Correspondence: Dr Sushil K. Kabra, Professor, Department of Pediatrics, AIIMS, New Delhi , India.

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1 JOURNAL OF TROPICAL PEDIATRICS, VOL. 58, NO. 5, 2012 Comparison of Effects of 3 and 7% Hypertonic Saline Nebulization on Lung Function in Children with Cystic Fibrosis: A Double-Blind Randomized, Controlled Trial by Sumita Gupta, 1 Faizan Ahmed, 2 Rakesh Lodha, 1 Y. K. Gupta, 3 and Sushil K. Kabra 1 1 Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India 2 Department of Rehabilitation Sciences, Jamia Hamdard, New Delhi, India 3 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India Correspondence: Dr Sushil K. Kabra, Professor, Department of Pediatrics, AIIMS, New Delhi , India. <skkabra@hotmail.com>. Summary Background: Beneficial effects of hypertonic saline on lung function in cystic fibrosis patients are well documented. However, the effects of various concentrations of hypertonic saline are not well studied. We, therefore, compared the effects of 3 and 7% hypertonic saline administered by nebulization on lung function in children with cystic fibrosis. Method: In a double-blind randomized controlled trial, 31 children with cystic fibrosis were randomized to receive either 3% saline or 7% saline nebulization twice daily for 28 days. Spirometry was performed and functional status was measured on Day 14 and 28. Results: Of 31 children enrolled in the study, 30 completed the 28 days follow up (15 in each group). Percentage change in Forced Expiratory Volume during first second (FEV 1 ) from baseline to Day 14 and on Day 28 was significantly higher in the group receiving 3% saline as compared with those receiving 7% saline inhalation. There was some decrease in FEV 1 (percentage predicted) immediately after 7% saline inhalation unlike 3% saline. The functional status remained comparable between the two groups. Conclusion: The results suggest that 3% hypertonic saline nebulization was better than 7% saline inhalation. There is a need for studies with larger sample size and longer duration to confirm our results. Key words: Cystic fibrosis, FEV 1, Forced Vital Capacity (FVC), Hypertonic saline. Introduction Cystic fibrosis is most common inherited life limiting illness among the Caucasian population. Respiratory manifestations are the major cause of morbidity and mortality [1]. Most of the studies on the pathogenesis of the lung disease in cystic fibrosis support the airway surface liquid volume hypothesis. According to this hypothesis, the defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene in the airways results in abnormal sodium, chloride and water movement across the epithelium, resulting in dehydration of pericellular environment, which in turn influences the mucus rheology and hence, the clearance of airway secretions. Thick, viscous mucus becomes the focus of repeated infections leading to lung damage [2 4]. Hypertonic saline is one of the various agents used to mobilize the secretions. Beneficial effects of hypertonic saline in improving lung function in cystic fibrosis patients are well documented [5 8]; however, little is known about the effects of increasing concentrations of hypertonic saline. Therefore, we compared the effects of 3 and 7% hypertonic saline administered by nebulization on lung function in children with cystic fibrosis. Acknowledgements We acknowledge Baxter Pharmaceuticals Limited for providing technical assistance for preparing the study drugs. Methods A double-blind randomized, controlled trial was conducted in the Pediatric Chest Clinic of All India Institute of Medical Sciences (AIIMS), New Delhi, India. Children suffering from cystic fibrosis ß The Author [2012]. Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 375 doi: /tropej/fms004 Advance Access published on 29 February 2012

2 and being followed up in the clinic were enrolled. The Ethics Committee of AIIMS approved the study. The trial was registered with the Clinical Trials Registry-India (CTRI/2010/091/001279). Inclusion criteria Children between the ages of 6 and 16 years, diagnosed with cystic fibrosis, on regular follow up for at least past 12 months, who were able to perform reproducible pulmonary function test, were eligible for the study. Diagnosis of cystic fibrosis was based on two abnormal sweat test results (sweat chloride > 60 meql) in the presence of suggestive clinical features. Exclusion criteria Children with a fall in FEV 1 by >15% following administration of bronchodilator and test dose of study drug by nebulization, those who required a change in antibiotic treatment during the past 4 weeks prior to enrollment and those not performing regular chest physiotherapy at home were excluded. Children who