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. 2023 Jun 14;6(6):CD001506.
doi: 10.1002/14651858.CD001506.pub5.

Nebulised hypertonic saline for cystic fibrosis

Peter Wark  1 , Vanessa M McDonald  2 , Sherie Smith  3
Affiliations

Nebulised hypertonic saline for cystic fibrosis

Peter Wark et al. Cochrane Database Syst Rev. .

Abstract

Background: Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.

Objectives: To investigate efficacy and tolerability of nebulised hypertonic saline treatment in people with cystic fibrosis (CF) compared to placebo or other treatments that enhance mucociliary clearance.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases. Most recent search: 25 April 2022.

Selection criteria: We included randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).

Data collection and analysis: Two authors independently reviewed all identified trials and data, and assessed trial quality. We assessed the certainty of the evidence using GRADE. For cross-over trials we stipulated a one-week washout period. We planned to use results from a paired analysis in the review, but this was only possible in one trial. For other cross-over trials, we chose to treat the trials as if they were parallel.

Main results: We included 24 trials (1318 participants, aged one month to 56 years); we excluded 29 trials, two trials are ongoing and six are awaiting classification. We judged 15 of the 24 included trials to have a high risk of bias due to participants' ability to discern the taste of the solutions. Hypertonic saline 3% to 7% versus placebo (stable disease) We are uncertain whether the regular use of nebulised hypertonic saline in stable lung disease leads to an improvement in forced expiratory volume in one second (FEV1) % predicted at four weeks, (mean difference (MD) 3.30%, 95% confidence interval (CI) 0.71 to 5.89; 4 trials, 246 participants; very low-certainty evidence). In preschool children we found no difference in lung clearance index (LCI) at four weeks, but a small improvement after 48 weeks of treatment with hypertonic saline compared to isotonic saline (MD -0.60, 95% CI -1.00 to -0.19; 2 trials, 192 participants). We are also uncertain whether hypertonic saline made a difference to mucociliary clearance, pulmonary exacerbations or adverse events compared to placebo. Hypertonic saline versus control (acute exacerbation) Two trials compared hypertonic saline to control, but only one provided data. There may be little or no difference in lung function measured by FEV1 % predicted after hypertonic saline compared to isotonic saline (MD 5.10%, 95% CI -14.67 to 24.87; 1 trial, 130 participants). Neither trial reported any deaths or measures of sputum clearance. There were no serious adverse events. Hypertonic saline versus rhDNase Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two trials (61 participants) provided data for inclusion in the review. We are uncertain whether there was an effect of hypertonic saline on FEV1 % predicted after three weeks (MD 1.60%, 95% CI -7.96 to 11.16; 1 trial, 14 participants; very low-certainty evidence). At three months, rhDNase may lead to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease (MD 8.00%, 95% CI 2.00 to 14.00; low-certainty evidence). We are uncertain whether adverse events differed between the two treatments. No deaths were reported. Hypertonic saline versus amiloride One trial (12 participants) compared hypertonic saline to amiloride but did not report on most of our outcomes. The trial found that there was no difference between treatments in measures of sputum clearance (very low-certainty evidence). Hypertonic saline compared with sodium-2-mercaptoethane sulphonate (Mistabron®) One trial (29 participants) compared hypertonic saline to sodium-2-mercaptoethane sulphonate. The trial did not measure our primary outcomes. There was no difference between treatments in any measures of sputum clearance, courses of antibiotics or adverse events (very low-certainty evidence). Hypertonic saline versus mannitol One trial (12 participants) compared hypertonic saline to mannitol, but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-certainty evidence). Hypertonic saline versus xylitol Two trials compared hypertonic saline to xylitol, but we are uncertain whether there is any difference in FEV1 % predicted or median time to exacerbation between groups (very low-certainty evidence). No other outcomes were reported in the review. Hypertonic saline 7% versus hypertonic saline 3% We are uncertain whether there was an improvement in FEV1 % predicted after treatment with 7% hypertonic saline compared with 3% (very low-certainty evidence).

Authors' conclusions: We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low-certainty evidence); there was no difference seen at 48 weeks (one trial; low-certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years. Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes. Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria. The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.

Trial registration: ClinicalTrials.gov NCT00635141 NCT00271310 NCT01619657 NCT02141191 NCT00405665 NCT01094704 NCT02303808.

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Conflict of interest statement

Peter Wark: I declare my position of Fiduciary Officer for Cystic Fibrosis Australia (the main patient body in Australia). I was an investigator and an author on one trial included in the review (Dentice 2016) and a co‐investigator on a further trial, the National Hypertonic Saline in Cystic Fibrosis Study trial (Elkins 2006a).

Vanessa M McDonald has participated in educational symposia funded by GlaxoSmithKline, AstraZeneca, and Menarini, and has participated on advisory boards for GlaxoSmithKline, Novartis, AstraZeneca, and Menarini (unrelated to the present work). She was a co‐investigator in the National Hypertonic Saline in Cystic Fibrosis Study trial (Elkins 2006a).

Sherie Smith has no conflicts of interest to declare.

Peter Wark and Vanessa M McDonald did not make inclusion decisions or assess risk of bias for their own studies (up to 2019 these judgements were undertaken by editorial base staff and verified by the clinical contact editor). Sherie Smith reassessed and verified these decisions for the 2023 update.

