Treatments vary for bronchiolitis related to RSV, new treatment in trials

Infectious Diseases in Children, December 2011

IDC NY 2011

See Also

RSV, metapneumovirus, influenza common causes of AOM ... RSV can reach epidemic levels outside of traditional peak in ... Children with RSV coinfection may have more severe disease ...

NEW YORK There are several current and emerging treatments for respiratory syncytial virus in pediatric patients, but oxygen and fluids remain effective therapy, according to a presentation here by Robert C. Welliver Sr., MD, during the 24th Annual Infectious Diseases in Children Symposium. Welliver, CMRI Hobbs-Recknagel Chair in Pediatrics, and chief of the section of infectious diseases at University of Oklahoma Health Sciences Center, discussed the management of bronchiolitis during a continuing medical education symposium sponsored by MedImmune. The pathogenesis of bronchiolitis is partially unrestricted viral replication, and the routine management of bronchiolitis includes administering humidified oxygen and nasal suctioning to clear upper airway, according to Welliver. It is important to monitor for apnea, hypoxemia and impending respiratory failure. The best predictors of respiratory failure are an initial oxygen saturation of less than 90% and aged younger than 2 months. Patients should be rehydrated with oral or IV fluids, and hydration status should be monitored. In a 1998 study by Dobson and colleagues published in Pediatrics, there was no difference in mean oxygen saturation between patients who received nebulized albuterol therapy and those who received placebo. There was also no difference in length of hospital stay between the two groups. Bronchodilators dont help, but many of us struggle when we see a gasping infant and reach for the bronchodilators. But many studies have shown that they do not help, Welliver said. Corticosteroids also had no benefit in 598 patients who presented to the ED. These patients were given dexamethasone 1 mg or placebo. There was no difference in respiratory rate, oxygen saturation and respiratory assessment change score between the groups after 4 hours, and no difference in the percentage of infants eventually hospitalized. Corticosteroids work in asthma, but they do not work in bronchiolitis. It seems like a logical jump that drugs that work in asthma would work, but they dont, Welliver said. Use of hypertonic saline appeared to show a benefit in bronchiolitis in a study of 96 infants aged 3 weeks to 18 months who were randomly assigned to 3% hypertonic saline or 0.9% normal saline. The length of stay in the pediatric ICU was 2.6 days for patients who received hypertonic saline vs. 3.5 days for patients who received normal saline, for a reduction of 26%. Saline may soften the secretions if you can get it down far enough into the lung, or it may simply induce coughing, but its true beneficial effects are not really known. Further study is needed before this can be accepted as standard therapy," he said.

In a study of montelukast (Singulair, Merck) for bronchiolitis, 979 patients were randomly assigned to montelukast 4 mg, montelukast 8 mg or placebo. There was no difference in symptom-free days, cough-free days, exacerbations or steroid usage between the three groups. A trial by Bisgaard in 2008 of montelukast for bronchiolitis had negative results. About one-third of days that were symptom-free, but two-thirds of patients continued to have symptoms, Welliver said. This was as negative of a study as you could find, unfortunately. Newer treatment Studies of motavizumab have shown that this therapy also did not shorten the number of days in the hospital for patients with bronchiolitis, and that oxygen had as good of a result as motavizumab. A 2010 study by DeVincenzo and colleagues indicated that short interfering RNS (siRNA) in respiratory syncytial virus (RSV) infection had no change in peak viral load, symptoms, physical exam and mucus weight. Although this was not a positive result, a current study in transplant patients with RSV is under way, according to Welliver. Those who received the ALN-RSV01 had a 44.2% positive culture compared with 71.4% in those who received saline. There was no difference in peak viral load, symptoms, physical exam or mucus weight. Fusion inhibitors, replication inhibitors and other RNA interference treatments are currently in development. Disclosure: Dr. Welliver receives consulting fees from Akebia and MedImmune.

Arch Pediatr Adolesc Med. 2009 Nov;163(11):1007-12. doi: 10.1001/archpediatrics.2009.196.

A randomized trial of nebulized 3% hypertonic saline with epinephrine in the treatment of acute bronchiolitis in the emergency department.
Grewal S, Ali S, McConnell DW, Vandermeer B, Klassen TP.

Source
Division of Pediatric Emergency, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. simran@ualberta.ca

Abstract
OBJECTIVE: To determine whether nebulized 3% hypertonic saline with epinephrine is more effective than nebulized 0.9% saline with epinephrine in the treatment of bronchiolitis in the emergency department. DESIGN:

Randomized, double-blind, controlled trial. SETTING: Single-center urban pediatric emergency department. PARTICIPANTS: Infants younger than 12 months with mild to moderate bronchiolitis. INTERVENTIONS: Patients were randomized to receive nebulized racemic epinephrine in either hypertonic or normal saline. OUTCOME MEASURES: The primary outcome measure was the change in respiratory distress, as measured by the Respiratory Assessment Change Score (RACS) from baseline to 120 minutes. The change in oxygen saturation was also determined. Secondary outcome measures included the rates of hospital admission and return to the emergency department. RESULTS: Forty-six patients were enrolled and evaluated. The 2 study groups had similar baseline characteristics. The RACS from baseline to 120 minutes demonstrated no improvement in respiratory distress in the hypertonic saline group compared with the normal saline control group. The change in oxygen saturation in the hypertonic saline group was not significant when compared with the control group. Rates of admission and return to the emergency department were not different between the 2 groups. CONCLUSIONS: In the treatment of acute bronchiolitis, hypertonic saline and epinephrine did not improve clinical outcome any more than normal saline and epinephrine in the emergency setting. This differs from previously published results of outpatient and inpatient populations and merits further evaluation. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN66632312 Int J Immunopathol Pharmacol. 2012 Apr-Jun;25(2):485-91.