were already receiving hypertonic saline nebulization and whose parents/guardians were willing for participation of their child, were eligible for the study after discontinuation of hypertonic saline nebulization for 2 weeks. Procedure Written consent was obtained from the parent/guardian of each child. The subjects were randomized to receive either 3 or 7% hypertonic saline nebulization. All enrolled subjects were given a test dose following a bronchodilator in the hospital to look for bronchoconstriction. A detailed history and findings of physical examination were recorded. In addition, information about pseudomonas colonization and mutation analysis were recorded. Intervention The intervention solutions (sterile 3 and 7% saline solutions) were made available in transparent collapsible bags of equal volume. These solutions were prepared by the Department of Pharmacology, All India Institute of Medical Sciences, with technical assistance from Baxter Pharmaceuticals Limited as per Good Manufacturing Practices guidelines, using Indian Pharmacopeia grade sodium chloride and sterile, double-distilled water. The sterility of the solutions was confirmed by culturing sample from each lot. Five milliliter of intervention solution was dispensed in sterile single-use containers for 2 weeks at a time, once at enrollment and then at 2 weeks of follow-up. Following baseline spirometry, test dose of study drug was nebulized after priming with salbutamol nebulization (2.5 mg in children weighing <20 kg and 5 mg if weight 20 kg) and spirometry was repeated. If the spirometry after administration of the study drug showed that the fall in FEV 1 was <15% of the baseline, child was continued on study drug. The subjects were asked to inhale 5 ml of the test drug after taking the bronchodilator, twice daily, administered by a jet nebulizer, at home for next 28 days, as explained by the therapist. This was followed by regular chest physiotherapy session. Routine medications were continued throughout the study. All enrolled patients were followed up for 4 weeks (follow-up visits on Day 14 and 28). On each visit, clinical details were recorded, spirometry and 3-min step test [9] were performed. Thereafter, the child received bronchodilator nebulization followed by hypertonic saline nebulization. This was followed by repeat spirometry and performance of 3-min step test. Assessment of adherence Subjects were asked to return all unused containers of the saline solution and to maintain a diary to record the treatment doses taken to assess adherence to the treatment. Outcome variables The primary outcome was improvement in FEV 1 ; the secondary outcome variables were improvement in FVC, and functional capacity. Spirometry was performed according to the American Thoracic Society guidelines [10] using Super Spiro Micromedics UK and functional capacity was assessed using 3-min step test. For 3-min step test, the subject was asked to step up and down a 15 cm height single step for 3 min at the rate of 30 steps per minute regulated by a metronome [9]. Metronome is a device that produces regular, metric beats-settable in beats per minute. The outcomes of functional capacity were assessed by measuring the Peak Expiratory Flow Rate (PEFR), oxygen saturation, heart rate, visual analog scale, 15-count score, pre- and post-3-min step test during each contact. PEFR was measured using a Wright s Peak flow meter. Child was asked to take a deep breath and then blow as hard and as fast as he/she could. The whole procedure was done thrice and the highest reading was recorded. Saturation and heart rate were recorded using a pulse oximeter. Visual Analogue Scale (VAS) and 15-count score were used to measure the perceived feeling of breathlessness. VAS was measured using a 10 cm long horizontal line, indicating no breathlessness on left-hand side and extreme breathlessness on the right-hand side (score of 10). The child marked on the line the point that he felt represented his perception of current state of breathlessness. The VAS score was determined by measuring in centimeters from the left hand end of the line to the point that the patient marked. To measure 15-count score [11] the child was asked to take a deep breath and then count out loud to Journal of Tropical Pediatrics Vol. 58, No. 5