Figures

1
1
Study flow chart
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Risk of bias summary table: review authors' judgements for each risk of bias item for each study
4
4
Forest plot of comparison: 1 Hypertonic saline 3% to 7% versus isotonic saline, outcome: 1.13 Average number of exacerbations
1.1
1.1. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 1: Change in FEV1 (% predicted)
1.2
1.2. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 2: Change in FVC (% predicted)
1.3
1.3. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 3: Mean change in FEV0.5 (mL)
1.4
1.4. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 4: Mean change in FEV0.75 (L)
1.5
1.5. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 5: LCI
1.6
1.6. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 6: LCI change from baseline
1.7
1.7. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 7: Radiolabelled isotope clearance (%)
1.8
1.8. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 8: Mucociliary clearance measured as area under the curve
1.9
1.9. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 9: Change in mucocilliary clearance rate (% clearance)
1.10
1.10. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 10: Exercise capacity (using a subjective visual analogue score)
1.11
1.11. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 11: Quality of life (change from baseline)
1.12
1.12. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 12: Feeling of cleared chest (using a subjective visual analogue scale)
1.13
1.13. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 13: Average number of pulmonary exacerbations
1.14
1.14. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 14: Average number of hospital admissions per participant
1.15
1.15. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 15: Mean adherence rate
1.16
1.16. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 16: Change in log10 colony forming units (CFU)/g from baseline at final visit
1.17
1.17. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 17: Mean time (years) to first detection of CF pathogens
1.18
1.18. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 18: Adverse events: acute fall in lung function
1.19
1.19. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 19: Adverse events 2 to 4 weeks
1.20
1.20. Analysis
Comparison 1: Hypertonic saline 3% to 7% versus isotonic saline, Outcome 20: Adverse events 48 to 52 weeks
2.1
2.1. Analysis
Comparison 2: Hypertonic saline 3% to 7% versus isotonic saline in acute lung disease, Outcome 1: Change in FEV1 from baseline (% predicted)
2.2
2.2. Analysis
Comparison 2: Hypertonic saline 3% to 7% versus isotonic saline in acute lung disease, Outcome 2: Change in FVC from baseline (% predicted)
2.3
2.3. Analysis
Comparison 2: Hypertonic saline 3% to 7% versus isotonic saline in acute lung disease, Outcome 3: Shuttle walk test
3.1
3.1. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 1: Change in FEV1 (% predicted)
3.2
3.2. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 2: Improvement in FEV1 >10%
3.3
3.3. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 3: Change in FVC (% predicted)
3.4
3.4. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 4: Exercise tolerance ‐ oxygen saturation
3.5
3.5. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 5: Exercise tolerance ‐ VAS for breathlessness
3.6
3.6. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 6: Exercise tolerance ‐ FCS
3.7
3.7. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 7: Mean percentage change in quality of life score
3.8
3.8. Analysis
Comparison 3: Hypertonic saline versus rhDNase, Outcome 8: Delivery time (minutes)
4.1
4.1. Analysis
Comparison 4: Hypertonic saline versus mannitol, Outcome 1: Delivery time (mins)
5.1
5.1. Analysis
Comparison 5: Hypertonic saline 7% versus xylitol, Outcome 1: FEV1 % predicted mean change from baseline
5.2
5.2. Analysis
Comparison 5: Hypertonic saline 7% versus xylitol, Outcome 2: FVC % predicted mean change from baseline
5.3
5.3. Analysis
Comparison 5: Hypertonic saline 7% versus xylitol, Outcome 3: Adherence to treatment ‐ mean number of doses taken
5.4
5.4. Analysis
Comparison 5: Hypertonic saline 7% versus xylitol, Outcome 4: Density of colonisation of pathogens ‐ change from baseline log CFU/mL
5.5
5.5. Analysis
Comparison 5: Hypertonic saline 7% versus xylitol, Outcome 5: Adverse events
6.1
6.1. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 1: FEV1 % predicted (absolute value)
6.2
6.2. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 2: FEV1 % predicted mean percentage change from baseline
6.3
6.3. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 3: FVC % predicted (absolute value)
6.4
6.4. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 4: FVC % predicted mean percentage change from baseline
6.5
6.5. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 5: Exercise capacity ‐ PEFR (L/min) via a 3‐minute step test
6.6
6.6. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 6: Exercise capacity ‐ SaO2 via a 3‐minute step test
6.7
6.7. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 7: Exercise capacity ‐ heart rate (bpm) via a 3‐minute step test
6.8
6.8. Analysis
Comparison 6: Hypertonic saline 7% versus hypertonic saline 3%, Outcome 8: Breathlessness via a 3‐minute step test
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Adde 2004 {published data only}
    1. Adde FV, Borges KT, Hatanaka AC, Nakaie CM, Cardieri JM, Oliveira RC, et al. Hypertonic saline X recombinant human DNase: a randomised crossover study in 18 cystic fibrosis patients. Journal of Cystic Fibrosis 2004;3(Suppl 1):S66. [CFGD REGISTER: BD113]
Amin 2010 {published data only}
    1. Amin R, Subbarao P, Jabar A, Balkovec S, Jensen R, Kerrigan S, et al. Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function. Thorax 2010;65(5):379-83. [CFGD REGISTER: BD158b] - PubMed
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Amin 2016 {published data only}
    1. Amin R, Stanojevic S, Kane M, Webster H, Ratjen F. A randomized controlled trial to evaluate the lung clearance index as an outcome measure for early phase studies in patients with cystic fibrosis. Respiratory Medicine 2016;112:59-64. [CFGD REGISTER: BD228] [PMID: ] - PubMed
    1. NCT02276898. A randomized-controlled trial of inhaled hypertonic saline (7%) to evaluate the lung clearance index [A randomized-controlled trial of inhaled hypertonic saline (7%) to evaluate the lung clearance index as a short-term pharmacodynamic biomarker in patients with cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT02276898 (first posted 28 October 2014).
Ballmann 1998 {published data only}
    1. Ballmann M, Hardt H. Hypertonic saline and recombinant human DNase: a randomised cross-over pilot study in patients with cystic fibrosis [abstract]. In: Proceedings of the 22nd European Cystic Fibrosis Conference; 1998 June 13-19; Berlin. 1998:80. [CFGD REGISTER: BD70a] - PubMed
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Cardinale 2003 {published data only}
    1. Cardinale F, Manca A, Mappa L, Tesse R, Cavallone R, Loffredo MS, et al. Effects of exhaled nitric oxide levels and lung function of ultrasonically nebulized hypertonic saline solution in cystic fibrosis. European Respiratory Journal 2003;22(Suppl 45):231s. [CFGD REGISTER: BD115]
Chadwick 1997 {published data only}
