Effects of inhaled hypertonic (7%) saline on lung function test in preschool children with cystic fibrosis: results of a crossover, randomized clinical trial

Cystic fibrosis (CF) is the most common hereditary disease in Caucasians. It is caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel. This mutations lead to an abnormal ion transport across the respiratory epithelium with a defective chloride secretion and excessive sodium absorption that finally cause dehydration of the airway surface liquid. The disruption of mucociliary clearance, apparently closely dependent on the presence of an inadequate volume of airway surface liquid, plays a basic role in the vicious cycle of airway obstruction, infection, inflammation and lung damage [1]. According to this hypothesis, inhaled hypertonic saline (HS) represents a well-documented therapy in adults [1, 2], as the already established but very expensive treatment with rhDNase [2, 3].

The effects of the HS on pulmonary function tests have been assessed in young children with CF [4‐6], providing to be associated with an improvement in lung function and marked benefits with respect to exacerbations [7].

This crossover, randomized double-blind study was designed to determine as primary outcomes, in preschool children with CF: the effects of an inhaled hypertonic solution on spirometry (measured as follows: forced volume vital capacity – FVC, forced expiratory volume in 1 s - FEV1 and forced expiratory flow 25–75% - FEF25-75) and airways resistance assessed by The Interrupter technique (Rint). As secondary outcome the possible side effects of the treatment were evaluated.

Insofar as 1 child had respiratory infections, he was excluded. A total of 12 children (six males, mean age ± SD: 5.7 ± 0.8 years) with a confirmed diagnosis of cystic fibrosis were enrolled (Table 1).

All the 12 patients completed the entire protocol. At T0 no differences were found in terms of mean FVC, FEV1 and FEF25-75 as well as mean expiratory and inspiratory Rint between HS and NS groups. The sputum following administration of HS were almost unchanged during the study protocol (not colonization with Burkholderia Cepacia nor new respiratory infections). We did not record any exacerbations of respiratory infections in both groups.

At T0 after bronchodilator, significant improvements of FVC, FEV1 and FEF25-75 were found in both groups (HS: FVC: 1.36 ± 0.4vs1.42 ± 0.4 L, p = 0.008; FEV1: 1.08 ± 0.2vs1.25 ± 0.4 L, p = 0.045; FEF25-75: 1.31 ± 0.3vs1.43 ± 0.2 L/s, p = 0.009. NS: FVC: 1.23 ± 0.3vs1.31 ± 0.4 L, ns; FEV1: 1.09 ± 0.3vs1.25 ± 0.2 L, p = 0.001; FEF25-75: 1.35 ± 0.3vs1.51 ± 0.4 L/s, p = 0.027). Significant Rint reductions were also measured (HS: Rint exp.: 1.51 ± 0.2vs1.25 ± 0.2 KPa, p < 0.0001; Rint insp.: 1.40 ± 0.2vs1.26 ± 0.2 KPa, p = 0.018. NS: Rint exp.: 1.49 ± 0.4vs1.23 ± 0.2 KPa, p = 0.029; Rint insp.:

After a 4-weeks treatment with HS, as compared to baseline values, only an improvement of %predicted FVC (p = 0.048) was found (Table 2). Worsening of %predicted FVC (p = 0.01), FEV₁ (p < 0.0001), %predicted FEV₁ (p < 0.0001), %predicted FEF_25-75 (p = 0.001), FEF25-75 (p = 0.012) and expiratory Rint (p = 0.02) was detected in NS groups (Table 3).

After a 16-weeks treatment with HS, as compared to baseline values, an improvement of FVC (p = 0.02) and %predicted FVC (p = 0.02) was found. A favorable trend of FEV1 was registered, although it failed to reach statistical significance. The mean values of expiratory and inspiratory resistance remained substantially unchanged (Table 2). On the contrary, a significant worsening of FEV₁ (p < 0.0001) and FEF_25-75 (p = 0.019) were found after the treatment with normal saline (Table 3).

The mean FVC, FEV1 and FEF25-75 improvements as well as expiratory and inspiratory Rint reductions, between T0 and T16 were higher in HS than in NS group, however, these were not-significant (data not shown).

Figure 2 graphically represents the mean absolute difference in FVC, FEV1, FEF25-75 and expiratory and inspiratory Rint from the baseline at T0, T4 and T16 for the two treatment groups. Inspection of the data showed that spirometric and Rint parameters appeared to constantly improve at T0 and T16 in HS group but remained essentially unchanged at T4 and slightly improved at T16 in NS group.

No serious adverse events occurred in both groups. In the HS group, cough was observed (two patients) and, generally, disappeared after the first administration of HS, while one child complained about the unpleasant taste.

