|Year : 2019 | Volume
| Issue : 2 | Page : 76-85
The role of nebulized hypertonic saline in the management of acute bronchiolitis
Dooa A.E Heiba
Department of Pediatrics, Respiratory, Allergy and Immunology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||09-Dec-2018|
|Date of Decision||30-Dec-2018|
|Date of Acceptance||30-Dec-2018|
|Date of Web Publication||6-Feb-2020|
Doctorate in Pediatrics Dooa A.E Heiba
Department of Pediatrics, Faculty of Medicine, Alexandria University
Source of Support: None, Conflict of Interest: None
Background Acute bronchiolitis is the most frequent lower respiratory tract infection in infants and the most frequent cause of hospitalization in this age group. It places enormous strains on pediatric inpatient services and pediatric ICUs, and despite the growing understanding of its pathogenesis, currently available therapies have failed to show consistent benefit, and supportive care remains the mainstay of bronchiolitis therapy. It is suggested that hypertonic saline nebulization may be useful in making secretions less viscous and promoting their excretion, thereby resulting in clinical improvement, and over the past decade, a growing number of randomized trials have suggested that early and repeated doses of nebulized 3% hypertonic saline improve clinical outcomes in hospitalized children compared with 0.9% normal saline.
Objectives The current study aimed to study the safety and efficacy of nebulized 3% hypertonic saline in hospitalized infants with a clinical diagnosis of bronchiolitis.
Patients and methods This double-blind, randomized controlled trial was conducted on 110 infants who were admitted to Alexandria University Children’s Hospital with a clinical diagnosis of acute bronchiolitis. The diagnosis of bronchiolitis was based on clinical evaluation. Patients were randomly allocated into two groups: one group received nebulized 3% hypertonic saline with 2.5-mg salbutamol at intervals of 4 h, whereas the second group received nebulized 0.9% normal saline with 2.5-mg salbutamol at intervals of 4 h.
Results There was no significant difference in the clinical severity score between the two studied groups in all days of admission, except for mild improvement on the second and third days of admission, yet it was not sufficient enough to make the patients eligible for discharge. Furthermore, there was no significant difference in length of hospital stay among infants who received hypertonic saline. Complications of nebulized hypertonic saline, namely, vomiting, agitation, exacerbation of cough, cyanosis, and apnea, were similar to normal saline.
Conclusion The use of nebulized 3% hypertonic saline in hospitalized infants with bronchiolitis is considered safe, but when compared with 0.9% normal saline, it did not improve the clinical severity score nor shorten the length of hospital stay in hospitalized infants with bronchiolitis.
Keywords: bronchiolitis, infants, nebulized hypertonic saline
|How to cite this article:|
Heiba DA. The role of nebulized hypertonic saline in the management of acute bronchiolitis. Alex J Pediatr 2019;32:76-85
| Introduction|| |
Bronchiolitis refers to inflammation of peripheral airways . It is characterized by respiratory symptoms, resulting in wheezing and/or crackles upon auscultation. It is usually a self-limiting illness. However, this condition may be associated with several severe complications, such as apnea, respiratory failure, or secondary bacterial infection ,.
The American Academy of Pediatrics guidelines 2014 defined bronchiolitis as ‘a constellation of clinical signs and symptoms occurring in children younger than 2 years, including a viral upper respiratory tract prodrome followed by increased respiratory effort and wheezing, a disorder commonly caused by viral lower respiratory tract infection in infants’ .
Acute bronchiolitis is predominantly a viral disease, with the leading cause being the respiratory syncytial virus. Other less common pathogens include parainfluenza viruses, adenovirus, influenza A and B, rhinovirus, human metapneumovirus, and Mycoplasma pneumoniae ,. There is no evidence of a bacterial cause for bronchiolitis, although bacterial pneumonia is sometimes confused clinically with bronchiolitis . As wheeze is sometimes a feature of bronchiolitis, asthma treatments are frequently used. Nevertheless, the pathophysiology of bronchiolitis is quite different, so it is important to recognize the pathologic picture that occurs in the airways of children with bronchiolitis for understanding the clinical manifestations and developing rational management .
The bronchioles represent the proximal extent of the pulmonary acinus and as such, corresponding to the central portion of the secondary pulmonary lobule. Bronchioles are sometimes histologically inconspicuous and easily obscured by inflammatory infiltrates . The pathogenesis of bronchiolitis is characterized by acute inflammation, edema, and necrosis of airway epithelium, excess mucus production, and ultimately leading to airway obstruction and impaired gas exchange .