    1. Chadwick SL, Moss SJ, Bott J, Geddes DM, Alton EWFW. Effect of hypertonic saline, isotonic saline and water challenges on the airways of cystic fibrosis patients. Thorax 1997;52(Suppl 6):A43. [CFGD REGISTER: BD94] 5500100000001189
Dentice 2016 {published data only}
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    1. Dentice R, Elkins M, Middleton P, Bishop J, Wark P, Dorahy D, et al. A randomised controlled trial of the effect of hypertonic saline (HS) inhalation on exacerbation resolution, hospital length of stay and time to relapse in adults with cystic fibrosis. Journal of Cystic Fibrosis 2013;12 Suppl 1:S38. [ABSTRACT NO.: WS19.4] [CFGD REGISTER: BD185a]
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Donaldson 2020 {published data only}
    1. Donaldson SH, Danielle Samulski T, LaFave C, Zeman K, Wu J, Trimble A, et al. A four week trial of hypertonic saline in children with mild cystic fibrosis lung disease: effect on mucociliary clearance and clinical outcomes. Journal of Cystic Fibrosis 2020;19(6):942-8. [CFGD REGISTER: BD206c] - PMC - PubMed
    1. Donaldson SH, Samulski D, LaFave C, Wu J, Zeman K, Salazar C, et al. Sustained effect of hypertonic saline on mucociliary clearance in CF children with mild lung disease. Pediatric Pulmonology 2013;48 Suppl 36:280. [ABSTRACT NO.: 210] [CENTRAL: 999885] [CFGD REGISTER: BD206]
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    1. NCT01031706. Effect of hypertonic saline on mucus clearance in children ages 5-12 with cystic fibrosis [Sustained impact of hypertonic saline on mucociliary clearance in young children with cystic fibrosis]. clinicaltrials.gov/ct2/show/study/NCT01031706 (first posted 15 December 2009).
Elkins 2006a {published data only}
    1. Bye P, Elkins M, Robinson M, Moriarty C, Rose B, Harbour C, et al. Long-term inhalation of hypertonic saline in patients with cystic fibrosis - a randomised controlled trial. Pediatric Pulmonology 2004;38(Suppl 27):329. [CFGD REGISTER: BD114a]
    1. Elkins M, Robinson M, Moriarty C, Sercombe J, Rose B, Harbour C, et al. Three methods of monitoring adherence in a long-term trial in cystic fibrosis. Journal of Cystic Fibrosis 2006;5 Suppl:S111. [CFGD REGISTER: BD114d]
    1. Elkins MR, Robinson M, Moriarty C, Sercombe J, Rose B, Harbour C. Three methods of monitoring adherence in the national hypertonic saline trial in cystic fibrosis [abstract]. Pediatric Pulmonology 2005;40(Suppl 28):268. [CFGD REGISTER: BD114c]
    1. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty C, Marks GB, et al. A controlled trial of long-term hypertonic saline in patients with cystic fibrosis. New England Journal of Medicine 2006;354(3):229-40. [CFGD REGISTER: BD114b] - PubMed
    1. NCT00271310. The effects of long term inhalation of hypertonic saline in subjects with cystic fibrosis [The effects of long term inhalation of hypertonic saline in subjects with cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT00271310 (first posted 30 December 2005).
Eng 1996 {published data only}
    1. Button BM, Riedler J, Eng P, Robertson CF. Inhaled hypertonic saline as an adjunct to chest physiotherapy in cystic fibrosis; the three year clinical experience. Pediatric Pulmonology 1996;Suppl 13:306. [CFGD REGISTER: BD71d]
    1. Eng P, Morton J, Douglas J, Riedler J, Wilson J, Robertson CF. Efficacy of short-term ultrasonically nebulised hypertonic saline in patients with cystic fibrosis. European Respiratory Journal 1995;8(Suppl 19):510s. [CFGD REGISTER: BD71c]
    1. Eng PA, Morton J, Douglass J, Riedler J, WIlson J, Robertson C. Short-term administration of ultrasonically nebulised hypertonic saline improves pulmonary function in patients with cystic fibrosis. Australian & New Zealand Journal of Medicine 1995;25:440. [CFGD REGISTER: BD71b]
    1. Eng PA, Morton J, Douglass JA, Riedler J, Wilson J, Robertson CF. Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatric Pulmonology 1996;21(2):77-83. [CFGD REGISTER: BD71a] - PubMed
Gupta 2012 {published data only}
    1. CTRI/2010/091/001279. A clinical trial to compare the effects of 3% and 7% hypertonic saline on lung function in children with cystic fibrosis [Comparison of effects of 3% and 7% hypertonic saline nebulisation on lung function in children with cystic fibrosis: a randomized controlled trial]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2010/091/001279 (first registered 16 September 2010). [CENTRAL: CN-01848671] [CFGD REGISTER: BD184b]
    1. Gupta S, Ahmed F, Lodha R, Gupta YK, Kabra SK. Comparison of effects of 3 and 7% hypertonic saline nebulization on lung function in children with cystic fibrosis: a double-blind randomized, controlled trial. Journal of Tropical Pediatrics 2012;58(5):375-81. - PubMed
Laube 2009 {published data only}
    1. Laube BL, Sharpless G, Carson KA, Kelly A, Mogayzel PJ. Acute inhalation of hypertonic saline does not improve mucociliary clearance in all children with cystic fibrosis. BMC Pulmonary Medicine 2011;11:45. [CENTRAL: 806034] [CFGD REGISTER: BD157b] [PMID: ] - PMC - PubMed
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Mainz 2015 {published data only}
    1. Mainz JG, Schaedlich K, Hentschel J, Schumacher U, Koitschev C, Koitschev A, et al. Sinonasal inhalation of isotonic vs. hypertonic saline (6.0%) in CF patients with chronic rhinosinusitis - results of a multicentre, double-blind, controlled prospective trial. Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society 2015;14 Suppl 1:S95. [ABSTRACT NO.: 146] [CENTRAL: 1081480] [CFGD REGISTER: CO59] - PubMed
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NCT01355796 {unpublished data only}
    1. NCT01355796. Inhaled xylitol versus saline in stable subjects with cystic fibrosis [Randomized cross over study of inhaled hypertonic xylitol versus hypertonic saline in stable subjects with cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT01355796 (first posted 18 May 2011).
PRESIS 2019 {published data only}
    1. NCT01619657. Preventive inhalation of hypertonic saline in infants with cystic fibrosis (PRESIS). clinicaltrials.gov/ct2/show/NCT01619657 (first posted 14 June 2012).
    1. Stahl M, Graeber SY, Sommerburg O, Ricklefs I, Diekmann G, Dopfer C, et al. Randomized double blind controlled pilot study on safety and efficacy of hypertonic saline as preventive inhalation therapy in infants with CF (PRESIS). Atemwegs- und Lungenkrankheiten. Conference: 40th Annual Joint Meeting of the Society for Pediatric Pneumology. Austria 2018;44(2):60-1. [CFGD REGISTER: BD249c]
    1. Stahl M, Graeber SY, Sommerburg O, Ricklefs I, Diekmann G, Dopfer C, et al. Randomized, double-blind, controlled pilot study on safety and efficacy of hypertonic saline as preventive inhalation therapy in infants with CF (presis). Pediatric Pulmonology 2017;52(Suppl 47):302. [CENTRAL: CN-01430895] [CFGD REGISTER: BD249b] [EMBASE: 619069144]
    1. Stahl M, Ricklefs I, Dopfer C, Barth S, Schlegtendal A, Graeber SY, et al. Randomised, double-blind, controlled pilot study on safety and efficacy of hypertonic saline as preventive inhalation therapy in infants with CF (PRESIS). Journal of Cystic Fibrosis 2018;17(Suppl 3):S25-6. [CFGD REGISTER: BD249a]
    1. Stahl M, Ricklefs I, Dopfer C, Barth S, Sommerburg O, Diekmann G, et al. Follow-up on PRESIS: long-term-efficacy of preventive inhalation therapy with hypertonic saline in infants with CF. Pediatric Pulmonology 2019;54 Suppl 2:363. [CFGD REGISTER: BD249f]
