Please compare and contrast clinical information regarding the use of nebulized 0.9%, 3%, and 7% sodium chloride inhalation solution.

Comment by InpharmD Researcher

Clinical evidence evaluating nebulized sodium chloride inhalation solutions indicates differing roles for isotonic (0.9%) and hypertonic (≥3%) concentrations across respiratory conditions. In bronchiolitis, 0.9% saline is commonly used as a control comparator, while hypertonic saline, most frequently 3%, has demonstrated modest improvements in clinical severity scores and small reductions in hospital length of stay or hospitalization risk in some analyses, although findings across trials are inconsistent and overall evidence certainty has been rated low to very low. Higher concentrations (e.g., 7%) have not shown consistent advantages over isotonic saline in emergency or short-stay bronchiolitis settings, whereas a randomized trial in cystic fibrosis reported that 7% hypertonic saline improved absolute lung function measures and reduced pulmonary exacerbations compared with 0.9% saline over 48 weeks. Reported adverse events with hypertonic saline were generally mild and self-limited, including cough, agitation, bronchospasm, desaturation, vomiting, and diarrhea.

Background

A 2014 clinical practice guideline evaluated evidence regarding therapies for bronchiolitis in infants aged 1 to 23 months, including nebulized sodium chloride solutions of varying concentrations. The guideline notes that most clinical trials investigating nebulized saline for bronchiolitis have used 3% hypertonic saline, while 0.9% sodium chloride (normal saline) is typically used as a comparator or placebo in randomized studies. Evidence summarized in the guideline indicates that nebulized hypertonic saline (primarily 3%) may improve clinical symptom scores after approximately 24 hours of treatment and may reduce hospital length of stay in settings where the average hospitalization exceeds three days; however, findings across randomized controlled trials are inconsistent. Consequently, the guideline recommends that nebulized hypertonic saline not be administered in the emergency department (moderate recommendation) but states that clinicians may administer nebulized hypertonic saline to hospitalized infants and children with bronchiolitis as a weak recommendation based on randomized trials with inconsistent results. Trials evaluating 7% sodium chloride have also been conducted, particularly in emergency department settings, but these studies generally did not demonstrate reductions in admission rates or length of stay compared with isotonic saline controls. Overall, the guideline concludes that hypertonic saline therapy, most commonly studied as 3% solution, may offer modest symptomatic benefit in certain inpatient contexts, whereas 0.9% saline functions primarily as a control intervention in clinical studies and higher concentrations such as 7% have not demonstrated consistent clinical advantages over isotonic saline in emergency or short-stay settings. [1]

A 2023 Cochrane systematic review evaluated the clinical effects of nebulized hypertonic saline (≥ 3%) compared with nebulized normal saline (0.9%) in infants with acute bronchiolitis across 34 randomized controlled trials involving 5205 participants. Most trials evaluated 3% sodium chloride, while a minority assessed higher concentrations ranging from 5% to 7%, with results commonly pooled as hypertonic saline (≥ 3%) for analysis. Compared with nebulized 0.9% saline or standard care, nebulized hypertonic saline (including 3% to 7% solutions) was associated with a modest reduction in mean hospital length of stay among hospitalized infants (mean difference [MD] -0.40 days; 95% confidence interval [CI] -0.69 to -0.11; 21 trials, 2479 infants). Hypertonic saline also demonstrated slightly improved post-treatment clinical severity scores during the first three days of therapy (day 1 MD -0.64; day 2 MD -1.07; day 3 MD -0.89) and a reduced risk of hospitalization among infants treated in outpatient or emergency department settings (risk ratio [RR] 0.87; 95% CI 0.78 to 0.97; 8 trials, 1760 infants) when compared with nebulized 0.9% saline. However, hypertonic saline did not demonstrate a clear reduction in hospital readmission within 28 days (RR 0.83; 95% CI 0.55 to 1.25). Across trials reporting safety outcomes, adverse events associated with hypertonic saline (including concentrations up to 7%) were generally mild and self-limited, with reported events including worsening cough, agitation, bronchospasm, bradycardia, desaturation, vomiting, and diarrhea. Overall, the certainty of evidence for these outcomes was rated as low to very low due to heterogeneity and risk of bias across studies. [2]

