkus PJ. Pharmacotherapy of impaired mucociliary clearance in non-CF pediatric lung disease. A review of the literature. Pediatr Pulmonol. 2007;42(11):989-1001. doi:10.1002/ppul.20693
[6] Gumeniuk G, Kuzmenko N, laremnko O. Comparison of effectiveness of acetylcysteine and 3% hypertonic saline inhalation in patients with COPD. European Respiratory Journal 2024 64(suppl 68): PA4771; DOI: https://doi.org/10.1183/13993003.congress-2024.PA4771

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What literature is available that compares acetylcysteine nebulization and sodium chloride 7% nebulization for respiratory secretions? Are there situations where one is preferred over the other?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Table 1 for your response.


 

Airway Clearance in Bronchiectasis: A Randomized Control Trial with N-Acetylcysteine and 3% Hypertonic Saline

Design

Randomized controlled trial

N= 136

Objective

To compare the role of nebulized N-acetylcysteine and 3% hypertonic saline in clearing the airway in patients with acute exacerbation of bronchiectasis

Study Groups

Group A (n= 68)

Group B (n= 68)

Inclusion Criteria

Confirmed cases of acute exacerbation of bronchiectasis

Exclusion Criteria

N/A

Methods

Group A received nebulization of N-acetylcysteine mixed in normal saline for ten minutes. Group B received nebulization with 10ml of 3% hypertonic saline for ten minutes. Nebulization was done three times in 24 hours.

Duration

24 hours of treatment with nebulization.

Outcome Measures

Primary: Oxygen saturation, sputum weight, presence of ronchi

Baseline Characteristics

 

Group A (n= 68)

Group B (n= 68)

Age, years

38.89 46.07

Mean blood pressure, mmHg

91.13 ± 1.11 96.48 ± 2.26

Female, n

31 21

Smoking, n

38 27

Education status, n

Literate

Illiterate

 

41

27

 

32

36

Residential area, n

Rural

Urban

 

47

21

 

41

27

Diabetics, n 15

10

Results

Endpoint

Group A (n= 68)

Group B (n= 68)

Oxygen saturation, %

Before treatment

After treatment

p-Value

 

92.11 ± 3.07

94.47 ± 2.18

0.001

 

92.36 ± 3.13

93.49 ± 2.27

0.012

Sputum weight, g

Before treatment

After treatment

p-Value

 

2.63 ± 2.39

7.41 ± 1.38

0.001

 

3.11 ± 2.01

5.56 ± 1.02

0.001

Ronchi, %

Before treatment

After treatment

p-Value

 

52%

76%

0.003

 

45%

74%

0.001

Adverse Events

Increased airway reactivity and rhonchi were observed with both treatments.

Study Author Conclusions

Both nebulized N-acetylcysteine and 3% hypertonic saline improve airway clearance and oxygen saturation in patients with acute exacerbation of bronchiectasis.

InpharmD Researcher Critique

The study is well-designed as a randomized controlled trial, providing valuable insights into the efficacy of N-acetylcysteine and hypertonic saline in acute bronchiectasis. However, limitations include a reduced sample size, single-center trial, and lack of follow-up after discharge. Additionally, the study did not directly compare N-acetylcysteine and hypertonic saline to one another, nor did it evaluate clinical outcomes, such as duration of hospital stay or ventilator time.



References:

Shehzad MI, Mannan MAU, Alam M, Rauf A, Sharif MI. Airway clearance in bronchiectasis: a randomized control trial of n-acetylcysteine with 3% hypertonic saline. Journal of Islamabad Medical & Dental College. 2019;8(3):146-150.