Riedler 1996 {published data only}
    1. Button BM, Riedler J, Eng P, Roberston CF. Inhaled hypertonic saline as an adjunct to chest physiotherapy in cystic fibrosis; the three year clinical experience. Pediatric Pulmonology 1996;Suppl 13:306. [CFGD REGISTER: BD69a]
    1. Riedler J, Reade T, Button B, Robertson CF. A pilot study of inhaled hypertonic saline to increase sputum production in adolescents with cystic fibrosis. European Respiratory Journal 1994;7(Suppl 18):430s. [CFGD REGISTER: BD69c]
    1. Riedler J, Reade T, Button B, Robertson CF. Inhaled hypertonic saline increases sputum expectoration in cystic fibrosis. Journal of Paediatric Child Health 1996;32(1):48-50. [CFGD REGISTER: BD69b] - PubMed
Robinson 1996 {published data only}
    1. Robinson M, Regnis JA, Bailey DL, King M, Bautovich GJ, Bye PT. Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine 1996;153(5):1503-9. [CFGD REGISTER: BD83] 5500100000001109 - PubMed
Robinson 1997 {published data only}
    1. Robinson M, Hemming A, Regnis J, Wong A, Bailey D, Bautotvich G, et al. Effect of increasing doses of hypertonic saline on mucociliary clearance inpatients with cystic fibrosis. Thorax 1997;52(10):900-3. [CFGD REGISTER: BD45b] - PMC - PubMed
    1. Robinson M, Hemming AL, Bailey DL, Mellis CM, Bautovich GJ, Bye PTP. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine 1996;153(Suppl):A70. [CFGD REGISTER: BD45a] 5500100000001559 - PubMed
    1. Robinson M, Parsons S, Hemming A, Bautovich G, Mellis CM, Bye PTP. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Australian and New Zealand Journal of Medicine 1997;27:258. [CFGD REGISTER: BD45c] 5500100000008140
Robinson 1999 {published data only}
    1. Robinson M, Daviskas E, Eberl S, Baker J, Anderson SD, Bye PT. Effect of inhaling a dry powder of mannitol on mucociliary clearance in adults with cystic fibrosis [abstract]. Pediatric Pulmonolgy 1998;Suppl 17:280. [CFGD REGISTER: BD84a]
    1. Robinson M, Daviskas E, Eberl S, Baker J, Chan H, Anderson, S, et al. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. European Respiratory Journal 1999;14(3):678-85. [CFGD REGISTER: BD84b] - PubMed
    1. Robinson M, Daviskas E, Eberl S, Baker J, Chan HK, Anderson SD, Bye PT. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study [abstract]. Pediatric Pulmonology 2000;29(6):484. [CFGD REGISTER: BD84c] - PubMed
Rosenfeld 2012 {published data only}
    1. Alpern AN, Brumback LC, Ratjen F, Rosenfeld M, Davis SD, Quittner AL. Initial evaluation of the Parent Cystic Fibrosis Questionnaire--Revised (CFQ-R) in infants and young children. Journal of Cystic Fibrosis 2015;14(3):403-11. [CENTRAL: 1130846] [CFGD REGISTER: BD175i] [PMID: ] - PubMed
    1. Brumback LC, Baines A, Ratjen F, Davis SD, Daniel SL, Quittner AL, et al. Pulmonary exacerbations and parent-reported outcomes in children <6 years with cystic fibrosis. Pediatric Pulmonology 2015;50:236-43. [CENTRAL: 1046755] [GR:: U01 HL092931/HL/NHLBI NIH HHS/United States] [JID:: 8510590] [PMCID:: PMC4213320] [PMID: ] [U01: HL092932/HL/NHLBI NIH HHS/United States] - PMC - PubMed
    1. Davis SD, Ratjen F, Brumback LC, Johnson RC, Filbrun AG, Kerby GS, et al. Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis. Journal of Cystic Fibrosis 2016;15(3):386-91. [CFGD REGISTER: BD175l] [PMID: ] - PMC - PubMed
    1. Davis SD, Rosenfeld M, Brumback L, Donaldson S, Johnson R, Rowbotham R, et al. Infant PFTs as an endpoint in the infant study of inhaled saline randomized controlled trial. Pediatric Pulmonology 2012;47(S35):302. [ABSTRACT NO.: 225] [CFGD REGISTER: BD175d] 5500100000011648
    1. NCT01293084. Hypertonic saline and mucociliary clearance in children [Acute inhalation of hypertonic saline does not improve mucociliary clearance in all children with cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT01293084 (first posted 10 February 2011).
SHIP 2019 {published data only}
    1. NCT02378467. Saline hypertonic in preschoolers (SHIP) [Saline hypertonic in preschoolers]. clinicaltrials.gov/ct2/show/NCT02378467 (first posted 4 March 2015). [CFGD REGISTER: BD258b]
    1. Ratjen F, Davis SD, Stanojevic S, Kronmal RA, Hinckley Stukovsky KD, Jorgensen N, et al. Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Respiratory Medicine 2019;7(9):802-9. [CENTRAL: CN-01951461] [CFGD REGISTER: BD258c] [PMID: ] - PubMed
    1. Rosenfeld M, Davis SD, Hinckley Stukovsky K, Jorgensen N, Enright E, Stanojevic S, et al. Multicenter randomized, controlled clinical trial of inhaled hypertonic saline in preschool children with CF: the Ship study. Pediatric Pulmonology 2018;53(S2):323. [CENTRAL: CN-01648968] [CFGD REGISTER: BD258a]
Singh 2020 {unpublished data only}
    1. NCT00928135. Aerosolized hypertonic xylitol versus hypertonic saline in cystic fibrosis (CF) subjects [Randomized controlled study of aerosolized hypertonic xylitol versus hypertonic saline in hospitalized patients with exacerbation of cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT00928135 (first posted 25 June 2009). [CFGD REGISTER: BD264a]
    1. Singh S, Hornick D, Fedler J, Launspach JL, Teresi ME, Santacroce TR, et al. Randomized controlled study of aerosolized hypertonic xylitol versus hypertonic saline in hospitalized patients with pulmonary exacerbation of cystic fibrosis. Journal of Cystic Fibrosis 2020;19(1):108-13. [CENTRAL: CN-01964766] [CFGD REGISTER: BD264b] [DOI: 10.1016/j.jcf.2019.06.016] [EMBASE: 2002325871] [PMID: ] - DOI - PMC - PubMed
Suri 2001 {published data only}
    1. Grieve R, Thompson S, Normand C, Suri R, Bush A, Wallis C. A cost-effectiveness analysis of rhDNase in children with cystic fibrosis. International Journal of Technology Assessment in Health Care 2003;19(1):71-9. [CFGD REGISTER: BD96h] - PubMed
    1. Suri R, Grieve R, Normand C, Metcalfe C, Thompson S, Wallis C, et al. Effects of hypertonic saline, alternate day and daily rhDNase on healthcare use, costs and outcomes in children with cystic fibrosis. Thorax 2001;56(Suppl 3):iii84. [CFGD REGISTER: BD96f] - PMC - PubMed
    1. Suri R, Grieve R, Normand C, Metcalfe C, Thompson S, Wallis C, et al. Effects of hypertonic saline, alternate day and daily rhDNase on healthcare use, costs and outcomes in children with cystic fibrosis. Thorax 2002;57(10):841-6. [CFGD REGISTER: BD96e] - PMC - PubMed
    1. Suri R, Marshall LJ, Wallis C, Metcalfe C, Bush A, Shute JK. Effects of recombinant human DNase and hypertonic saline on airway inflammation in children with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine 2002;166(3):352-5. [CFGD REGISTER: BD96d] - PubMed
    1. Suri R, Metcalfe C, Lees B, Flather M, Normand C, Thompson S, et al. A cross-over comparative study of hypertonic saline alternate day and daily rhDNase in children with Cystic Fibrosis. Thorax 2000;55:A75. [CFGD REGISTER: BD96g]
Weller 1980 {published data only}
    1. Weller P, Ingram D, Preece M, Matthew D. A controlled trial of intermittent aerosol therapy in patients with cystic fibrosis [abstract]. In: Proceedings of the 9th Meeting European Working Group for Cystic Fibrosis; 1979 June 12-13; Noordwijkerhout, The Netherlands. 1979:58. [CFGD REGISTER: BD26b]
    1. Weller P, Ingram D, Preece M, Matthew D. Controlled trial of intermittent aerosol therapy with sodium 2-mercaptoethane sulphonate in cystic fibrosis. Thorax 1980;35(1):42-6. [CFGD REGISTER: BD26a] - PMC - PubMed