Effectiveness of nebulized hypertonic saline and epinephrine in hospitalized infants with bronchiolitis.
Miraglia Del Giudice M, Saitta F, Leonardi S, Capasso M, Niglio B, Chinellato I, Decimo F, Maiello N, Capristo C, Perrone L, Peroni D.

Abstract
The objective of the study is to verify effects of nebulized 3% saline hypertonic solution (HS) in comparison to normal saline (NS) in addition to epinephrine in hospitalized children with bronchiolitis. Infants were randomly assigned either to receive every 6 hours nebulized NS (group I) or 3% HS (group II) in addition to epinephrine (1.5 mg) and to conventional treatment. The main endpoints of this study were the length of stay (LOS) in hospital and the clinical response score (CSS). Patients presented a significant decrease in CSS from the first through the third day of treatment, present in the first group but even more evident in the second group (p=0.0001). Comparison between group I and II data shows significant decrease in CSS in the 3% HS-treated patients both at the second (p<0.005) and at the third day of treatment (p<0.005). Infants in the NS control group had a mean LOS of 5.61.6 days, whereas children treated with 3% HS were discharged with a LOS of 4.91.3 days, reaching a significant decrease in stay (p<0.05). In hospitalized patients bronchiolitis nebulized 3% HS and epinephrine significantly decreased symptoms and LOS as compared to 0.9% NS and epinephrine
1

Pulm Pharmacol Ther. 2011 Dec;24(6):633-7. doi: 10.1016/j.pupt.2011.09.004. Epub 2011 Sep 29.

The efficacy of nebulized salbutamol, hypertonic saline and salbutamol/hypertonic saline combination in moderate bronchiolitis.
Ipek IO, Yalcin EU, Sezer RG, Bozaykut A.

Source
Department of Pediatrics, Istanbul Medipol University, School of Medicine, Turkey.

Abstract
BACKGROUND: The mainstay of treatment in bronchiolitis includes oxygenation, aspiration of secretions from the respiratory tract and maintenance of hydration. The first choice medical agent in clinical practice is nebulized bronchodilators, although their place in treatment is controversial. OBJECTIVES: We investigated the therapeutic benefit of nebulized hypertonic (3%) saline (HS), by comparing four different nebulized regimens in the treatment of bronchiolitis in the emergency department. METHODS: A total of 120 infants were included in this randomized, double-blind, prospective study. Infants were grouped according to the nebulized treatment they received: group 1 - salbutamol + normal saline (NS), group 2 - salbutamol + HS, group 3 - HS, group 4 - NS. Heart beat, Clinical Bronchiolitis Severity Score

(CBSS) and oxygen saturation of the patients were determined before and after the nebulizations and at 4872 h after admission by the designated study physician. RESULTS: Post-treatment mean CBSS were significantly lower than pre-treatment scores in all groups (p = 0.0001) with no significant difference within groups. Improvement percentages for CBSSs were significantly higher in infants without a history of atopy treated with HS and NS (p = 0.023, p = 0.0001, respectively). CONCLUSIONS: The CBSSs of all the infants improved after three doses of nebulized therapy regardless of the treatment regimens. The combination of salbutamol with hypertonic saline did not lead to an additive effect in the improvement of CBSSs compared to the standard salbutamol + NS combination. Atopic children benefited from salbutamol/NS combination whereas non-atopic children improved with HS and NS nebulizations based on improvement percentages of CBSS
Arch Pediatr. 2012 Jun;19(6):635-41. doi: 10.1016/j.arcped.2012.03.018. Epub 2012 Apr 30.

[Nebulized hypertonic saline and acute viral bronchiolitis in infants: current aspects].
[Article in French] Sauvaget E, David M, Bresson V, Retornaz K, Bosdure E, Dubus JC.

Source
Unit de pneumologie et mdecine infantile, CHU Timone-Enfants, 264, rue Saint-Pierre, 13385 Marseille cedex 5, France.

Abstract
Acute viral bronchiolitis affects infants, is frequent, and can be severe. Its treatment is only based on symptoms. Hypertonic saline (HS) may act favorably in this situation by fighting virus-induced dehydration of the airway liquid surface. Because of an osmotic action, HS attracts the water from the epithelial cells and improves mucociliary clearance. Five double-blind placebo-controlled studies concerning hospitalized infants with acute viral bronchiolitis showed that repeated nebulizations of 3% HS induce a 20% improvement in the clinical severity score and reduced the hospital length of stay by 24h. Tolerance is excellent. On the other hand, a few questions remain unresolved: what is the optimal salt concentration? What is the recommended nebulizer? What is the best frequency for nebulizer use? Can nebulized HS be used at home? What are the results with systematic physiotherapy when HS is used? Copyright 2012 Elsevier Masson SAS. All rights reserved

J Pediatr. 2010 Oct;157(4):630-4, 634.e1. doi: 10.1016/j.jpeds.2010.04.074. Epub 2010 Jun 19.