3 The number of breaths taken to count was the score. Higher count indicated increased breathlessness. Randomization and blinding Random sequence was generated using a computer program by a person not involved in the study. The intervention solutions (sterile 3 and 7% saline solutions) were sequentially numbered as per the random number list by another person not involved in the study. The collapsible bags were similar in appearance. Sample size With the hypothesis that at end of 28 days 3 and 7% saline will produce similar improvement in FEV 1 with <10% difference with -error of 5% and power of study 80%, the sample size required is 394 patients in each group. This was not possible due to logistic reasons. Therefore, we conducted a pilot study with 15 patients in each group. Statistical tests The measurements that were used to analyze the long-term effects were those made prior to administration of the drugs on all the contact days. Student s t-test was used to analyze the difference between means such as FEV 1 and FVC. Chi-square test, Mann Whitney and Wilcoxon test were used to analyze non-parametric variables. Results Thirty-one children with cystic fibrosis were enrolled, 16 in 3% hypertonic saline group and 15 in 7% hypertonic saline group. Thirty children completed the study, 15 in each group (Fig. 1). Baseline characteristics The two groups had similar characteristics with respect to age, gender, height, weight, mutation score, clinical score, pulmonary function, functional status and clinical features (Table 1). Changes in pulmonary function The mean FEV 1 (percentage predicted) improved in both the groups from baseline to Day 28. The difference was not significant on Day 14 or Day 28 between the two groups (p > 0.05) (Table 2). The mean percentage change in FEV 1 on Days 14 and 28 was significantly high in group receiving 3% saline as compared with group receiving 7% saline (Table 3). FIG. 1. Trial profile. Journal of Tropical Pediatrics Vol. 58, No

4 TABLE 1 Baseline characteristics of children at the time of enrollment Characteristic 3% hypertonic saline n ¼ 15 7% hypertonic saline n ¼ 15 Age (years) Gender Male 9 (60.00) 13 (86.67) Female 6 (40.00) 2 (13.33) Height (cm) Weight (kg) Mutations Homozygous delta F (20.00) 1 (6.67) Heterozygous mutation 0 (0.00) 2 (13.33) Others mutations 9 (60.00) 7 (46.67) Mutation analysis not done 3 (20.00) 5 (33.33) Cough 11 (73.33) 12 (80.00) Wheeze 6 (40.00) 5 (33.00) Breathlessness 9 (60.00) 8 (53.30) FEV 1 (% predicted) FVC (% predicted) PEFR (l 1 min 1 ) Oxygen saturation (%) Heart rate (per min) Visual analogue scale (cm) count score (mean rank) The mean FVC was similar in both the groups at baseline, Days 14 and 28. The improvement in group receiving 3% saline was significantly more from baseline to Day 28; however, rest of intra-group comparisons did not show any statistically significant differences (Table 4). The mean percentage improvement in FVC was comparable on Day 14; however, the change from TABLE 2 Changes in percentage predicted FEV 1 in relation to time Contact day 3% hypertonic saline, 7% hypertonic saline, p-value Baseline Day Day p comparing baseline with Day 14: p comparing baseline with Day 14: p comparing baseline with Day 28: 0.036* p comparing baseline with Day 28: * p<0.05 Time period TABLE 3 Percentage change in FEV 1 in relation to time 3% hypertonic saline, 7% hypertonic saline, p-value Day 14 vs. Baseline * Day 28 vs. Baseline * * There is a significant difference between the two groups p<0.05 baseline to Day 28 was significantly more in group receiving 3% saline (Table 5). Untoward incidence There was no immediate reduction in FEV 1 following 3% hypertonic saline inhalation. However, the mean reduction in FEV 1 after 7% saline was 3.6% at baseline and 1.07% on Day Journal of Tropical Pediatrics Vol. 58, No. 5

5 TABLE 4 Changes in percentage predicted FVC in relation to time Contact day 3% hypertonic saline, 7% hypertonic saline, p-value Baseline Day Day p comparing baseline with Day 14: p comparing baseline with Day 14: p comparing baseline with Day 28: 0.003* p comparing baseline with Day 28: * p<0.05 Time period Functional capacity All the outcome variables studied for assessing functional capacity remained comparable between the two groups on Days 14 and 28 (Table 6). The mean PEFR showed improvement from l/min at baseline to l/min on Day 28 in 3% hypertonic saline groups and from 194 l/min at baseline to 212 l/min on Day 28 in 7% hypertonic saline group. The mean saturation changed from 96.3% at baseline to 97.3% on Day 28 in 3% hypertonic saline group and remained unchanged for 7% hypertonic saline group, which had a mean of 96.7%. The mean heart rate of the two groups was comparable with no significant change on all three evaluations. VAS and 15-count score were used to assess the degree of breathlessness. The VAS showed small insignificant improvements from 0.61 to 0.27 cm and from 0.31 to 0.3 cm in 3 and 7% hypertonic saline groups, respectively. The mean ranks of 15-count score of the two groups were comparable on all contact days with no significant difference. Discussion We planned this study to examine whether 3 and 