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Three Part Question

In [older children and adults with stable cystic fibrosis who have failed to show improvement with rhDNase] does [treatment with nebulised hypertonic saline] improve [lung function (FEV1) and pulmonary exacerbation rate compared to 0.9% saline]?

Clinical Scenario

You see a 9-year-old girl with stable cystic fibrosis in your outpatient clinic and review her treatment regime with regard to lung function. Over the last 4 months she has been on nebulised recombinant deoxyribonuclease (rhDNase) 2.5 mg once daily, but her lung function has not shown any improvement. She has also had one pulmonary exacerbation requiring intravenous antibiotics over this period. You are aware that although rhDNase is widely used in the management of lung disease in cystic fibrosis, approximately 50% of patients may gain no clinically significant benefit,(Fuchs, Ballman, Suri 2001) and studies have shown that response after a 3-month trial of therapy is a good predictor of longer term response (Davies, Suri 2004) Given that your patient may be a poor responder to rhDNase, you wonder if treatment with nebulised hypertonic saline would improve pulmonary outcomes.

Search Strategy

Pubmed
Searching the Cochrane library with the terms ‘hypertonic saline’ AND ‘cystic fibrosis’ returned three reviews, one of which was relevant. From this review three articles were relevant and were extracted for analysis
Pubmed:limited to clinical trials, randomised control trials (RCTs) and meta-analyses using the terms “Saline Solution, Hypertonic”[Mesh] AND “Cystic Fibrosis”[Mesh] was carried out. The search returned five articles since the publication of the Cochrane Review, three of which were relevant. Of these, one article used data previously published and included in the Cochrane Review

Search Outcome

5 papers were relevant

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ballmann and von der Hardt 2002	14 patients, mean (SD) age 13.3 (2.9) years with stable disease. Mean (SD) FEV1 75.6% (14%) of predicted value. Patients inhaled 10 ml HS twice daily or 2.5 mg rhDNase once daily for 3 weeks.	Open-labelled randomised cross-over trial (level b)	FEV at 3 weeks	Increased by 7.7% (SD 14%) compared to baseline after treatment with HS. 60% of patients gained no clinically significant benefit from rhDNase.* Of these, 50% gained a clinically significant benefit from HS, similar to the overall percentage of patients gaining the same benefit from HS (40%).	Small study, short duration and no control group. Concentration of HS not stated. No mention of whether an intention-to-treat analysis had been used. Authors state that there were no phase or carryover effects. An improvement of at least 10% in FEV1 was judged clinically significant
Suri et al, 2004	48 patients, age 7–17 years with stable disease. Mean (SD) FEV1 48% (15%) of predicted value. Patients inhaled 5 ml of 7% HS twice daily, 2.5 mg rhDNase once daily, or 2.5 mg rhDNase on alternate days, for 12 weeks.	Open-labelled randomised cross-over trial (level 2b)	FEV (at 12 weeks).	Increased by 3% (SD 21%) compared to baseline after treatment with HS (p value not provided).	No control group. Unstable baseline, possible carryover effects. Authors warn that effects of HS may have been masked by beneficial effects of treatment with rhDNase. Individual patient results were not described, so further analysis was not possible
			Pulmonary exacerbations	50% of patients gained no clinically significant benefit from rhDNase. Of these, 30% gained a clinically significant benefit from HS, similar to the overall percentage of patients gaining the same benefit from HS (35%). No significant difference in the number of exacerbations between the two groups
Eng et al, 1996	52 patients, ≥7 years of age with stable disease. FEV1 30–70% of predicted value. Patients inhaled 10 ml of either 6% HS or 0.9% saline twice daily for 2 weeks.	Open- labelled RCT (level 1b)	FEV at 2 weeks	Significant improvement from baseline in HS group compared to IS (15% vs 2.8%, p=0.004	Short duration. No mention of whether an intention-to-treat analysis had been used. rhDNase not used by any of the patients.
Elkins et al, 2006	164 patients, ≥6 years of age with stable disease. FEV1 ≥40% of predicted value. Patients inhaled 4 ml of either 7% HS or 0.9% saline twice daily for 48 weeks.	Double-blind RCT (level 1b)	FEV1 (averaged over 48 weeks of treatment).	As a percentage of individual baseline values, FEV1 was 3.2% higher in HS group (95% CI 0.1% to 6.2%) than IS group.	Modest improvement in lung function. CIs of the two groups overlapped at all time points. Impressive decrease in exacerbation rate but largely confined to the first 3 months. Analysis of the effect of HS in non-responders to rhDNase could not be carried out from the data provided
			Pulmonary exacerbations (over 48 weeks of treatment)	Relative reduction of 56% in favour of HS group (p=0.02). Exacerbation-free survival after 48 weeks, as measured by requirement for antibiotic therapy, was significantly greater in HS group (76% of patients vs 62%, p=0.03). Effects of HS on either outcome did not differ between users and non-users of rhDNase.
Donaldson et al, 2006	24 patients, ≥14 years of age with stable disease. FEV1 ≥50% of predicted value. Patients inhaled 5 ml of 7% HS four times daily with or without pretreatment with amiloride over 2-week baseline and treatment periods.	Randomised parallel group trial (level 2b)	FEV, (forced expiratory volume in 1 s)	Mean difference between HS treatment period and baseline was 6.62% (95% CI 1.6% to 11.7%; p=0.02).	Small study, short duration. Randomisation method not described. No IS group, so effects of HS could only be compared to baseline. Effect of HS between users and non-users of rhDNase not examined. An improvement of at least 10% in FEV1 was judged clinically significant