Nebulized 5% or 3% hypertonic or 0.9% saline for treating acute bronchiolitis in infants.

Al-Ansari K, Sakran M, Davidson BL, El Sayyed R, Mahjoub H, Ibrahim K.

Source

Division of Pediatric Emergency Medicine, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.

Abstract
OBJECTIVE: To compare the efficacy and safety of 5%, 3%, and 0.9% saline solution for treating acute bronchiolitis in the prehospital setting. STUDY DESIGN: This was a double-blind trial including consecutive infants aged <18 months treated in an urban urgent care setting. A total of 165 patients were randomized to receive nebulized 5%, 3%, or 0.9% (normal) saline with epinephrine every 4 hours. The primary efficacy outcome was bronchiolitis severity score improvement at 48 hours (chi2 analysis). Scores and oxygen saturation immediately before and after each treatment were recorded to assess safety. RESULTS: A total of 187 previously healthy infants (median age, 3.1 months) diagnosed with bronchiolitis were enrolled. Positivity for respiratory syncytial virus was similar in the 3 treatment groups (mean, 56%). At 48 hours, the mean severity score for the 5% saline group was 3.69+/-1.09, and that for the 0.9% saline group was 4.12+/-1.11 (P=.04; difference, 0.43, 95% confidence interval for the difference, 0.02-0.88). The mean severity score for the 3% saline group was intermediate at 4.00+/-1.22. Revisit rates after discharge were similar in the 3 treatment groups. No adverse reactions or other safety concerns were identified. CONCLUSIONS: Nebulization with 5% hypertonic saline is safe, can be widely generalizable, and may be superior to current treatment for early outpatient treatment of bronchiolitis. Copyright (c) 2010 Mosby, Inc. All rights reserved
Evid Based Med 2011;16:82-83 doi:10.1136/ebm1188

Therapeutics

Randomised controlled trial

Repeated dosing of nebulised 5% saline improves respiratory scores in inpatients with mild to moderate bronchiolitis at 48 h
1. Shawn Ralston + Author Affiliations 1. Department of Pediatrics, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA

1.

Correspondence to

Shawn Ralston

University of Texas Health Science Center San Antonio, 7703 Floyd Curl Dr, MSC 7829, San Antonio, TX 78229, USA; ralstons@uthscsa.edu Commentary on: 1. Al-Ansari K, 2. Sakran M, 3. Davidson BL, 4. et al . Nebulized 5% or 3% hypertonic or 0.9% saline for treating acute bronchiolitis in infants. J Pediatr 2010; 157:6304, 634.e1 .

Context
Nebulised hypertonic saline for acute viral bronchiolitis was first brought to public scrutiny in 2002. It was previously shown to be effective in patients with cystic fibrosis, and the first study in bronchiolitis, a small outpatient trial where ambulatory children were given the medication repeatedly over 5 days, showed promise.1 Further studies followed, and a dichotomy has emerged, with inpatient studies reporting consistently positive impacts on length of stay2, ,6 and emergency department studies failing to find any impact on admission rates.7,,9 It has been proposed that repeated treatments may be required before any benefit is observed because of a theoretical mechanism of action involving rehydration of the airway surface liquid.10 This study evaluated the clinical utility of the therapy in a short stay unit and attempted to establish

Paediatr Child Health. 2011 March; 16(3): 157158. PMCID: PMC3077306

When should nebulized hypertonic saline solution be used in the treatment of bronchiolitis?
Jeffrey Hom, MD MPH1 and Ricardo M Fernandes, MD2 Author information Article notes Copyright and License information This article has been cited by other articles in PMC. Bronchiolitis is a common lower respiratory infection that leads to frequent hospitalization at a rate of 31.2 per 1000 infants per year (1). Salbutamol, racemic adrenaline, corticosteroids and nebulized normal saline (NS) are commonly used therapies that all appear to have questionable efficacy in specific settings (2). The present review examines the effectiveness of nebulized 3% hypertonic saline solution (HS) in improving clinical scores, reducing the hospitalization rate and decreasing the length of stay (LOS), and reports adverse events attributed to HS. Go to:

PART A: EVIDENCE-BASED ANSWER AND SUMMARY

MEDLINE, EMBASE and the Cochrane Library were searched for randomized controlled trials that treated children with nebulized HS for bronchiolitis. One Cochrane meta-analysis published in 2008 (3) concluded that HS improved clinical scores on the first and second but not on the third day of treatment, did not decrease the hospitalization rate in the single small outpatient study, but did reduce LOS. The present review includes the four studies (47) from the meta-analysis and three subsequent studies (810). The challenge of the review is the heterogeneity of these studies. The mean ages of the children in the studies ranged from 2.6 months (6) to 12.5 months (4). Children were enrolled from outpatient community clinics in Israel (4), paediatric emergency departments (EDs) in Canada (9) and Turkey (10), and inpatient wards in Israel (5,6), China (8), and both the United Arab Emirates and Canada (7). None of the studies enrolled children who required intensive care unit admission. Five studies (46,8,10) used the Wang clinical scoring system. The Respiratory Distress Assessment Instrument (7) and the Respiratory Assessment Change Score (9) were used by one study each. All studies randomly assigned children to nebulized treatment groups of either 0.9% NS or 3% HS (410). In six studies (46,810), a protocol-specified bronchodilator was mixed and nebulized along with a saline solution, including terbutaline (4), salbutamol (8) or adrenaline (5,6,9), at variable dosing frequencies and durations. Two of these six studies (5,6) permitted the treating clinicians to provide add-on nebulization treatments at their own discretion. The ED study from Turkey (10) had four treatment arms combining salbutamol or adrenaline with 0.9% NS or 3% HS, with a fifth arm receiving only 0.9% NS. In the seventh study (7), clinicians added a bronchodilator to the NS or HS at their discretion, with 37% of the treatments including salbutamol and 23% including adrenaline. Results of clinical scores were inconsistent. The outpatient study and three inpatient studies (46,8) demonstrated a statistically significant greater improvement in the HS than in the NS group. These scores improved as the number of HS treatments increased. The remaining inpatient study (7) calculated a clinical score during enrollment, not after saline treatments. Finally, the two studies from the ED (9,10) failed to show any differences in clinical scores between the treatment groups. In the outpatient clinic (4), two children from the NS group (n=32) required hospitalization, compared with three children from the HS group (n=33). In the ED study from Turkey (10), one child from the NS and salbutamol group (n=36), and one child from the HS and adrenaline group (n=39) required hospitalization. The remaining three arms did not have any children requiring hospitalization. In the ED study from Canada (9), 13 children from the NS group (n=23) and eight children from the HS group (n=23) required hospitalization (risk ratio 0.61; 95% CI 0.22 to 1.19). The LOS of hospitalized children was statistically significantly shorter in the HS group in all four studies (5 8). Typically, HS shortened the LOS by approximately one day (typically from approximately four to three days), with the largest decrease being 1.4 days (8). However, the mean LOS was also longest in the latter study (6.0 days in the HS group versus 7.4 days in the NS group) (8). There is concern that HS could precipitate bronchospasm in children with reactive airway disease. No serious adverse events were attributed to HS in the included trials, but because very few children received HS without a bronchodilator, this fact is not totally reassuring. In summary, HS was associated with improved clinical scores in four of seven studies with no obvious pattern. Hospitalization rates were not clearly impacted by therapy, but a trend toward a decreased rate was shown in one ED study (9). However, a shortened LOS was consistently observed in noncritical hospitalized patients. Go to:

PART B: CLINICAL COMMENTARY

Treatment of bronchiolitis is an ever-controversial topic in paediatrics. Frequently used interventions, including bronchodilators and steroids, have failed to show consistent and clinically relevant effects in metaanalyses of randomized trials. Current practice guidelines recommend only supportive measures, given the absence of clear evidence for any other approach. The debate is set to continue as recent exploratory results from the large Canadian Bronchiolitis Epinephrine Steroid Trial (CanBEST) (11) revisit old strategies by suggesting the benefit of combining steroids and adrenaline in reducing admission rates. For clinicians on the front line during every bronchiolitis season, the uncertainties of research findings are as striking as the burden of morbidity. Hospitalizations have been rising steadily in Canada and the United States (12,13), and there is persisting variation in management. A vaccine for respiratory syncytial virus has proven elusive and an effective treatment to reduce post-bronchiolitis wheezing is yet to be found. It is disappointing, to say the least, that the best we can offer our patients is monitoring, respiratory support and adequate hydration. A new therapeutic approach is, therefore, welcome even if the intervention ie, HS sounds simple and is not new to paediatric respiratory disease. Recent trials have highlighted its use in cystic fibrosis, with modest middle-term improvements in clinical and lung function outcomes (14). HS has the potential to hydrate airway surface liquid, thus improving impaired mucociliary clearance, and also to reduce airway wall edema through water absorption from the mucosa (15). All of these are predominant pathological features of acute bronchiolitis, and provide a rationale for the use of this treatment in this condition. There are some promising results in the trials reviewed in part A of the present article. A mean reduction in LOS of approximately one day is clinically meaningful; no intervention tested against placebo for inpatient management has shown an effect size of this magnitude (16). In contrast, there was no improvement in clinical scores of outpatients in the ED setting, but one trial (9) did show a lower, albeit nonsignificant, admission rate, which may warrant further research. Adverse events were rare in trials that used saline alone or with a fixed bronchodilator, which confirms the favourable safety profile shown in infants with cystic fibrosis (17). So, is HS the next big thing for bronchiolitis management? Decades of championing a number of failed interventions would suggest that caution should be advised. All trials included in the present review were small, often single centred and exploratory, and replication is needed to validate these findings. The absence of standardized, validated and patient-important outcomes has been a serious threat to bronchiolitis trial validity, and these trials are no exception. Clinically relevant differences for respiratory scores are unknown, and outpatient trials were under-powered to assess admission rates. Additionally, the approach to dosages, administration regimens and cointerventions is different in all trials. This limits analysis of a stand-alone effect of HS, as well as possible synergistic interactions, either using saline alone or with a specific bronchodilator. Larger trials assessing clinically relevant outcomes in both inpatient and outpatient settings are, therefore, needed. Overall, results for nebulized HS are encouraging, and paediatricians should consider using it for inpatient management of bronchiolitis, because no other intervention has proven useful. For children in the ED, results are negative in studies completed to date. In this setting, bronchodilators such as adrenaline may provide minimal relief, and a combination of adrenaline and steroids shows promise, but needs to be studied further in future trials. Supportive measures remain the mainstay of bronchiolitis inpatient and outpatient management. Go to:

Acknowledgments
Ricardo M Fernandes is supported by the Calouste Gulbenkian Foundation (Programme for Advanced Medical Education; www.gulbenkian.pt). Go to:

Footnotes
NOTE: Ricardo M Fernandes is a PhD student. The Evidence for Clinicians columns are coordinated by the Child Health Field of the Cochrane Collaboration (www.cochranechildhealth.org). To submit a question for upcoming columns, please contact us at child@ualberta.ca . Go to:

REFERENCES
1. Simoes EAF, Carbonell-Estrany X. Impact of severe disease caused by respiratory synctial virus in children living in developed countries. Pediatr Inf Dis J. 2003;22(Suppl):S1320. [PubMed] 2. King VJ, Viswanathan M, Bordley C, et al. Pharmacologic treatment of bronchiolitis in infants and children: A systematic review. Arch Pediatr Adolesc Med. 2004;158:12737. [PubMed] 3. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2008;4:CD006458. [PubMed] 4. Sarrell EM, Tal G, Witzling M, et al. Nebulized 3% hypertonic saline solution treatment in ambulatory children with viral bronchiolitis decreases symptoms. Chest. 2002;122:201520. [PubMed] 5. Mandelberg A, Tal G, Witzling M, et al. Nebulized 3% hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis. Chest. 2003;123:4817. [PubMed] 6. Tal G, Cesar K, Oron A, Houri S, Ballin A, Mandelberg A. Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalization stay: 2 years experience. IMAJ. 2006;8:16973. [PubMed] 7. Kuzik BA, Al Qadhi SA, Kent S, et al. Nebulized hypertonic saline in the treatment of viral bronchiolitis in infants. J Pediatr. 2007;151:26670. [PubMed] 8. Luo Z, Liu E, Luo J, et al. Nebulized hypertonic saline/salbutamol solution treatment in hospitalized children with mild to moderate bronchiolitis. Pediatr Int. 2010;52:199202. [PubMed] 9. Grewal S, Ali S, McConnell DW, Vandermeer B, Klassen TP. A randomized trial of nebulized 3% hypertonic saline with epinephrine in the treatment of acute bronchiolitis in the emergency department. Arch Pediatr Adolesc Med. 2009;163:100717. [PubMed] 10. Anil AB, Anil M, Saglam AB, Cetin N, Bal A, Aksu N. High volume normal saline alone is as effective as nebulized salbutamol-normal saline, epinephrine-normal saline, and 3% saline in mild bronchiolitis. Pediatr Pulmonol. 2010;45:417. [PubMed] 11. Plint AC, Johnson DW, Patel H, et al. Epinephrine and dexamethasone in children with bronchiolitis. N Engl J Med. 2009;360:207989. [PubMed] 12. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 19801996. JAMA. 1999;282:14406. [PubMed] 13. Langley J-M, LeBlanc J-C, Smith B, Wang E-E. Increasing incidence of hospitalization for bronchiolitis among Canadian children, 19802000. J Infect Dis. 2003;188:17647. [PubMed]

14. Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev. 2009;2:CD001506. [PubMed] 15. Mandelberg A, Amirav I. Hypertonic saline or high volume normal saline for viral bronchiolitis: Mechanisms and rationale. Pediatr Pulmonol. 2010;45:3640. [PubMed] 16. Bialy L, Smith M, Bourke T, Becker L. The Cochrane Library and bronchiolitis: An umbrella review. Evidence-Based Child Health: A Cochrane Review Journal. 2006;1:93947. 17. Dellon EP, Donaldson SH, Johnson R, Davis SD. Safety and tolerability of inhaled hypertonic saline in young children with cystic fibrosis. Pediatr Pulmonol. 2008;43:11006. [PubMed] N Engl J Med. 2009 May 14;360(20):2079-89. doi: 10.1056/NEJMoa0900544.

Epinephrine and dexamethasone in children with bronchiolitis.

Plint AC, Johnson DW, Patel H, Wiebe N, Correll R, Brant R, Mitton C, Gouin S, Bhatt M, Joubert G, Black KJ, Turner T, Whitehouse S, Klassen TP; Pediatric Emergency Research Canada (PERC).

Source
Department of Pediatrics, University of Ottawa and Children's Hospital of Eastern Ontario, Ottawa, Canada.