Viral infection occurs through the upper respiratory tract and spreads lower within a few days, resulting in inflammation of the bronchiolar epithelium, with peribronchial infiltration of white blood cell types, mostly mononuclear cells, and edema of the submucosa and adventitia. Plugs of sloughed, necrotic epithelium and fibrin in the airways cause partial or total obstruction to airflow. The degree of obstruction may vary as these areas are cleared, resulting in rapidly changing clinical signs that confound an accurate assessment of the severity of illness. A ‘ball-valve’ mechanism can result in trapping of air distal to obstructed areas, with subsequent absorption, atelectasis, and a mismatch of pulmonary ventilation and perfusion that may lead to hypoxemia. Atelectasis may be accelerated by the lack of collateral channels in young children and potentially by the administration of high concentrations of supplemental oxygen, which is absorbed more rapidly than room air. Smooth muscle constriction seems to have little role in the pathologic process, which may explain the limited benefit of bronchodilators observed in clinical studies .
The distribution of involvement in bronchiolitis is patchy, as some areas are obstructed and some are not. Those that are completely obstructed become atelectatic; those that are partially obstructed become overinflated. The unaffected areas remain normal and hyperventilated in an attempt to maintain normal arterial partial pressure of oxygen and partial pressure of carbon dioxide. The consequences of these changes are small airway obstruction, air trapping, increased inspiratory, expiratory resistance, increased work of breathing, and hypoxemia .
In general, the diagnosis of acute bronchiolitis is usually based on clinical grounds. It is usually accepted that acute bronchiolitis refers to the first episode of acute wheezing in infants less than 2 years of age, starting as a viral upper respiratory infection . So, the diagnosis is clinical. Typically, a 2–6-month-old infant will present with worsening respiratory distress starting with a 2–3-day prodrome of coryzal symptoms. The infant is tachypnoeic with a recession and usually has showers of fine crackles. All over the chest, wheezing may be present, but this is not prerequisite for the diagnosis. Most but not all infants are febrile. The infant is rarely systemically toxic (drowsy, lethargic, irritable, pale, mottled, and tachycardic), and this feature should prompt a search for another diagnosis .
Routine laboratory tests are of minimal diagnostic use in most cases of bronchiolitis or pneumonia caused by respiratory syncytial virus. The white blood cell count is normal or elevated, and the differential count may be normal with either a neutrophilicor mononuclear predominance. Bacterial cultures of the throat grow only normal flora. Hypoxemia is frequent and tends to be more marked than anticipated based on the clinical findings . The standard treatment remains supportive care and includes ensuring adequate oxygen exchange, fluid intake, and feeding of the infant . All other medications including inhaled bronchodilators , inhaled epinephrine , corticosteroids in any form , chest physiotherapy , aerosolated ribavirin, and Heliox inhalation by tight mask are controversial . It has been hypothesized that hypertonic saline improves respiratory symptoms via (i) decreasing mucosal edema, (ii) decreasing inflammatory mediators, (iii) mechanically clearing inspissated mucus, and (iv) improving mucociliary function. Hypertonic saline can reduce the adhesion of virus and consequent airway inflammation reaction as well as the risk of a secondary bacterial infection .
| Aim|| |
The work aimed to study the safety and efficacy of nebulized 3% hypertonic saline in hospitalized infants with a clinical diagnosis of bronchiolitis.
| Patients and methods|| |
This double-blind (both participants and outcome assessors were blinded) randomized controlled trial was conducted on 110 infants with the clinical diagnosis of bronchiolitis admitted to Alexandria University Children’s Hospital with a clinical diagnosis of acute bronchiolitis, during the period from September 2015 to January 2017. The sample size was justified by the Biostatistics Department, High Institute of Public Health, the University of Alexandria, using G. power software .
Infants aged 6 weeks up to 24 months admitted with a clinical diagnosis of bronchiolitis were eligible for inclusion in the study. Bronchiolitis was considered in cases with the first episode of wheezing along with prodrome of upper respiratory tract infection including rhinorrhea, cough, and sometimes low-grade fever, which may progress to dyspnea .
The following were the exclusion criteria:
- Refusal of a parent or legal guardian to participate in the study.
- Infants with congenital heart diseases.
- Infants with chronic respiratory illnesses.
- Infants with a previous wheezing episode.
- Infants having primary immune deficiency.
- Severe cases of bronchiolitis requiring ICU admission .
- Infants with an altered level of consciousness.
- Oxygen saturation of less than 88% at the time of recruitment.
