ORIGINAL ARTICLE INFECTIOUS DISEASES Nebulized hypertonic saline treatment in hospitalized children with moderate to severe viral bronchiolitis Z. Luo, Z. Fu, E. Liu, X. Xu, X. Fu, D. Peng, Y. Liu, S. Li, F. Zeng and X. Yang Respiratory Department, Children s Hospital, Chong Qing Medical University, Chongqing, China Abstract The objective of this study was to determine the efficacy and safety of frequently inhaled nebulized hypertonic saline (HS) in infants with moderate to severe bronchiolitis. One hundred and twenty-six infants were randomized to receive either nebulized 3% hypertonic saline (HS) or 0.9% normal saline (NS), but only 112 patients completed the whole study. Cough, wheezing, pulmonary physical signs, clinical severity scores and the hospital length of stay (LOS) were recorded. The wheezing remission time was 4.8 ± 1.0 days in the NS group and 3.6 ± 0.9 days in the HS group (p <0.01). The cough remission time was 5.5 ± 0.9 days in the NS group and 4.3 ± 0.7 days in the HS group (p <0.01). The moist crackles disappeared at 6.2 ± 0.7 days in the NS group and at 4.4 ± 0.9 days in the HS group (p <0.01). The clinical severity scores decreased more significantly in the HS group than in the NS group on each day within 96 h after enrolment (p <0.01). The LOS decreased from 6.4 ± 1.4 days in the NS group to 4.8 ± 1.2 days in the HS group (p <0.01). The treatment was well tolerated, with no adverse effects attributable to nebulized HS. The conclusions are that frequently inhaled HS relieved symptoms and signs faster than NS, and shortened LOS significantly for infants with moderate to severe bronchiolitis, without apparent adverse effects. Keywords: Bronchiolitis, hypertonic saline solution, RSV Original Submission: 17 January 2010; Revised Submission: 30 May 2010; Accepted: 17 June 2010 Editor: M. Drancourt Article published online: 15 July 2010 Clin Microbiol Infect 2011; 17: 1829 1833 10.1111/j.1469-0691.2010.03304.x Corresponding author and reprint requests: Z. Luo, Respiratory Department, Children s Hospital, Chongqing Medical University, Chongqing, 400014, China E-mail: luozhengxiu816@163.com Introduction Bronchiolitis is infection of the bronchial and bronchiolar epithelium, which is mainly caused by respiratory syncytial virus (RSV). The primary treatment remains largely supportive, with mechanical ventilatory support as needed [1]. Other types of treatment remain controversial [1,2]. It has been shown that nebulized hypertonic saline (HS) decreases the hospital length of stay (LOS) as compared with normal saline (NS) among infants hospitalized with viral bronchiolitis [3,4]. We and other researchers demonstrated that nebulized HS and bronchodilators decreased symptoms and LOS for infants with mild to moderate viral bronchiolitis [5 7]. Both of the aforementioned studies used three times per day dosing, which is significantly less than the three to six times per hour regimens often used to children in respiratory distress [8 10]. Children with moderate to severe bronchiolitis have difficulty in breathing. Frequently inhaled nebulized HS reduced the LOS for infants with moderately severe bronchiolitis [3]. The present study was performed to investigate frequently inhaled nebulized HS for moderate to severe bronchiolitis in a prospective, randomized, double-blind, controlled fashion. The primary objective was to compare the symptoms, signs, clinical severity scores and the LOS of these infants with those of a control group of infants receiving frequently inhaled nebulized NS. Materials and Methods Patients Infants aged <24 months with a first episode of wheezing admitted to the Children s Hospital, Chongqing Medical University in China for the treatment of moderate to severe bronchiolitis were eligible for the study. The patients were ranked as moderately to severely ill according to the clinical score system, as follows [11]. (i) respiratory rate: 0 points, <30 breaths/min; 1 point, 31 45 breaths/min; 2 points, 46 60 breaths/min; 3 points, >60 breaths/min. (ii) Wheezing: 0 points, none; 1 point, terminal expiratory or heard only Journal Compilation ª2011 European Society of Clinical Microbiology and Infectious Diseases
1830 Clinical Microbiology and Infection, Volume 17 Number 12, December 2011 CMI with a stethoscope; 2 points, entire expiration or audible on expiration without a stethoscope; 3 points, inspiration and expiration without a stethoscope. (iii) Retractions: 0 points, none; 1 point, intercostal only; 2 points, tracheosternal; 3 points, severe with nasal flaring. (iv) General condition: 0 points, normal; 3 points, irritable, lethargic, poor feeding. Regarding the clinical total score, the disease severity can be divided into the following ranks: 0 4.9 points, mild; 5 8.9 points, moderate; and 9 12 points, severe disease. Exclusion criteria The exclusion criteria were as follows: age >24 months, previous episode of wheezing, chronic cardiac and pulmonary disease, immunodeficiency, accompanying respiratory failure, requiring mechanical ventilation, inhaling the nebulized 3% HS solution 12 h before