A 2022 meta-analysis evaluated the efficacy and safety of nebulized 3% hypertonic saline (HS) compared with 0.9% normal saline (NS) in infants with acute bronchiolitis. The analysis included 27 randomized controlled trials involving 3495 infants younger than 24 months who received either 3% HS or 0.9% NS via nebulization. Outcomes assessed across studies included length of hospital stay (LOS), rate of hospitalization (ROH), clinical severity score (CSS), rate of readmission (ROR), respiratory distress assessment instrument (RDAI), and adverse events (AEs). Compared with 0.9% NS, treatment with 3% HS was associated with a statistically significant reduction in LOS (MD -0.60 days; 95% [CI -1.04 to -0.17), a decreased rate of hospitalization (odds ratio [OR] 0.74; 95% CI 0.59 to 0.91), and improvements in clinical severity scores at day 1 (MD -0.79; 95% CI -1.23 to -0.34), day 2 (MD -1.26; 95% CI -2.02 to -0.49), and day ≥3 (MD -1.27; 95% CI -1.92 to -0.61). Improvements were also observed in RDAI scores (MD -0.60; 95% CI -0.95 to -0.26). No statistically significant difference was observed in the rate of readmission between groups (OR 0.77; 95% CI 0.51 to 1.16). Adverse events reported across 17 studies included cough, vomiting, diarrhea, agitation, rhinorrhea, hoarseness, and vigorous crying; these events resolved without reported serious complications. Overall, the study concluded that nebulized 3% HS demonstrated improved clinical outcomes compared with nebulized 0.9% NS in infants with acute bronchiolitis, although heterogeneity across studies and variability in study quality were noted as limitations. [3]

An updated 2018 Cochrane review evaluated use of nebulized hypertonic saline versus placebo or other treatments in patients with cystic fibrosis to determine mucociliary clearance efficacy. Seventeen trials were identified which compared hypertonic saline 3% to 7% to placebo, as well as hypertonic saline versus mucus mobilizing treatments; however, studies comparing 3% to 7% or hypertonic saline versus acetylcysteine were not identified. In general, nebulized hypertonic saline resulted in reduced pulmonary exacerbations, increase in quality of life for adults, and improved lung function by 4 weeks, although the effect on lung function was not sustained at 48 weeks. Evidence ranged from very low to moderate due to high risk of bias, as patients were able to discern the taste of the solutions. [4]

A 2019 review and meta-analysis evaluated mucoactive agents (e.g. N-acetylcysteine, hypertonic saline, 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, N-acetylcysteine increased mean mucus weight from 2.65 ± 3.47 g to 7.50 ± 6.29 g, while isotonic saline had no effect. N-acetylcysteine also improved mucus viscosity. Overall, data suggests that hypertonic saline and N-acetylcysteine are ineffective for atelectasis/mucus plugging while intubated. [5]

A systematic review assessed the efficacy and safety of nebulized hypertonic saline (HS) in infants with acute bronchiolitis compared to 0.9% saline or standard care. It included 24 randomized or quasi-randomized trials involving 3,209 patients, and 1,706 patients received nebulized HS. Patients treated with nebulized HS had a significantly shorter length of stay compared with those receiving 0.9% saline or standard care (mean difference [MD] 20.45 days, 95% CI 20.82 to 20.08). The HS group also had a significantly lower post-treatment clinical score in the first 3 days of admission (5 trials involving 404 inpatients; day 1: MD 20.99, 95% CI 21.48 to 20.50; day 2: MD 21.45, 95% CI 22.06 to 20.85; day 3: MD 21.44, 95% CI 21.78 to 21.11). Nebulized HS reduced the risk of hospitalization by 20% compared with 0.9% saline among outpatients (7 trials involving 951 patients; risk ratio 0.80, 95% CI 0.67 to 0.96). No significant adverse events related to HS inhalation were reported. The study showed that nebulized HS is a safe and potentially effective treatment of infants with acute bronchiolitis. However, the quality of evidence was moderate due to inconsistent results between trials and selection bias. [6]

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 functions 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. [7]

Literature Review

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

Please compare and contrast clinical information regarding the use of nebulized 0.9%, 3%, and 7% sodium chloride inhalation solution.

Level of evidence

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

Please see Table 1 for your response.