Abstract
BACKGROUND: Although numerous studies have explored the benefit of using nebulized epinephrine or corticosteroids alone to treat infants with bronchiolitis, the effectiveness of combining these medications is not well established. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial in which 800 infants (6 weeks to 12 months of age) with bronchiolitis who were seen in the pediatric emergency department were randomly assigned to one of four study groups. One group received two treatments of nebulized epinephrine (3 ml of epinephrine in a 1:1000 solution per treatment) and a total of six oral doses of dexamethasone (1.0 mg per kilogram of body weight in the emergency department and 0.6 mg per kilogram for an additional 5 days) (the epinephrine-dexamethasone group), the second group received nebulized epinephrine and oral placebo (the epinephrine group), the third received nebulized placebo and oral dexamethasone (the dexamethasone group), and the fourth received nebulized placebo and oral placebo (the placebo group). The primary outcome was hospital admission within 7 days after the day of enrollment (the initial visit to the emergency department). RESULTS: Baseline clinical characteristics were similar among the four groups. By the seventh day, 34 infants (17.1%) in the epinephrine-dexamethasone group, 47 (23.7%) in the epinephrine group, 51 (25.6%) in the dexamethasone group, and 53 (26.4%) in the placebo group had been admitted to the hospital. In the unadjusted analysis, only the infants in the epinephrine-dexamethasone group were significantly less likely than those in the placebo group to be admitted by day 7 (relative risk, 0.65; 95% confidence interval, 0.45 to

0.95, P=0.02). However, with adjustment for multiple comparisons, this result was rendered insignificant (P=0.07). There were no serious adverse events. CONCLUSIONS: Among infants with bronchiolitis treated in the emergency department, combined therapy with dexamethasone and epinephrine may significantly reduce hospital admissions. (Current Controlled Trials number, ISRCTN56745572.) 2009 Massachusetts Medical Society Pediatr Pulmonol. 2010 Jan;45(1):41-7. doi: 10.1002/ppul.21108.

High volume normal saline alone is as effective as nebulized salbutamol-normal saline, epinephrinenormal saline, and 3% saline in mild bronchiolitis.
Anil AB, Anil M, Saglam AB, Cetin N, Bal A, Aksu N.

Source
Department of Pediatrics, Tepecik Training and Research Hospital, Izmir, Turkey. aysebernaanil@hotmail.com

Abstract
The objective of this study was to investigate the effectivenesses of nebulized salbutamol, epinephrin, 3% saline, and normal saline (0.9% NaCl) in the treatment of mildly affected infants with acute bronchiolitis. We enrolled 186 children (mean age 9.5 +/- 5.3 months, range 1.5-24 months, 65.1% male) with a first episode of wheezing diagnosed as mild bronchiolitis in emergency department. Patients were randomized in a doubleblind fashion to receive 4 ml dose either of 1.5 mg epinephrine plus normal saline (group 1; n = 38) or 1.5 mg epinephrine plus 3% saline (group 2; n = 39) or 2.5 mg salbutamol plus normal saline (group 3; n = 36) or 2.5 mg salbutamol plus 3% saline (group 4; n = 36) or normal saline alone (group 5; n = 37) at 0 and 30 min. Thus, all treatment modalities included high amount of NaCl (72-240 mg). Clinical score, oxygen saturation and heart rate were assessed at 0, 30, 60, and 120 min. After discharge, patients were reassessed by telephone contact at 48 hr and 6 months. The baseline characteristics were similar in all groups (P > 0.05). The outcome of patients at 120 min was found significantly better than the baseline values (P < 0.05). There were no significant differences between the outcome variables of the groups (P > 0.05). No adverse effects attributable to nebulized therapy were seen. In conclusion, all treatment modalities used in this study, including a total of 8 ml normal saline inhalation at 30-min interval showed clinically significant and swift improvement in mildly affected ambulatory infants with acute bronchiolitis
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Indian Pediatr. 2012 Jul;49(7):543-7. Epub 2010 Oct 30.

Nebulized hypertonic-saline vs epinephrine for bronchiolitis; proof of concept study of cumulative sum (CUSUM) analysis.
Gupta N, Puliyel A, Manchanda A, Puliyel J.

Source
Department of Pediatrics and Neonatology, St Stephens Hospital, Delhi, India. drneeraj79@yahoo.co.in

Abstract
OBJECTIVE: To apply cumulative sum (CUSUM) to monitor a drug trial of nebulized hypertonic-saline in bronchiolitis. To test if monitoring with CUSUM control lines is practical and useful as a prompt to stop the drug trial early, if the study drug performs significantly worse than the comparator drug. DESIGN: Prospective, open label, controlled trial using standard therapy (epinephrine) and study drug (hypertonic-saline) sequentially in two groups of patients. SETTING: Hospital offering tertiary-level pediatric care. PATIENTS: Children, 2 months to 2 years, with first episode of bronchiolitis, excluding those with cardiac disease, immunodeficiency and critical illness at presentation. INTERVENTIONS: Nebulized epinephrine in first half of the bronchiolitis season (n = 35) and hypertonic saline subsequently (n = 29). Continuous monitoring of response to hypertonic-saline using CUSUM control charts developed with epinephrineresponse data. Main outcome measures: Clinical score, tachycardia and total duration of hospital stay. RESULTS: In the epinephrine group, the maximum CUSUM was +2.25 (SD 1.34) and minimum CUSUM was -2.26 (SD 1.34). CUSUM score with hypertonic saline group stayed above the zero line throughout the study. There was no statistical difference in the post-treatment clinical score at 24 hours between the treatment groups {Mean (SD) 3.516 (2.816): 3.552 (2.686); 95% CI: -1.416 to 1.356}, heart rate {Mean (SD) 136 (44): 137(12); 95% CI: -17.849 to 15.849) or duration of hospital stay (Mean (SD) 96.029 (111.41): 82.914 (65.940); 95% CI: -33.888 to 60.128}. CONCLUSIONS:

The software we developed allows for drawing of control lines to monitor study drug performance. Hypertonic saline performed as well or better than nebulized epinephrine in bronchiolitis CJEM. 2010 Nov;12(6):477-84.