References to studies excluded from this review

ACTRN12619001681145 {published data only}
    1. ACTRN12619001681145. Effect of the MetaNeb® on measures of lung clearance index, other measures of lung function and patient reported outcomes in individuals admitted to hospital for an acute exacerbation of their Cystic Fibrosis: a randomised controlled trial. anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12619001681145 (first posted 18 September 2019). [CFGD REGISTER: PE354a]
ACTRN12621000855820 {published data only}
    1. ACTRN12621000855820. Immediate effects of the MetaNeb® on regional lung perfusion, ventilation and other measures of lung function compared to those of huff and cough in adults with stable cystic fibrosis. trialsearch.who.int/Trial2.aspx?TrialID=ACTRN12621000855820 (first posted 12 July 2021).
Aquino 2012 {published data only}
    1. Aquino ES, Goto DM, Santos AS, Coelho CC, Fuccio MB, Saldiva PHN, et al. Effects of hypertonic saline solution and continuous positive airway pressure on respiratory mucus contact angle and mucus transportability by cough in cystic fibrosis patients. In: American Thoracic Society International Conference; 2008 May 16-21; Toronto. 2008:Poster #G7. [CENTRAL: CN-00679594] [CFGD REGISTER: PE199b]
    1. Aquino ES, Shimura F, Santos AS, Goto DM, Coelho CC, Fuccio MB, et al. CPAP has no effect on clearance, sputum properties, or expectorated volume in cystic fibrosis. Respiratory Care 2012;57(11):1914-9. [CFGD REGISTER: PE199a] - PubMed
Brivio 2016 {published data only}
    1. Brivio A, Ceruti C, Gambazza S, Colombo C. Randomized double-blind monocentric trial on tolerability, acceptability and efficacy of two formulations of inhaled 7% hypertonic saline with and without hyaluronic acid in reducing airways inflammation in patients with cystic fibrosis - preliminary results. Journal of Cystic Fibrosis 2013;12 Suppl 1:S104. [ABSTRACT NO.: 217] [CENTRAL: 999881] [CFGD REGISTER: BD208a]
    1. Brivio A, Conese M, Gambazza S, Biffi A, Tirelli AS, Russo M, et al. Pilot Randomized Controlled Trial Evaluating the Effect of Hypertonic Saline With and Without Hyaluronic Acid in Reducing Inflammation in Cystic Fibrosis. Journal of Aerosol Medicine and Pulmonary Drug Delivery 2016;29(6):482-9. [CENTRAL: 1155400] [CFGD REGISTER: BD208b] [PMID: ] - PubMed
Brown 2010 {published data only}
    1. Brown AW, Laube BL, Zeman K, Lechtzin N, Sharpless G, Wu J, et al. Durability of hypertonic saline for enhancing mucociliary clearance in cystic fibrosis. Pediatric Pulmonology 2010;45 Suppl 33:303. [ABSTRACT NO.: 237] [CFGD REGISTER: BD173] 5500100000010577
    1. Trimble AT, Whitney Brown A, Laube BL, Lechtzin N, Zeman KL, Wu J, et al. Hypertonic saline has a prolonged effect on mucociliary clearance in adults with cystic fibrosis. Journal of Cystic Fibrosis 2018;17(5):650-6. [CENTRAL: CN-01645710] [CFGD REGISTER: BD173c] [EMBASE: 620273897] - PMC - PubMed
Buonpensiero 2010 {published data only (unpublished sought but not used)}
    1. Buonpensiero P, De Gregorio F, Sepe A, Di Pasqua A, Ferri P, Siano M, et al. Hyaluronic acid improves "pleasantness" and tolerability of nebulized hypertonic saline in a cohort of patients with cystic fibrosis. Advances in Therapy 2010;27(11):870-8. [CENTRAL: 781252] [CFGD REGISTER: BD156c] [EMBASE: 2010642492] [PMID: ] - PubMed
    1. Buonpensiero P, De Gregorio F, Sepe A, Di Pasqua A, Ferri P, Siano M, et al. Hyaluronic acid improves tolerability of hypertonic saline in CF patients. Journal of Cystic Fibrosis 2010;9 Suppl 1:S63. [ABSTRACT NO.: 245] [CENTRAL: 775087] [CFGD REGISTER: BD156b] - PubMed
    1. Buonpensiero P, De Gregorio F, Sepe A, Di Pasqua A, Ferri P, Siano M, et al. Inhaled hyaluronic acid improves pleasantness and tolerability of nebulised hypertonic saline in patients with cystic fibrosis. Pediatric Pulmonology 2009;44 Suppl 32:243. [ABSTRACT NO.: 93] [CFGD REGISTER: BD156a] - PubMed
    1. NCT01658449. Comparison of the tolerability of two formulations of hypertonic saline in cystic fibrosis patients. clinicaltrials.gov/ct2/show/NCT01658449 (first posted 7 August 2012).
Corcoran 2017 {published data only}
    1. Corcoran TE, Godovchik JE, Donn KH, Busick DR, Goralski J, Locke LW, et al. Overnight delivery of hypertonic saline by nasal cannula aerosol for cystic fibrosis. Pediatric Pulmonology 2017;52(9):1142-9. [CFGD REGISTER: BD207] [CTG: ] - PMC - PubMed
    1. NCT02141191. A study of lung clearance after hypertonic saline delivery using the tpad device [A randomized crossover mucociliary clearance study of aerosolized 7% NACL solution administered overnight by the tpad device to subjects with cystic fibrosis]. clinicaltrials.gov/show/nct02141191 (first posted 19 May 2014). [CENTRAL: CN-01596846] [CFGD REGISTER: BD207b]
DeCono 2008 {published data only}
    1. De Cono N, Schelstraete P, Haerynck F, Van daele S, Sanders M, De Baets F. Hypertonic saline: effect on mucus rheology and spirometry. Journal of Cystic Fibrosis 2008;7(Suppl 2):S24. [ABSTRACT NO.: 93] [CFGD REGISTER: BD130]
Dentice 2012 {published data only}
    1. ACTRN12611000673943. A randomised trial of the effect of timing of nebulised hypertonic saline in relation to airway clearance physiotherapy, in people with cystic fibrosis lung disease [Randomised trial of the effect of timing of nebulised hypertonic saline in relation to airway clearance physiotherapy, on subjective efficacy, tolerability and overall satisfaction, and lung function parameters in adults with cystic fibrosis lung disease]. trialsearch.who.int/Trial2.aspx?TrialID=ACTRN12611000673943 (first registered 4 July 2011). [CFGD REGISTER: BD160e]
    1. Dentice R, Elkins M, Bye P. Hypertonic saline before vs during vs after physiotherapy techniques for airway clearance in people with cystic fibrosis: A randomised trial. Physiotherapy 2011;97:eS308-9. [ABSTRACT NO.: RR-PL-3136] [CENTRAL: 1089301] [CFGD REGISTER: BD160d] [EMBASE: 71882596]
    1. Dentice R, Elkins MR, Bye PT. A randomised trial of the effect of timing of hypertonic saline inhalation in relation to airway clearance physiotherapy in adults with cystic fibrosis. Pediatric Pulmonology 2010;45 Suppl 33:384. [ABSTRACT NO.: 459] [CFGD REGISTER: BD160a]
    1. Dentice RL, Elkins MR, Bye P. Adults with cystic fibrosis prefer hypertonic saline before or during airway clearance techniques: a randomised crossover trial. Journal of Physiotherapy 2012;58(1):33-40. [CFGD REGISTER: BD160b] - PubMed