A Controlled Trial of Long-Term Inhaled Hypertonic Saline in Patients with Cystic Fibrosis
Design	Double-blind, parallel-group trial N= 164
Objective	To test the safety and efficacy of inhaled hypertonic saline in a long-term trial for patients with cystic fibrosis
Study Groups	Hypertonic saline (n= 83) Control (n= 81)
Inclusion Criteria	Patients with stable cystic fibrosis, at least six years old, with FEV1 within 10% of the best value in the past six months and at least 40% of the predicted value
Exclusion Criteria	Pregnant or breast-feeding women, persons colonized with Burkholderia cepacia, cigarette smokers, and those who used hypertonic saline or non-routine antibiotics in the previous 14 days
Methods	Participants inhaled 4 ml of either 7% hypertonic saline or 0.9% saline twice daily for 48 weeks, with quinine sulfate added to mask taste. A bronchodilator was given before each dose, and standard therapies were continued.
Duration	48 weeks
Outcome Measures	Primary: Rate of change in lung function (FVC, FEV1, FEF25–75) Secondary: Absolute lung function levels, incidence of pulmonary exacerbations, time free of exacerbations, antibiotic use, days unable to participate in usual activities, microbiologic analyses, quality of life, body-mass index
Baseline Characteristics		Control (n= 81)	Hypertonic Saline (n= 83)
	Age, year	18.7 ± 9.2	18.4 ± 9.3
	Female	42%	46%
	Body-mass index	20.1 ± 3.6	19.9 ± 3.9
	FEV1 (% of the predicted value)	76 ± 21	73 ± 21
	FVC (% of the predicted value)	88 ± 18	85 ± 18
	FEF_25-75 (% of the predicted value)	61 ± 35	56 ± 34
	Regular use of bronchodilator	54%	47%
	Regular use of rhDNase	36%	39%
	Regular use of antibiotic	40%	42%
	Regular use of physiotherapy	70%	71%
Results	Treatment with nebulized 7% hypertonic saline did not significantly alter the linear rate of decline in lung function over 48 weeks compared with isotonic saline (p= 0.79). However, when lung function was evaluated as the absolute level averaged across post-randomization visits, patients receiving hypertonic saline demonstrated significantly higher values. Mean FEV₁ was 68 mL higher (95% CI 3 to 132) and FVC was 82 mL higher (95% CI 12 to 153) compared with the control group (overall p= 0.03), while FEF_25–75 did not significantly differ between groups. Hypertonic saline was also associated with a clinically meaningful reduction in pulmonary exacerbations. The mean number of exacerbations requiring intravenous antibiotics was 0.39 in the hypertonic saline group versus 0.89 in the control group (difference 0.5; 95% CI 0.14 to 0.86; p= 0.02), corresponding to a 56% relative reduction. The proportion of patients remaining free of exacerbations at 48 weeks was 76% with hypertonic saline versus 62% with isotonic saline (p= 0.03). When exacerbations were defined by clinical signs and symptoms, the mean number of exacerbations was 1.32 with hypertonic saline compared with 2.74 with control (difference 1.42; 95% CI 0.86 to 1.99; p< 0.001). Median antibiotic use for exacerbations was significantly reduced (11 vs 50 antibiotic-days; p< 0.001), and patients receiving hypertonic saline experienced fewer days absent from normal activities (7 vs 24 days; p< 0.001). Hypertonic saline did not significantly change sputum bacterial density or airway inflammatory markers compared with control.
Adverse Events	Adverse events included respiratory exacerbations, chest pain, gastrointestinal symptoms, headache, joint pains, pharyngitis, and tonsillitis. Fewer adverse events in the hypertonic-saline group (mean, 2.89 vs. 5.17 per 336 days; p< 0.001). Adverse drug reactions more common in the hypertonic-saline group (p= 0.001).
Study Author Conclusions	Hypertonic saline preceded by a bronchodilator is an inexpensive, safe, and effective additional therapy for patients with cystic fibrosis, improving lung function and reducing exacerbations.
Critique	This well-designed randomized, double-blind trial provides strong evidence for the clinical benefit of nebulized 7% saline compared with isotonic saline in cystic fibrosis, particularly in reducing exacerbations. However, the study did not evaluate intermediate concentrations such as 3% saline, which limits direct comparison across commonly used hypertonic saline concentrations.

References:
[1] [1] Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354(3):229-240. doi:10.1056/NEJMoa043900.