treatment, and prematurity, with birth at <34 weeks of gestation. Study design Infants with moderate to severe bronchiolitis were assessed within 2 h for entry into the study. If inclusion/exclusion criteria were satisfied, then informed consent was obtained. Patients were randomized to receive 4 ml of a solution containing either HS or NS. The random code was generated by computer. The code was concealed in a sealed, opaque envelope until the child was recruited. The solution was administered in a double-blind fashion every 2 h for three doses, followed by every 4 h for five doses, followed by every 6 h until discharge [3]. Each of the two groups received the same supportive and comprehensive treatments, including sputum aspiration, water electrolyte balance maintenance and oxygen therapy. All inhaled treatments were delivered to infants from standard air-compressed nebulizers (PARI Corporation, Starnford, Germany). Patients were examined at the time of study entry and every 12 h after enrolment. No detectable differences in colour, smell or other physical properties existed between HS and NS. The identities of the solution were not available to the investigators, nurses or parents. The decisions to discharge babies were made by attending physicians when the patients had experienced no respiratory symptoms and signs during the past 12 h. The attending physicians were also blind to the solution. Sample and method for detecting RSV DNA was extracted from 200 ll of airway aspirate with the QIAamp DNA Mini kit (Qiagen, MD, USA), and samples were eluted in 200 ll of AE buffer. Viral antigen was analysed for RSV by direct fluorescent assay (D3 direct fluorescent assay Respiratory Viruses Screening & ID Kit; Diagnostic Hybrids, Hannover, Germany). Ethics The study was approved by the ethics and human research committees of the Children s Hospital, Chongqing Medical University. Written informed consent was obtained from at least one parent of each infant before enrolment. Observation and evaluation We evaluated these patients symptoms (cough, wheezing, hoarse voice, vomiting, diarrhoea, general condition), signs (temperature, respiratory rate, heart rate, retraction, pulmonary signs, heart sounds) every 12 h after enrolment. We recorded the clinical severity scores every 12 h after enrolment, the day when cough, wheezing and pulmonary moist crackles disappeared, and the LOS. Statistical analyses SPSS edition 11.5 was used to analyse all the data. Chisquare tests were used to compare categorical variables. One-way analysis of variance (ANOVA) was used for the continuous variables. The mean ± standard deviation (x ± s) expresses the central trend of the data. A p-value <0.05 was considered to be statistically significant. Results Participants flow and baseline data One hundred and thirty-five patients with moderate to severe bronchiolitis were recruited from November 2008 to November 2009 at the Children s Hospital, Chongqing Medical University, but only 112 patients completed the whole study (Fig. 1). Among the 112 patients, 57 were enrolled in the HS group (32 males; 25 females), with an average age of 5.9 ± 4.1 months and a disease course of 3.4 ± 1.7 days. Fifty-five participants were in the NS group (31 males; 24 females), with an average age of 5.8 ± 4.3 months and a disease course of 3.2 ± 1.4 days. No significant differences existed between the two groups (summarized in Table 1). Outcomes of therapeutic effects In the HS group, as compared with the NS group, the time required for wheezing and coughing relief was reduced by 1.2 days on average, the moist crackles vanished 1.8 days earlier, and the LOS decreased by 1.6 days (Table 2). The clinical severity scores at baseline were 8.8 ± 1.1 in the HS group and 8.5 ± 1.5 in the NS group. The clinical severity scores in the HS group on the first, second, third and fourth days were 5.7 ± 1.5, 3.5 ± 1.1, 2.4 ± 0.9 and 1.7 ± 0.6, respectively. In the NS group, the clinical severity scores on the first, second, third and fourth days were 7.3 ± 1.7,
CMI Luo et al. Nebulized hypertonic saline treatment in hospitalized children 1831 135 patients with moderate to severe ill bronchiolitis were recruited 126 patients participated in the study 9 childrens parents refused to participate in the study 64 patients in the treatment group 62 patients in the control group 7 patients discharged within 12 h after enrolment 57 patients completed the whole study 55 patients completed the whole study 7 patients discharged within 12 h after enrolment FIG. 1. Flow diagram of the study. TABLE 1. Comparison of basic clinical information between the two groups Basic information NS group (n = 55) HS group (n = 57) p-value Female/male 77.4 78.1 0.98 Age (months) 5.8 ± 4.3 5.9 ± 4.1 0.71 Duration of wheezing 3.2 ± 1.4 3.4 ± 1.7 0.77 on admission Systemic glucocorticoid 35 (77.8) 43 (75.4) 0.82 use before admission, no. (%) Clinical score on admission 8.5 ± 1.5 8.8 ± 1.1 0.42 RSV detection rate (%) 40 (72.7%) 42 (73.7%) 0.91 HS, hypertonic saline; NS, normal saline; RSV, respiratory syncytial virus. Clinical scores 10 9 8 7 6 5 4 3 2 Study group Control group TABLE 2. Comparison of symptoms, signs and hospital length of stay (LOS) between the two groups (x ±s) Group Sample size Wheezing relief Cough relief Moist crackles vanished LOS HS group 57 3.6 ± 0.9 4.3 ± 0.7 4.4 ± 0.9 4.8 ± 1.2 NS group 55 4.8 ± 1.0 5.5 ± 0.9 6.2 ± 0.7 6.4 ± 1.4 t-value 4.372 4.915 8.011 4.566 p-value <0.01 <0.01 <0.01 <0.01 HS, hypertonic saline; NS, normal saline. 