    1. Dentice RL, Elkins MR, Bye PT. Online Supplementary Material - Table 3: Individual outcome data to "Adults with cystic fibrosis prefer hypertonic saline before or during airway clearance techniques: a randomised crossover trial" [online]. Journal of Physiotherapy 2012;58(1):33-40 Online. [CFGD REGISTER: BD160c] - PubMed
Donaldson 2006 {published data only}
    1. Donaldson SH, Bennett W, Zeman K, Knowles MR, Boucher RC. Efficacy of amiloride and hypertonic saline in cystic fibrosis. Pediatric Pulmonology 2003;Suppl 25:251. [CFGD REGISTER: BD110a]
    1. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. New England Journal of Medicine 2006;354(3):241-50. [CFGD REGISTER: BD110b] - PubMed
    1. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Online supplement to 'Mucus clearance and lung function in cystic fibrosis with hypertonic saline'. New England Journal of Medicine 2006;354(3):241-50 Online. [CFGD REGISTER: BD110c] - PubMed
    1. NCT00274391. Efficacy of amiloride and hypertonic saline in cystic fibrosis [Efficacy of amiloride and hypertonic saline in cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT00274391 (first posted 10 January 2006).
Elkins 2006b {published data only}
    1. ACTRN12606000053527. Pilot trial of the tolerability of hypertonic saline when delivered by a high-output nebuliser twice or four times daily to people with cystic fibrosis [Pilot trial of the tolerability of hypertonic saline when delivered by a high-output nebuliser twice or four times daily to people with cystic fibrosis]. trialsearch.who.int/Trial2.aspx?TrialID=ACTRN12606000053527 (first registered 7 February 2006). [CFGD REGISTER: BD124b]
    1. Elkins MR, Tingpej P, Moriarty CP, Yozghatlian V, Rose BR, Harbour C, et al. Tolerability of hypertonic saline when delivered rapidly via the Eflow® rapid nebulizer in subjects with cystic fibrosis. Pediatric Pulmonlogy 2006;41 (Suppl 29):292. [CFGD REGISTER: BD124a]
EUCTR2007‐002707‐40‐BE {unpublished data only}
    1. EUCTR2007-002707-40-BE. The effect of inhalation with hypertonic saline (7%) on lung function and sputum rheology in cystic fibrosis patients. www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002707-40 (first registered 28 June 2007).
Genkova 1998 {published data only}
    1. Genkova N, Bosheva M, Ivancheva D. Inhaled hypertonic saline solution in cystic fibrosis. In: 22nd European Cystic Fibrosis Conference; 1998 June 13-19; Berlin. 1998.
Grasemann 2013 {published and unpublished data}
    1. Grasemann H, Tullis E, Ratjen F. A randomized controlled trial of inhaled L-arginine in patients with cystic fibrosis. Journal of Cystic Fibrosis 2013;12(5):468-74. [CFGD REGISTER: GN233b] - PubMed
    1. Grasemann H, Tullis E, Ratjen F. A randomized placebo controlled study on the effects of L-arginine inhalation in patients with cystic fibrosis . Pediatric Pulmonology 2011;46 Suppl 34:293-4. [CFGD REGISTER: GN233c]
    1. Grasemann H, Tullis E, Ratjen F. Inhaled L-arginine in patients with cystic fibrosis - a randomized controlled trial. Journal of Cystic Fibrosis 2011;10 Suppl 1:S21. [ABSTRACT NO.: 81] [CFGD REGISTER: GN233a] - PubMed
    1. NCT00405665. The short term safety and efficacy of inhaled L-arginine in patients with cystic fibrosis [Pilot Study of the Short Term Safety and Efficacy of Inhaled L-arginine in Patients With Cystic Fibrosis]. clinicaltrials.gov/ct2/show/NCT00405665 (first posted 30 November 2006).
IRCT20180307038994N1 {published data only}
    1. IRCT20180307038994N1. Comparison of the nebulized mannitol with nebulized hypertonic saline on pulmonary function in patients with cystic fibrosis. trialsearch.who.int/Trial2.aspx?TrialID=IRCT20180307038994N1 (first received 15 April 2018).
IRCT20191112045413N2 {published data only}
    1. IRCT20191112045413N2. Study the Effectiveness of Outpatient treatment in Cystic Fibrosis Patients in Exacerbation Phase. trialsearch.who.int/Trial2.aspx?TrialID=IRCT20191112045413N2 (first registered 14 February 2020).
IRCT20201017049055N1 {published data only}
    1. IRCT20201017049055N1. Evaluation of the effectiveness of 7% plus hypertonic saline in comparison with 7% hypertonic saline in reducing the growth of Pseudomonas aeruginosa in lung of the patient with cystic fibrosis disease. trialsearch.who.int/Trial2.aspx?TrialID=IRCT20201017049055N1 (first registered 23 April 2021).
King 1997 {published data only}
    1. King M, Dasgupta B, Tomkiewicz RP, Brown NE. Rheology of cystic fibrosis sputum after in vitro treatment with hypertonic saline alone and in combination with recombinant human deoxyribonuclease. American Journal of Respiratory and Critical Care Medicine 1997;156(1):173-7. - PubMed
Kobylyansky 2000 {published data only}
    1. Kobylyansky VI, Gembitskaya TE. Study of the mucociliary and cough clearance in patients with mucoviscidosis and evaluation of hypertonic sodium chorlide solution influence on them. European Respiratory Journal 2000;16(Suppl 31):121S. [CFGD REGISTER: BD111] 5500100000002413
NCT01094704 {published data only}
    1. NCT01094704. Durability of hypertonic saline for enhancing mucociliary clearance in cystic fibrosis. clinicaltrials.gov/show/NCT01094704 (first posted 29 March 2010).
Nenna 2017 {published data only}
    1. ISRCTN13412080. Effects of inhaled hypertonic saline in children with cystic fibrosis [Effects of inhaled hypertonic (7%) saline on lung function test in preschool children with cystic fibrosis: a crossover, randomized clinical trial]. trialsearch.who.int/Trial2.aspx?TrialID=ISRCTN13412080 (first registered 6 July 2016).
    1. Nenna R, Midulla F, Lambiase C, De Castro G, Zicari AM, Indinnimeo L, et al. Effects of inhaled hypertonic (7%) saline on lung function test in preschool children with cystic fibrosis: results of a crossover, randomized clinical trial. Italian Journal of Pediatrics 2017;43(1):60. [CFGD REGISTER: BD238] [DOI: 10.1186/s13052-017-0376-6] - DOI - PMC - PubMed
O'Neill 2017 {published data only}
    1. NCT01753869. Timing of hypertonic saline inhalation relative to airways clearance in cystic fibrosis [Timing of hypertonic saline inhalation relative to airways clearance in cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT01753869 (first posted 20 December 2012). [CFGD REGISTER: BD231c]
    1. O'Neill K, Moran F, Tunney MM, Elborn JS, Bradbury I, Downey DG, et al. Timing of hypertonic saline and airway clearance techniques in adults with cystic fibrosis during pulmonary exacerbation: pilot data from a randomised crossover study. BMJ Open Respiratory Research 2017;4(1):e000168. [CFGD REGISTER: BD231b] [DOI: 10.1136/bmjresp-2016-000168] - DOI - PMC - PubMed