7% saline inhalation provided similar improvement in the pulmonary function of children with cystic fibrosis. We observed that both concentrations of hypertonic saline had beneficial effects on pulmonary function. There was a significant difference in percentage change in FEV 1 between the two groups with a relatively greater improvement in 3% hypertonic saline group. The functional status and the clinical scores showed only minor changes with both the concentrations. TABLE 5 Percentage change in FVC in relation to time 3% hypertonic saline, 7% hypertonic saline, p-value Day 14 vs. Baseline Day 28 vs. Baseline * * p<0.05 Various studies have been conducted establishing the efficacy of hypertonic saline nebulization in improving mucociliary clearance in cystic fibrosis patients. Eng et al. [12] have documented an improvement of 15% in FEV 1 from baseline with 6% hypertonic saline as compared with isotonic saline. In a 48-week study done by Elkins et al. [8], there was an increase of 68 ml in FEV 1 and of 82 ml in FVC with 7% hypertonic saline as compared with 0.3 ml in FEV 1 and 0.5 ml in FVC with isotonic saline. In addition, there were a significantly higher percentage of patients without exacerbation in the hypertonic saline group. Most of the studies have compared varying concentration of hypertonic saline with isotonic saline and hypertonic saline has been documented to be more efficacious than isotonic saline [7, 8, 12, 13]. Other studies where hypertonic saline has been compared with other mucous mobilizing agents have shown that hypertonic saline is either better or almost comparable to the other drugs except Human Recombinant DNase (rhdnase) [14 19]. rhdnase has documented benefits in cystic fibrosis; however, being an expensive drug it is not within the reach of children with cystic fibrosis in the developing countries. In such a scenario, hypertonic saline represents a cost effective, potential alternative to improve mucociliary clearance in the context of long-term maintenance therapy. Worldwide, varying concentration of hypertonic saline are used for their mucociliary clearanceenhancing properties; however, the benefits of using higher concentration of hypertonic saline are not well explored. A study conducted by Robinson et al. [13] to compare the effects of increasing doses of hypertonic saline (0.9, 3, 7 and 12%) using Journal of Tropical Pediatrics Vol. 58, No

6 TABLE 6 The outcomes of functional capacity in two groups Variables Baseline Day 14 Day 28 3% saline 7% saline p-value 3% saline 7% saline p-value 3% saline 7% saline p-value PEFR (l/ min) SaO2 (%) Heart rate, per min Visual analogue scale (cm) Fifteen count score (mean rank) radio-aerosol technique concluded that the effects of hypertonic saline appears to be dose dependent. The effects of 3 and 7% hypertonic saline nebulization on lung function were found to be comparable but there was a significant increase in the percentage clearance after 1 h with 12% hypertonic saline solution compared with 3% hypertonic saline [13]. Results of our study suggest that the efficacy of two different concentrations of hypertonic saline were comparable with a significant percentage improvement with 3% hypertonic saline. In a study done by Smith et al. [20] it was found that increased NaCl concentrations inhibits bactericidal activity in the airway surface liquid. Many trials have documented a fall in FEV 1 and FVC following administration of higher concentration of hypertonic saline. There was a mean percentage fall in FEV 1 immediately after inhalation of 7% hypertonic saline (3.7%) and 12% hypertonic saline (4.9%) in the study done by Robinson et al. [13]. Elkins et al. [8] reported a fall of 94 ml in FEV 1 after the first dose of 7% hypertonic saline, which is greater than the reported final improvement in FEV 1 of 68 ml. Likewise in our study, even though both the groups received bronchodilators prior to hypertonic saline nebulization, we observed a fall in mean FEV 1 on Day 1 (3.6%) and on Day 28 ( 1.07%) in 7% hypertonic saline group immediately after nebulization and no fall was observed in 3% hypertonic saline group on either of the days. The probable reasons for the fall in FEV 1 with the use of higher concentration saline inhalation may possibly be due to bronchoconstriction, which may be further compounded with increased osmosis leading to accumulation of water in the smaller airways and obstructing them. With time, the water may be reabsorbed improving FEV 1. Rodwell et al. [21] in their study demonstrated hypersensitive response to hyperosmolar saline (10%) in cystic fibrosis subjects. According to them, transient airway narrowing of the airways could result from the possible movement of the hydrated mucus