5.9 ± 1.5, 4.1 ± 1.1 and 3.1 ± 0.7, respectively. The clinical severity scores decreased more significantly in the HS group than in the NS group on each day within 96 h after enrolment (Fig. 2). Adverse events All participants tolerated therapy without apparent adverse effects and were eventually discharged after achieving full 1 0 0 1 2 3 4 Days of hospitalization FIG. 2. Clinical severity scores vs. hospitalization days in the two groups. recovery. No infants were withdrawn by the medical staff because of clinical deterioration or the need for intensivecare support. The coughing and wheezing never worsened over the course of the treatment. Although five infants had hoarse voices, only two of these infants were receiving HS, and the hoarse voice disappeared after 3 4 days. Discussion Bronchiolitis is the most common lower respiratory tract infection in infants. Wheezing is the primary clinical symptom. The use of inhaled HS to treat viral bronchiolitis was first reported in 2003 [5], and the evidence in favour was
1832 Clinical Microbiology and Infection, Volume 17 Number 12, December 2011 CMI strengthened with the publication of a 2-year extension of the original study [6]. We previously demonstrated that nebulized HS and salbutamol decreased the clinical symptoms more quickly and shortened the LOS for infants with mild to moderate bronchiolitis [7]. The current study demonstrated that frequently inhaled HS is an effective treatment for infants with moderate to severe bronchiolitis. It took less time to relieve symptoms and pulmonary signs: 1.2 days on average for wheezing and cough alleviation, and 1.8 days for pulmonary moist crackles to vanish. The clinical severity scores decreased more significantly in the HS group than in the NS group on each day within 96 h after hospitalization. The LOS was reduced by 1.6 days, from 6.4 ± 1.4 to 4.8 ± 1.2 days. In our study, patients were discharged when the patients had experienced no respiratory symptoms and signs during the past 12 h, whereas in other studies, the discharge criteria were clinical score <4 and S a O 2 of at least 95% in room air for 4 h, so the LOS in our study is longer than in other studies, where the LOS was typically 3 6 days. A normal height of the periciliary liquid is crucial for normal airway mucociliary clearance. RSV infection depletes the mucous layer water content, damages the airway surface liquid epithelium, and reduces the height of the periciliary liquid and clearance of mucus [12]. HS may reverse some of the pathophysiological abnormalities in viral bronchiolitis. In vitro, HS increases airway surface thickness, decreases epithelial oedema, improves mucus elasticity and viscosity [13,14], accelerates the transport rates of mucus [14,15], and improves clearance of mucus [16]. In vivo, HS increases the rate of mucociliary transport, even in normal subjects [17]. HS breaks the ionic bonds within the mucous gel and reduces oedema of the airway wall in viral bronchiolitis [5,18], causes sputum induction and cough, helps to clear the sputum, and improves airway obstruction [5]. In this trial, we did not detect the actual mechanisms. HS improves mucociliary function and promotes the elimination of mucus, thereby reducing the adhesion of the virus and consequent airway inflammation reaction, as well as the risk of a secondary bacterial infection. However, further investigation is needed to verify these assumptions. The pathology of bronchiolitis is peribronchiolar mononuclear infiltration, epithelial cell necrosis, sub-mucosal oedema and an increase in the rate of mucous secretion, and therefore an increase in the mucin/water ratio [19], which causes relative a reduction in the airway surface liquid [20]. The pathophysiology of bronchiolitis is quite distinct from that of asthma; these patients are less, if at all, responsive to bronchodilators [8]. Nebulized HS alone is safe for infants with moderately severe bronchiolitis [3]. In the current study, we demonstrated that HS is safe for infants with moderate to severe bronchiolitis; there were no apparent adverse effects attributable to frequently inhaled HS. Patients finished the entire treatment without bronchospasm, cough or wheezing aggravation. In summary, inhaled HS is efficient and safe for infants with moderate to severe bronchiolitis. Transparency Declaration All authors declare no potential conflicts of interest. References 1. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics 2006; 118:1774 1793. 2. Wright RB, Pomerantz WJ, Luria JW. New approaches to respiratory infections in children: bronchiolitis and croup. 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