The present double-blind, randomized crossover study on 12 preschool children with cystic fibrosis, in clinically stable conditions, shows that the inhalation of HS twice daily is a safe treatment. To our knowledge, this is the first study testing Rint technique, an objective measurement of lung function in this range age [10, 12‐14], over a course of HS treatment in children with cystic fibrosis. Our data, seems to confirm, on a little young population in the early phase of lung involvement, the short and middle-term benefits of HS, widely described in literature on adult patients [1, 2, 7, 15, 16]. In fact, a significant improvement of spirometric parameters was registered after 16-week HS therapy, while a worsening of those parameters was found in NS group. Similarly, Rosenfeld et al. have demonstrated a significant improvement of FEV0.5 in the group of 7% HS children younger than 6 years with cystic fibrosis, even if a reduction of pulmonary exacerbations was not reached [6]. These small changes may reflect a trend of improvement in airway performance that may result in clinically relevant implications. Subbarao et al. [4] was the pilot study that analyzed the utility, safety and tolerability of HS in children. The sole previous study on lung functions (by spirometry and the raised volume rapid thoracoabdominal compression technique) in preschool children (5.7 ± 0.8 years) with cystic fibrosis who had received HS therapy was by Dellon et al. [5].

The favorable effect of inhaled HS on airway is carried out by several postulated molecular mechanisms: HS breaks ionic bonds within the mucus and shields the negative charges thereby reducing the viscosity of secretions; it rehydrates airway surface improving mucus rheology; finally, it induces cough [1, 17, 18]. Moreover, HS contributes to the improvement of expiratory as well as inspiratory reduction of airway resistances by reducing the inflammatory edema of the airway.

In our small series, HS proved to be a safe and tolerable treatment. The most common adverse event expected with the introduction of the therapy were cough, throat irritation and unpleasant salty taste [2]. In our study two patients referred an increase of cough and one complained about oropharyngeal irritation. Cough typically decreased over time. However, we used a premedication with bronchodilator to prevent airway bronchoconstriction.

The present study may be of interest also from a methodological point of view, because it is the first to utilize the interrupter resistance technique, the gold standard for this age range, to assess lung function in preschool children. In fact, measurement of lung function in young children may be difficult and is prone to an increased failure rate and increased variability. Conventional lung function tests such as spirometry and body plethysmography have limited application because these techniques require a high degree of understanding and cooperation of the subject [19, 20].

Children in this age group are too old to be sedated but are unable to actively cooperate in many of the physiological maneuvers required for the lung function tests. Probably for this reason, statistically significant results of FEV1 with the spirometry have not been obtained.

Rint and spirometry reflect different aspects of the lung function and are not exactly interchangeable: Rint is more affected by large airway function and it measures the total resistance system and some added chest wall resistance. Moreover, it is a quick, noninvasive measure of respiratory resistance during tidal breathing that may be more easily performed in the preschooler than spirometry [21, 22]. This technique appeared as a reliable tool in the diagnostic work-up of pulmonary function in young CF patients [10, 12‐14], even if its use that has been standardized by the ERS/ATS task force reported little evidence supporting the clinical utility in the preschool population with CF [22]. We consider that Rint and spirometry could play a role in the evaluation of pre-school children with CF because they may improve our ability to detect and treat early lung disease and exacerbations, particularly in pediatric respiratory centers where other more expensive techniques are not available.

Nowadays HS therapy may not be considered as an alternative treatment to rhDNase who has demonstrated a greater ability to improve lung function [3, 23‐25] and to reduce pulmonary complications, but we should always keep in mind that rhDNase therapy is expensive, and its use is currently restricted in many countries only for patients with moderate or severe respiratory effort.

The treatment with hypertonic solution is quite cheap and safe and permitted at least a short and middle-term improvement of the respiratory function. The recent availability of the formulation of HS together with hyaluronic acid may be helpful in further avoiding the cough and the burning sensation consequent to the sole HS [26]. However, in children with CF, to avoid the potential risk posed by contamination of HS solutions we should recommend to use sterile unit-dose formulations [27].

Some limitations may be identified in our study, particularly the small number of the series, the single-center enrollment and a lack of wash-out period between the baseline measures.

Moreover, we decided to evaluate CF children in stable conditions with quite normal spirometric and Rint parameters at the enrollment. Finally, we limited the lung function tests to spirometry and Rint, insofar as multiple-breath inert gas and forced oscillation technique were not available.

Seven percent hypertonic saline therapy seems to be a useful and safe treatment in young CF children with clinically stable conditions. Recently, the CF Foundation recommends that HS be offered to patients based on individual circumstances, either for chronic use or during acute pulmonary exacerbation [28]. Studies on larger series would be useful to define the effect of this therapy in particular on spirometric parameters and clinical outcomes.