Effect of inhaled hypertonic saline on hospital admission rate in children with viral bronchiolitis: a randomized trial.
Kuzik BA, Flavin MP, Kent S, Zielinski D, Kwan CW, Adeleye A, Vegsund BC, Rossi C.

Source
Department of Paediatrics, Royal Victoria Hospital, Barrie, Ontario, Canada. briankuzik@hotmail.com

Abstract
OBJECTIVE: We sought to determine whether inhaled 3% hypertonic saline (HS) reduces admission to hospital in ambulatory children with moderately severe viral bronchiolitis. Secondary objectives compared changes in respiratory scores before and after treatment and assessed the need for unscheduled medical intervention within 7 days. METHODS: Children under the age of 2 years presenting with moderately severe viral bronchiolitis to the emergency department of 4 general hospitals from November 2008 to March 2009 were randomly assigned to receive 3 consecutive 4-mL doses of nebulized 3% HS (treatment group) or 0.9% normal saline (NS; control group) in a double blind fashion, each coadministered with 1 mg salbutamol. Outcome measures included the difference in hospital admission rate and changes in respiratory distress scores. RESULTS: A total of 81 children (mean age 8.9 mo, range 0.7-22 mo) were assessed over 88 visits on an intention-to-treat basis. No statistically significant differences were found between treatment groups. Children in the HS group had a nonsignificant trend toward greater improvement compared with NS controls with a same-day admission rate of 18% (95% confidence interval [CI] 9%-32%) versus 27% (95% CI 16%-42%), respectively. Respiratory Assessment Change Scores (RACS) favoured the HS group over NS controls (mean RACS 4.7 [95% CI 3.6-5.8] v. 3.7 [95% CI 2.5-4.9], respectively), although the CIs overlap and these differences were not statistically significant. CONCLUSION: The short-term use of nebulized 3% HS did not result in any statistically significant benefits, although a nonsignificant trend toward a decrease in admission rate and improvement in respiratory distress was found. A larger study would be required to determine whether these trends arise from a clinically relevant treatment effect

Isr Med Assoc J. 2006 Mar;8(3):169-73.

Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalization stay: 2 years experience.

Tal G, Cesar K, Oron A, Houri S, Ballin A, Mandelberg A.

Source
Pediatric Pulmonary Unit, Wolfson Medical Center, Holon, Israel.

Abstract
BACKGROUND: We recently published preliminary evidence on the effectiveness of hypertonic saline in infants with viral bronchiolitis. OBJECTIVE: To further establish the efficacy of nebulized hypertonic saline in these infants. METHODS: In a continuing, second-year randomized, doubleblind controlled trial, an additional 41 infants (age 2.6 +/- 1 months) hospitalized with viral bronchiolitis were recruited during the winter of 2001-2002. The infants received inhalation of 1.5 mg epinephrine dissolved either in 4 ml normal (0.9%) saline (Group I, n=20) or 4 ml hypertonic (3%) saline (Group II, n=22). The therapy was repeated three times daily until discharge. Pooling our 2 years of experience (2000-2002), a total of 93 hospitalized infants with viral bronchiolitis were recruited; 45 were assigned to Group I and 48 to Group II. RESULTS: The clinical scores at baseline were 7.6 +/- 0.7 for Group I vs. 7.4 +/- 1.3 for Group II (P = NS). However, the clinical scores at days 1 and 2 after inhalation differed significantly between the two groups, invariably favoring Group II: 7 +/- 1 vs. 6.25 +/- 1.1 (P< 0.05), 6.45 +/- 1 vs. 5.35 +/- 1.35 (P< 0.05), respectively. Adding aerosolized 3% saline to 1.5 mg epinephrine reduced the hospitalization stay from 3.5 +/- 1.7 days in Group I to 2.6 +/- 1.4 in Group II (P< 0.05). The pooled data of both years revealed that adding 3% saline to the inhalation mixture decreased hospitalization stay from 3.6 +/- 1.6 to 2.8 +/- 1.3 days (P< 0.05). CONCLUSIONS: This second-year experience and our 2 year pooled data analysis strengthen the evidence that the combination of 3% saline/1.5 mg epinephrine benefits hospitalized infants with viral bronchiolitis
Indian Pediatr. 2012 Dec 5. pii: S097475591200360. [Epub ahead of print]

Hypertonic (3%) Saline for Acute Viral Bronchiolitis: A Randomized Trial.

Sharma BS, Gupta MK, Rafik SP.