- Severe respiratory distress requiring respiratory support other than supplemental oxygen.
- Infants with atopic manifestations, for example, eczema, allergic rhinitis, and food allergy.
Patients were randomly allocated into two groups: group A received 4 ml of nebulized 3% hypertonic saline with 2.5 mg salbutamol at intervals of 4 h, and group B received 4 ml of nebulized 0.9% normal saline with 2.5 mg salbutamol at intervals of 4 h. There was no detectable difference in color, smell, or other physical properties between 0.9% saline solution and 3% hypertonic saline solution. All patients were thoroughly examined at the start of the study and every 12 h thereafter using the clinical score of Wang et al. ([Table 1]) . Length of hospital stay, complications, and final fate were compared. Signed informed consent was obtained from the parents or legal guardians of all children. All patients were enrolled within 24 h of admission to the hospital.
|Table 1 Wang’s clinical severity score: the score assigns a value between 0 and 3 to each variable; higher scores indicate worse condition.|
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- Data were collected and entered into the computer using Statistical Package for Social Science program for statistical analysis (version 21) . Data were entered as numerical or categorical, as appropriate.
- Kolmogorov–Smirnov test of normality revealed no significance in the distribution of the variables, so the parametric statistics was adopted .
- Data were described using minimum, maximum, mean, and SD.
- Categorical variables were described using frequency and percentage.
- Comparisons were carried out between two studied independent normally distributed variables using the independent sample t test .
- χ2 test was used to test the association between qualitative variables . Yates’ correction for continuity (or Yates’ χ2 test) was used when indicated (2 × 2 table with the expected value for any cell <5 and grand total >40) .
- Box and Whiskers plot and time-series line graphs were used accordingly.
An alpha level was set to 5% with a significance level of 95%, and a beta error accepted up to 20% with a power of study of 80%.
This study was approved by Medical Research Ethics Committee at Alexandria Faculty of Medicine, and an informed consent was obtained from children’s guardians.
| Results|| |
There was no significant difference between both groups regarding demographic data ([Table 2]).There was also no significant difference in the clinical severity score (Wang) on admission between the two studied groups (t=0.200, P=0.842) ([Figure 1]).
|Figure 1 Clinical severity score on admission of the two studied groups.|
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During the course of admission, there was no significant difference between the two groups in relation to the daily measured respiratory rate, with the exception of the second and third day, in which the hypertonic saline group had significantly lower respiratory rate ([Figure 2]). The same observation was also noticed when comparing the clinical severity score, as there was no significant difference in the clinical severity score between the two studied groups except in the second and third days where there were significant decreases in the clinical severity score in group A which received hypertonic saline; however, this decrease was not sufficient enough to make the patient fit for discharge ([Figure 3]).
|Figure 3 Mean values of clinical severity score (Wang) during admission days.|
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Regarding the outcome of the studied cases, the current study showed no significant difference between the two studied cases in relation to occurrence of complications ([Table 3]). Moreover, the use of hypertonic saline did not affect the rate of discharge either per day ([Figure 4]) or in total ([Table 4]) ([Figure 5]).
|Table 3 Comparison between the two studied groups according to complications|
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Finally, the use of hypertonic saline had no effect on the length of the hospital stay, as both groups had no statistically significant difference in length of the hospital stay (t=1.295, P=0.198) ([Figure 6]).
| Discussion|| |
Acute bronchiolitis is the most frequent lower respiratory tract infection in infants; it is also the most frequent cause of hospitalization in this age group ,.
The current study was conducted to evaluate the possible efficacy of nebulized 3% hypertonic saline in hospitalized infants with a clinical diagnosis of bronchiolitis. A total of 110 patients were included in the study, and their ages ranged from 2 months up to 18 months, with a mean age of 4.82±3.74 months. This mean age is almost similar to the study done by Kuzik et al. , in which the mean age was 4.7 months, but is slightly younger than the study done by Luo et al. , where the mean age of the studied infants was 5.8±4.4 months, and definitely older than the study of Mandelberg et al. , in which the mean age of the included cases was 2.9±2.1 months. The WHO states that approximately 75% of cases of bronchiolitis occur in children younger than 1 year of age and 95% in children younger than 2 years of age, with the peak incidence in those aged from 2 to 8 months .
Regarding sex, the current study showed that males were more affected than females (62.7%), which is in agreement with many studies linked to bronchiolitis like Silver et al. , Kuzik et al. , Sharma et al. , and Florin et al. , where males represented 64.5, 58.3, 76.2, and 60.44% of the studied population, respectively.