blocking the airways. Reversal of the narrowing occurred with coughing or when the mucus was expectorated or swallowed. A recent report raised the question of whether an increased concentration of hypertonic saline is useful or not as the authors have shown in their study that use of 3% hypertonic saline is effective and has the additional advantage of not causing a substantial change in FEV 1, oxygen saturation or symptom score [22, 23]. The functional status between the two groups was found to be comparable on all 3-contact days. There were insignificant changes in all the variables in both the groups. The clinical features also remained almost unchanged and comparable between the two groups. This may be attributed to the short duration of the study. 380 Journal of Tropical Pediatrics Vol. 58, No. 5

7 Another important aspect is the cost and the availability of drugs. Though both the drugs are cost effective, 3% hypertonic saline is easily commercially available in India unlike 7% hypertonic saline, which has to be specially compounded, posing some degree of inconvenience to the parents. Strengths of study This is a double-blind randomized, controlled study on children with Cystic Fibrosis comparing 3 and 7% saline. Earlier studies have compared hypertonic saline with isotonic saline. We tried to evaluate effect on pulmonary functions as well as functional status of children using two strengths of hypertonic saline. Summary and conclusion We conclude that 3% hypertonic saline nebulization is better than 7% hypertonic saline with fewer complications. Being widely available commercially, 3% saline has an additional advantage. There is a need for studies with larger sample size and longer duration to establish the comparability of effects of various concentrations of hypertonic saline and the potential side effects of higher concentrations of hypertonic saline. References 1. Davis PB. Cystic fibrosis since Am J Respir Crit Care Med 2006;173: Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion; not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998;95: Boucher RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004;23: Boucher RC. Cystic fibrosis: a disease of vulnerability to airway surface dehydration. Trends Mol Med 2007; 13: Tarran R, Donaldsen S, Boucher RC, et al. Rationale for hypertonic saline therapy for cystic fibrosis lung disease. Semin Respir Crit Care Med 2007;28: Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Eng J Med 2006;354: Riedler J, Reade T, Button B, et al. Inhaled hypertonic saline increase sputum expectoration in cystic fibrosis. J Paediatr Child Health 1996;32: Elkins MR, Robinson MR, Rose BR, et al. A controlled trial of long term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006;354: Narang I, Pike S, Rosenthal M, et al. Three-minute step test to assess exercise capacity in children with cystic fibrosis with mild lung disease. Pediatr Pulmonol 2003;35: Taussig LM, Chernick V, Wood R, et al. Standardization of lung function testing in children. J Pediatr 1980;97: Prasad SA, Randall SD, Balfour-Lynn IM, et al. Fifteen-count breathlessness score: an objective measure for children. Pediatr Pulmonol 2000;30: Eng PA, Morton J, Douglass JA, et al. Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatr Pulmonol 1996;21: Robinson M, Hemming AL, Regnis JA, et al. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Thorax 1997; 52: Robinson M, Regnis JA, Bailey DL, et al. Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis. Am J Respir Crit Care Med 1996;153: Ballmann M, Hardt HVD. Hypertonic saline and recombinant human DNase: a randomized cross-over pilot study in patients with cystic fibrosis. J Cyst Fibros 2002;1: 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 randomized trial. Lancet 2001;358: Adde FV, Borges KTL, Hatanaka ACF, et al. Hypertonic saline X recombinant human DNase a randomized cross-over study in 18 cystic fibrosis patients. J Cyst Fibros 2004;3(Suppl 1): Weller P, Ingram D, Preece M, et al. Controlled trial of intermittent aerosol therapy with sodium 2-mercaptoethane sulphonate in cystic fibrosis. Thorax 1980;35: Robinson M, Daviskas E, Eberl S, et al. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. Eur Respir J 1999;14: Smith JJ, Travis SM, Greenberg EP, et al. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 1996;85: Rodwell LT, Anderson SD. Airway responsiveness to hyperosmolar saline challenge in cystic fibrosis: a pilot study. Pediatr Pulmonol 1996;21: Kastelik JA, Aziz I, Morice AH, et al. Sputum induction in young cystic fibrosis patients. Eur Respir J 2001; 17: Aziz I, Kastelik JA, et al. Hypertonic saline for cystic fibrosis. N Eng J Med 2006;354: Journal of Tropical Pediatrics Vol. 58, No