Comment(s)

Given our clinical question, two points must be addressed. First, does hypertonic saline improve pulmonary outcomes in cystic fibrosis? If so, would it specifically benefit patients in whom rhDNase therapy has failed? The outcome measures looked at were FEV1 and number of pulmonary exacerbations as they are commonly used predictors of long-term morbidity and mortality (Liou).

Across trials, nebulised hypertonic saline produced a modest improvement in lung function. Confidence intervals for gain in FEV1, however, are wide, suggesting that some patients using hypertonic saline may gain significant benefit, while others may gain none or may even get worse. The variation in the improvement seen between trials may be related to the volume of saline used: Elkins et al, Donaldson et al and Suri et al all used 5 ml of hypertonic saline or less and reported smaller improvements in lung function compared to Ballmann and von der Hardt and Eng et al, who used 10 ml of hypertonic saline. The trial by Elkins et al offers the first evidence of long-term efficacy of hypertonic saline in patients with cystic fibrosis. Significantly, it reports a marked reduction in the frequency of pulmonary exacerbations. The divergence between the small improvements in lung function and large reductions in the frequency of exacerbations reported raises questions as to which outcomes measures are most useful.

Data focusing specifically on whether subgroups of patients with cystic fibrosis respond better to rhDNase or hypertonic saline, or whether response to one predicts response to the other, are limited. The long-term trial by Elkins et al showed that the beneficial effects of hypertonic saline on both outcome measures were independent of concurrent use of rhDNase. Patients with a modest response to rhDNase may therefore benefit from using hypertonic saline as an adjuvant therapy. The crossover trials by Ballmann and von der Hardt and Suri et al, whose results should be interpreted with caution due to possible phase and carryover effects, showed a large variation in response to rhDNase and hypertonic saline, raising the possibility that some individuals may respond better to one treatment compared to the other. Both trials suggested that a poor response to rhDNase did not predict a poor response to hypertonic saline. In fact, patients on rhDNase whose FEV1 increased by ≤10% (poor responders) had a similar likelihood of showing a clinically significant (≥10%) increase in FEV1 with hypertonic saline as any other patient. Therefore, in patients who respond poorly to rhDNase, hypertonic saline may still be useful for improving lung function.

Concerns still remain with regard to certain practical issues. Hypertonic saline used as an adjuvant to rhDNase would be very time consuming for the patient, which is an important factor for adherence. Hypertonic saline is also associated with symptoms of cough, chest tightness, pharyngitis or wheeze in 8% of patients. In the long-term trial by Elkins compliance with hypertonic saline was only 64%.8 Four per cent of patients also do not tolerate hypertonic saline due to acute bronchospasm, hence assessment of tolerability at the commencement of therapy is important.

Editor Comment

FEV1, forced expiratory volume in 1 s; HS, hypertonic saline; rhDNase, recombinant deoxyribonuclease; IS, isotonic saline.

Clinical Bottom Line

Hypertonic saline improves lung function (FEV1) and pulmonary exacerbation rate in older children and adults with stable cystic fibrosis. (Grade B)

Patients who respond poorly to rhDNase may still benefit from treatment with hypertonic saline. (Grade C)

References

1. Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637–42.
2. Ballmann M, von der Hardt H. Hypertonic saline and recombinant human DNase: a randomised cross-over pilot study in patients with cystic fibrosis. J Cyst Fibros 2002;1:35–7
3. Suri R, Metcalfe C, Lees B, et al. Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Lancet 2001;358:1316–21
4. Davies J, Trindade MT, Wallis C, et al. Retrospective review of the effects of rhDNase in children with cystic fibrosis. Pediatr Pulmonol 1997;23:243–8.
5. Suri R, Metcalfe C, Wallis C, et al. Predicting response to rhDNase and hypertonic saline in children with cystic fibrosis. Pediatr Pulmonol 2004;37:305–10.
6. Wark PA, McDonald V, Jones AP. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev 2005;3:CD001506.
7. Eng PA, Morton J, Douglass JA, et al. Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatr Pulmonol 1996;21:77–83.
8. Elkins MR, Robinson M, Rose BR, et al. National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006;354:229–40.
9. Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med 2006;354:241–50.
10. Liou TG, Adler FR, Fitzsimmons SC, et al. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001;153:345–52.
11. Smith G. A patient's view of cystic fibrosis. J Adolesc Health Care 1986;7:134–8.
12. Bye PT, Elkins MR. Other mucoactive agents for cystic fibrosis. Paediatr Respir Rev 2007;8: 30–9