The exact reason for this is unknown; however, male predominance in bronchiolitis represents a pattern similar to other respiratory viral infections, as described by Iwane et al. , in population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children.
The current study recorded a clinical severity score of 7.24±0.95 for cases on admission, which was higher than Teunissen et al. , Luo et al. , and Flores et al. , in which the clinical severity score for cases on admission was 6.2±2, 5.7±1.2, and 5.9±1.75, respectively, but this might be explained by the fact that the current study was conducted in university children’s hospital, which is considered a major referral center for other city hospitals.
In the current study, the cases were divided into two groups: group A, which received 4 ml of nebulized 3% hypertonic saline with 2.5-mg salbutamol at intervals of 4 h, and group B, which received 4 ml of nebulized 0.9% normal saline with 2.5-mg salbutamol at intervals of 4 h.
Regarding the change in respiratory rate results, it was found that there was no statistically significant difference in nearly all days of admission except day 2 and 3 in which the hypertonic saline group showed better respiratory rates. However, this difference was not sufficient enough for discharge. Ipek et al.  also found no statistically significant difference in the respiratory rates between the studied groups and concluded that nebulized hypertonic saline had no beneficial effect above normal saline in relation to the improvement of the respiratory rate of cases of bronchiolitis.
Regarding clinical severity score. The results of the current study showed that there was no significant improvement in the clinical severity score between the two studied groups in all days of admission except for mild improvement on the second and third days of admission, yet it was not sufficient enough to make the patients eligible for discharge. These results were similar to Flores et al. , who studied the efficacy of nebulized hypertonic saline in infants hospitalized with bronchiolitis and found no statistically significant difference in clinical severity score between both groups, and so did not support the routine use of nebulized hypertonic saline in infants with bronchiolitis. Similarly, Teunissen et al. , Silver et al. , Florin et al. , Sharma et al. , and Everard et al. , who all studied the efficacy of nebulized hypertonic saline in infants hospitalized with bronchiolitis, found no improvement in clinical severity score over nebulized normal saline and also did not recommend its routine use. On the contrary, Mandelberg et al. , Luo et al. , Miraglia Del Giudice et al. , and Kuzic et al.  found that hypertonic saline improves the clinical severity score more than normal saline. This may be attributed to the fact that Mandelberg et al.  and Miraglia Del Giudice et al.  used epinephrine instead of salbutamol, which may favor the results in the direction of hypertonic saline.In relation to the length of hospital stay, the current study found that there was no significant decrease in length of hospital stay in infants who received hypertonic saline, which is similar to Everard et al. , who found that nebulized hypertonic saline did not shorten the length of hospital stay in infants hospitalized with bronchiolitis compared with those who received nebulized normal saline.
Silver et al. , Sharma et al. , Flores et al. , Teunissen et al. , and Ipek et al.  also studied the efficacy of nebulized hypertonic saline in infants hospitalized with bronchiolitis and found that hypertonic saline did not shorten the length of hospital stay compared with normal saline and so did not recommend its routine use.
On the contrary, Miraglia Del Giudice et al. , Mandelberg et al. , Luo et al. , and Kuzic et al.  found that using nebulized hypertonic saline instead of normal saline shortens the length of hospital stay, and the results of these studies recommend routine use of the nebulized hypertonic saline in hospitalized patient with bronchiolitis. However, according to Bronchiolitis Clinical Guidelines Commissioned by the National Institute for Health and Care Excellence , these studies had limitations and their evidence base was low, for example, randomization was unclear in the study done by Miraglia Del Giudice et al. . In the study done by Mandelberg et al. , they used epinephrine instead of salbutamol. Patients received supportive and comprehensive treatments including sputum aspiration, water electrolyte balance maintenance, and oxygen therapy in the study by Luo et al. , and 38 of 88 infants had a previous history of wheezing in the study by Kuzic et al. .
| Conclusion|| |
Nebulized 3% hypertonic saline did not improve the clinical severity score when compared with 0.9% normal saline in hospitalized infants with bronchiolitis. Furthermore, the utilization of nebulized 3% hypertonic saline, although considered safe, did not shorten the length of hospital stay in hospitalized infants with bronchiolitis. Based on the results of the current study, the author does not recommend routine use of nebulized hypertonic saline in hospitalized infants with bronchiolitis unless further large-scale, multicenters trials are conducted proving the clinical benefits of nebulized hypertonic saline.
The research was supported by Alexandria Faculty of Medicine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]