Source
Department of Pediatrics, SPMCHI, SMS Medical College, Jaipur, Rajasthan. Correspondence to: Dr Bhagwan Sahai Sharma, B-2, New Hira Bagh Flats, Near Nurse's Hostel, SMS Hospital Campus, Jaipur, Rajasthan 302 004, India. drbssharma@gmail.com.

Abstract
OBJECTIVE: To compare the length of hospital stay (primary) and improvement in clinical severity scores (secondary) among children with bronchiolitis nebulized with 3% hypertonic saline or 0.9% saline. DESIGN: Randomized double blind controlled trial. Setting: Tertiary care teaching hospital PATIENTS: Hospitalized children (124 months) with acute bronchiolitis of moderate severity. Intervention: Nebulization of 4 ml of 3 % hypertonic saline or 4 ml of 0.9% saline along with 2.5 mg salbutamol at 4 hourly intervals till the patient was ready for discharge. RESULTS: Baseline characteristics were similar in two groups. [Mean age, months, 4.934.31 hypertonic saline group, 4.184.24 normal saline group, mean duration of symptoms at admission, days 3.62.87 hypertonic saline group, 3.82.34 normal saline group, and baseline O2 saturation % 94.432.77 hypertonic saline group and 95.232.45 normal saline group]. Median clinical severity score at admission was 6 (IQR-1) in both the groups. Clinical severity scores monitored afterwards 12 hourly till discharge (132 hours) did not show statistically significant differences in 3% and 0.9% saline groups. Mean length of hospital stay (time to reach predefined clinical severity score<3) was 63.93%22.43 hours in 3% saline group and 63.5121.27hours in 0.9% saline group (P=0. 878). No adverse events were reported by the parents, caregivers or treating medical attendants in both groups. Conclusion: Nebulized 3% saline is not superior to 0.9% saline in infants with clinically diagnosed acute bronchiolitis.
The Journal of Pediatrics Volume 158, Issue 3 , Page 515, March 2011

5% hypertonic saline with epinephrine is safe and may be effective in the treatment of bronchiolitis
yes platform+medline author author

Kristin Shadman, MD

University of Wisconsin, American Family Children's Hospital, Madison, Wisconsin

Abstract Full Text PDF References

Article Outline
I. Question II. Design III. Setting IV. Participants V. Intervention VI. Outcomes VII. Main Results VIII. Conclusions IX. Commentary X. References XI. Copyright

Al-Ansari K, Sakran M, Davidson BL, El Sayyed R, Mahjoub H, Ibrahim K. Nebulized 5% or 3% hypertonic or 0.9% saline for treating acute bronchiolitis in infants. J Pediatr 2010;157:630-4. Back to Article Outline

Question
Among infants with acute bronchiolitis in an urgent care setting, does the use of nebulized saline solution improve respiratory symptoms? Back to Article Outline

Design
Double-blind, randomized trial. Back to Article Outline

Setting
Urban urgent care setting in Qatar. Back to Article Outline

Participants
171 infants aged <18 months (mean age, 3.1 months) clinically diagnosed with bronchiolitis. Back to Article Outline

Intervention
Infants were randomized to receive nebulized 5%, 3%, or 0.9% (normal) saline with epinephrine every 4 hours. Back to Article Outline

Outcomes
The primary efficacy outcome was improved bronchiolitis severity score at 48 hours. Safety was assessed by monitoring severity score and oxygen saturation with each treatment. Back to Article Outline

Main Results
Positivity for respiratory syncytial virus was similar in the 3 treatment groups (mean, 56%). At 48 hours, the mean severity score was 3.69 1.09 for the 5% saline group and 4.12 1.11 for the 0.9% saline group ( P = .04; difference, 0.43; 95% CI for the difference, 0.02-0.88). The mean severity score for the 3% saline group was intermediate, at 4.00 1.22. The revisit rate after discharge was similar in the 3 treatment groups. No adverse reactions or other safety concerns were identified. Back to Article Outline

Conclusions
Nebulization with 5% hypertonic saline is safe, can be widely generalizable, and may be superior to current early outpatient treatments for bronchiolitis. Back to Article Outline

Commentary
Previous studies have demonstrated that the use of 3% nebulized saline may reduce hospital lengths of stay and improve clinical 1 severity scores. This study suggests that higher concentrations of hypertonic saline can be safely used to treat bronchiolitis in the hospital setting. The authors describe a prehospital setting with a length of stay up to 7 days. This description most resembles inpatient care in US hospitals. The primary outcome of this study suggests that higher levels of hypertonic saline may statistically improve severity scores at 48 hours for the 5% saline group compared with the 0.9% saline group. Some caution is warranted, given that patients discharged before 48 hours were not included in the analysis. This exclusion might contribute to the lack of statistical difference among the groups' severity scores at 24 hours. The 3% saline group demonstrated an intermediate reduction in severity score, suggesting a dose-related response; however, the study was not adequately powered to allow a comparison of the 3 groups. The authors note the similar length of stay in the 3 groups, but again the numbers are small. A larger study would be helpful to examine whether there is a dose-response curve for hypertonic saline in bronchiolitis, as well as whether higher concentrations would alter the length of stay. In addition, a recent study demonstrated the safe use of 3% hypertonic saline without bronchodilators 2 in bronchiolitis. A similar study of higher saline concentrations without bronchodilators could be undertaken.