    1. O’Neill K, Moran F, Bradbury I, Downey DG, Rendall J, Tunney MM, et al. Exploring the timing of hypertonic saline (HTS) and airways clearance techniques (ACT) in cystic fibrosis (CF): a cross over study. Thorax 2016;71(Suppl 3):A134-5. [CFGD REGISTER: BD231a]
Ros 2012 {published data only}
    1. Ros M, Casciaro R, Lucca F, Alatri F, Salonini E, Favilli F, et al. Tolerability and acceptability in patients with cystic fibrosis (CF) of two formulations of 7% hypertonic saline: a prospective multicenter clinical study. Pediatric Pulmonology 2012;47(S35):364. [ABSTRACT NO.: 390] [CFGD REGISTER: BD181a] 5500100000011650
    1. Ros M, Casciaro R, Lucca F, Troiani P, Salonini E, Favilli F, et al. Hyaluronic acid improves the tolerability of hypertonic saline in the chronic treatment of cystic fibrosis patients: a multicenter, randomized, controlled clinical trial. Journal of Aerosol Medicine and Pulmonary Drug Delivery 2014;27(2):133-7. [CFGD REGISTER: BD181b] - PubMed
Ruiz de Valbuena Maiz 2012 {published data only}
    1. NCT01377792. Study of long-term treatment with hypertonic saline in patients with cystic fibrosis [Phase 4 study of the efficacy of long-term treatment with hypertonic saline on pulmonary exacerbations in patients with cystic fibrosis]. clinicaltrials.gov/ct2/show/NCT01377792 (first received 21 June 2011). [CFGD REGISTER: BD182b]
    1. Ruiz de Valbuena Maiz M, Lamas A, Maiz L, Giron R, Barrio M, Campo R, et al. Study of the efficacy of long-term treatment with high volume compared to standard volume of hypertonic saline on pulmonary exacerbations in patients with cystic fibrosis. Pediatric Pulmonology 2012;47 (S35):360. [ABSTRACT NO: 379: 379] [CFGD REGISTER: BD182a]
San Miguel‐Pagola 2016 {published data only}
    1. Herrero Cortina B, San Miguel Pagola M, Cebria i Ranzo MA, Gomez Romero M, Diaz Gutierrez F, Reychler G. Short-term effects of hypertonic saline nebulization combined with oscillatory positive expiratory pressure in cystic fibrosis:randomised crossover trial. Journal of Cystic fibrosis 2016;15 Suppl 1:S33. [ABSTRACT NO.: WS21.3] [CFGD REGISTER: BD229a] - PubMed
    1. NCT02303808. Positive expiratory pressure during inhalation of hypertonic saline in patients with cystic fibrosis [Effect of introducing a positive expiratory pressure device during inhalation of hypertonic saline in patients with cystic fibrosis: a randomized crossover trial]. clinicaltrials.gov/ct2/show/NCT02303808 (first received 01 December 2014).
    1. San Miguel Pagola M, Herrero Cortina B, Cebria i Iranzo MA, Gomez Romero M, Diaz Gutierrez F, Reychler G. Hypertonic saline nebulization combined with oscillatory positive expiratory pressure accelerate sputum clearance in cystic fibrosis: A randomised crossover trial. European Respiratory Journal 2016;48(Suppl 60):PA1369. [CFGD REGISTER: BD229b] - PubMed
    1. San Miguel-Pagola M, Reychler G, Cebria i Iranzo MA, Gomez-Romero M, Diaz-Gutierrez F, Herrero-Cortina B. Impact of hypertonic saline nebulisation combined with oscillatory positive expiratory pressure on sputum expectoration and related symptoms in cystic fibrosis: a randomised crossover trial. Physiotherapy 2020;107:243-51. [CFGD REGISTER: BD229d] - PubMed
Tiddens 2022 {unpublished data only}
    1. ACTRN12615001067561. Saline hypertonic in preschoolers with cystic fibrosis and lung structure as measured by computed tomography (CT) [A Phase 3 randomised, double-blind, controlled trial of inhaled 7% hypertonic saline versus 0.9% isotonic saline for 48 weeks on lung structure in patients with cystic fibrosis at 3-6 years of age, in parallel with the North American SHIP clinical trial, as measured by computed tomography (CT)]. apps.who.int/trialsearch/Trial3.aspx?trialid=ACTRN12615001067561 (first received 13 October 2015).
    1. EUCTR2015-004143-39-NL. Saline hypertonic in preschoolers and lung structure as measured by computed tomography [A Phase 3 randomised, double-blind, controlled trial of inhaled 7% hypertonic saline versus 0.9% isotonic saline for 48 weeks in patients with Cystic Fibrosis at 3-6 years of age in parallel with the North American SHIP clinical trial - Ship-CT study]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2015-004143-39-NL (first received 21 December 2015). [CENTRAL: CN-01854740] [CFGD REGISTER: BD262c]
    1. ISRCTN13083896. Saline hypertonic in preschoolers with cystic fibrosis and lung structure as measured by computed tomography (CT). trialsearch.who.int/Trial2.aspx?TrialID=NTR5502 (date first registered 29 September 2015). [CFGD REGISTER: BD262g]
    1. NCT02950883. Saline hypertonic in preschoolers + CT (SHIP-CT) [Saline hypertonic in preschoolers with cystic fibrosis and lung structure as measured by computed tomography (CT)]. clinicaltrials.gov/ct2/show/NCT02950883 (first received 01 November 2016).
    1. NTR5502. Saline hypertonic in preschoolers and lung structure as measured by computed tomography [A Phase 3 randomised, double-blind, controlled trial of inhaled 7% hypertonic saline versus 0.9% isotonic saline for 48 weeks in patients with Cystic Fibrosis at 3-6 years of age in parallel with the North American SHIP clinical trial - Ship-CT study]. www.who.int/trialsearch/Trial2.aspx?TrialID=NTR5502 2015. [CENTRAL: CN-01880673] [CFGD REGISTER: BD262d]
Van Ginderdeuren 2008 {published and unpublished data}
    1. Van Ginderdeuren F, Verbanck S, Van Cauwelaert K, Vanlaethem S, Schuermans D, Vincken W, et al. Chest physiotherapy in cystic fibrosis: short-term effects of autogenic drainage preceded by wet inhalation of saline versus autogenic drainage preceded by intrapulmonary percussive ventilation with saline. Respiration 2008;76(2):175-80. [CFGD REGISTER: BD178] - PubMed
Van Ginderdeuren 2011 {published data only}
    1. Van Ginderdeuren F, Vanlaethem S, Eyns H, De Schutter I, Dewachter E, Malfroot A. Influence of inhaled hypertonic saline (NaCl 6%) before or during autogenic drainage on sputum weight, oxygen saturation, heart frequency and dyspnea in cystic fibrosis patients. Journal of Cystic Fibrosis 2011;10(Suppl 1):S62. [CFGD REGISTER: BD164]
Vanlaethem 2008 {published data only}
    1. Vanlaethem S, Van Ginderdeuren F, Eyns H, Malfroot A. Influence of inhaled hypertonic saline combined with airway clearance on SpO2, heart rate, dyspnoea and wet sputum weight in hospitalised CF patients. Journal of Cystic Fibrosis 2008;7(Suppl 2):S71. [CENTRAL: 643104] [CFGD REGISTER: BD129]

References to studies awaiting assessment

Balinotti 2015 {published data only}
    1. Balinotti J, Rodriguez V, Zaragoza S, Lubovich S, Kofman C, Garcia Bournissen F. Effect of early intervention with inhaled hypertonic saline on lung function in infants and toddlers with cystic fibrosis diagnosed by neonatal screening. American Journal of Respiratory and Critical Care Medicine 2015;191(Meeting Abstracts):A3342. [CENTRAL: 1127230] [CFGD REGISTER: BD227b]
    1. Teper A, Balinotti J, Rodriguez V, Zaragoza S Lubovich S, Kofman C, Garcia Bournissen F. Effect of early intervention with inhaled hypertonic saline on lung function in infants and toddlers with cystic fibrosis (CF) diagnosed by neonatal screening. Journal of Cystic Fibrosis 2015;14 Suppl 1:S49. [ABSTRACT NO.: ePS04.8] [CFGD REGISTER: BD227a]
Dwyer 2013 {unpublished data only}
    1. ACTRN12610000754044. Trial of different concentrations of nebulised saline for cystic fibrosis saline at lower tonicity in cystic fibrosis (SALTI-CF) trial [The effect of nebulised 0.9% vs 3% vs 6% saline on lung function and quality of life in people with cystic fibrosis]. apps.who.int/trialsearch/Trial3.aspx?trialid=ACTRN12610000754044 (first received 13 September 2010).
    1. Dwyer T, Elkins M, Dentice R, Forbes S, MacArthur M, Cooper P, et al. Saline at a lower tonicity in cystic fibrosis (SALTI-CF) trial - a randomised controlled trial comparing 0.9% v 3% v 6% nebulised saline. Journal of Cystic Fibrosis 2013;12 Suppl 1:S19. [ABSTRACT NO.: WS9.5] [CFGD REGISTER: BD186]
Hofmann 1997 {published data only}
    1. Hofmann T, Senier I, Ziersch A, Geidel C, Regnis J, Lindemann H. Additive effects of amiloride and hypertonic saline on respiratory ion transport in cystic fibrosis [abstract]. In: Proceedings of the 21st European Cystic Fibrosis Conference; 1997; Davos. 1997:119. [CFGD REGISTER: BD75]
Lennox 2016 {published data only}
    1. Lennox A, Brown S, Corcoran TE, Myerburg MM, Pilewski JM. Pilot study of inhaled sodium bicarbonate: safety and ph changes after 1-2 doses. Pediatric Pulmonology 2016;51 (Suppl 45):281. [ABSTRACT NO.: 236] [CFGD REGISTER: BD255a]
    1. NCT03391414. Effects of inhaled bicarbonate on airway pH in cystic fibrosis. clinicaltrials.gov/show/NCT03391414 (first posted 5 January 2018). [CFGD REGISTER: BD255b]
Palacio 2014 {published data only}
    1. Palacio S, Giugno H, Diaz Casaux A, Lucero B, Smith S, Giorgetti M, et al. Inhaled 7% hypertonic saline treatment in preschool children with cystic fibrosis [abstract]. Journal of Cystic Fibrosis 2014;13 Suppl 2:S7, Abstract no: WS3.5. [CENTRAL: 1000053] [CFGD REGISTER: BD205]
SIMPLIFY 2022 {published data only}
    1. Mayer-Hamblett N, Nichols DP, Odem-Davis K, Riekert KA, Sawicki GS, Donaldson SH, et al. Evaluating the impact of stopping chronic therapies after modulator drug therapy in cystic fibrosis: The SIMPLIFY Clinical Trial Study Design. Annals of the American Thorac Society 2021;18(8):1397-405. [CFGD REGISTER: BD315b] [DOI: 10.1513/AnnalsATS.202010-1336SD] - DOI - PMC - PubMed
    1. Mayer-Hamblett N, Ratjen F, Russell R, Donaldson SH, Riekert KA, Sawicki GS, et al. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials. Lancet Respiratory Medicine 2022 Nov 4 [Epub ahead of print]:S2213-2600(22)00434-9. [CFGD REGISTER: BD315c] [DOI: 10.1016/S2213-2600(22)00434-9] - DOI - PMC - PubMed
    1. NCT04378153. Impact of Discontinuing Chronic Therapies in People With Cystic Fibrosis on Highly Effective CFTR Modulator Therapy (SIMPLIFY). clinicaltrials.gov/ct2/show/NCT04378153 (first posted 7 May 2020). [CFGD REGISTER: BD315a]

References to ongoing studies

ISRCTN14081521 {published data only}
    1. ISRCTN14081521. A randomised open-label trial to assess change in respiratory function for people with cystic fibrosis (pwCF) established on triple combination therapy (Kaftrio™) after rationalisation of nebulised mucoactive therapies (the CF STORM trial). trialsearch.who.int/Trial2.aspx?TrialID=ISRCTN14081521 (first posted 31 March 2021).
NCT02343445 {unpublished data only}
    1. NCT02343445. Clearing lungs with ENAC inhibition in cystic fibrosis (CLEAN-CF) [A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of P-1037 solution for inhalation in patients with cystic fibrosis (CF)]. clinicaltrials.gov/ct2/show/NCT02343445 (first posted 22 January 2015).

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References to other published versions of this review

Wark 1999
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Wark 2003
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Wark 2009
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Wark 2018
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