Early Studies. Then, the Meta-analysis. Recent Studies Al-Ansari. Recent Studies Luo University of Texas Health Science Center at San Antonio

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1 Pediatrics Grand Rounds Objectives Review the available literature on the use of nebulized hypertonic saline in the treatment of acute viral bronchiolitis Review proposed mechanism(s) of action and safety profile for hypertonic saline in bronchiolitis Shawn Ralston, MD Viral bronchiolitis is the leading diagnosis at hospitalization for infants under 1 year of age It results in approximately 150,000 hospitalizations per year at a cost of over $500 million Standard of care in the US (as defined by the AAP Practice Parameter) is symptomatic care Diagnosis and management of bronchiolitis. Pediatrics 2006;118(4): % of all infants in the US will be admitted for bronchiolitis A trial of beta agonist therapy is condoned in the practice parameter but not recommended: RECOMMENDATION 2a Bronchodilators should not be used routinely in the management of bronchiolitis (recommendation: evidence level B; RCTs with limitations; preponderance of harm of use over benefit). RECOMMENDATION 2b Yorita KL, Holman RC, Sejvar JJ, Steiner CA, Schonberger LB. Infectious disease hospitalizations among infants in the United States. Pediatrics 2008;121: Pelletier AJ, Mansback JM, Camargo CA. Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics 2006;118: Pathology in bronchiolitis is not beta-agonist reversible airway obstruction Little benefit gained from routine beta-agonist usage, no impact on admission rates or LOS, no impact on oxygen saturation (or a negative impact), minor and equivocal impact on respiratory scores Gadomski AM, Bhasale AL. Bronchodilators for bronchiolitis. Cochrane Database of Systematic Reviews. 2006, Issue 3. Art. No.: CD DOI: / CD pub2 A carefully monitored trial of alpha-adrenergic or beta-adrenergic medication is an option. Inhaled bronchodilators should be continued only if there is a documented positive clinical response to the trial using an objective means of evaluation (option: evidence level B; RCTs with limitations and expert opinion; balance of benefit and harm).

2 And, along comes hypertonic saline.. Sarrell EM, Tal G, Witzling M, Someck E, Houri S, et al. Nebulized 3% saline solution treatment in ambulatory children with viral bronchiolitis decreases symtpoms. Chest 2002;122: Mandelberg A, et al. Nebulized 3% hypertonic saline solution treatment in hospitalized infants with bronchiolitis. Chest 2003;123: Tal G, et al. Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalizations stay: 2 years experience. IMAJ 2006;8: Early Studies Sarell 2002 outpatient trial (n=70), no impact on hospitalization rates, but + impact on respiratory scores, all treatments given with 5mg terbutaline Mandelberg 2003 inpatient (n=52), +impact on both scores and LOS, all treatments given with 1.5 mg epinephrine Tal inpatient (n=41), +impact on both scores and LOS, all treatments given with 1.5 mg epinephrine Leading to the Multicenter Trial Kuzik BA, et al. Nebulized hypertonic saline in the treatment of viral bronchiolitis in infants. J Pediatr 2007;151: Multicenter, Canada and UAE, inpatient (n=96), +impact on LOS with a 30% reduction amounting to about 1 day Then, the Meta-analysis Zhang L, et al Cochrane. Analyzed the three Israeli studies and Kuzik Inpatient pooled results (3 studies, 189 patients) showed a 0.94 day decrease in LOS (CI 1.48 to 0.4) Recent Studies Luo 2009 Luo Zhengxiu, et al. International Pediatrics Chong Qing Medical University Wards. N=93 inpatients, 1.4 d decrease in LOS (6.4 vs. 4.8 days) At least a day off time to resolution of wheezing, cough and moist crackles..whatever those are. Recent Studies Al-Ansari Al-Ansari K, et al. J Peds Infants admitted to a Qatari hospital short stay unit. N=187, no impact on LOS (1.5 d), three arms comparing 5% to 3% to NS, with sig difference in severity scores at 48hr only for 5% vs. NS

3 Recent Studies Luo 2010 Luo Zhengxiu, et al. Clinical Microbiology and Infection Chong Qing group again. N=126 inpatients, 1.6 d decrease in LOS, at least 1 d decrease in other symptoms, this time it was 3% saline vs. NS without any bronchodilators prescribed. Only prior study to do this was Kuzik where about 30% of doses of 3% given without bronchodilators. Emergency Dept Studies Grewal S, et al. Archives Candadian ED. (n=46) Two arms, epi + NS vs. epi + HS, and up to two doses. Outcome was RACS. Everybody got better. Anil AB, et al. Ped Pulm Turkish ED. (n=186) Five arm study, albuterol and epi combined with either NS or HS vs. NS placebo give twice. 120 mins duration. Everybody got better. So why might this actually work? In vitro, HS increases airway surface thickness, decreases epithelial edema and improves mucus rheology and transport rates In vivo, HS increases mucociliary transport in normal subjects Theory of dehydration of ASL It is proposed that mucociliary failure such as occurs in CF also occurs in severe bronchiolitis due to dehydration of the ASL Airway surface liquid (ASL) is the combined mucus layer (top) and the cell surface periciliary liquid This gets dehydrated and inspissated in CF with even minor insults Mandelberg A, Amirav I. Pediatric Pulmonology 45:36-40 (2010). from Mandelberg and Amirav, modified from Randell and Donaldson What might HS do in bronchiolitis? Hydrates the ASL Breaks ionic bonds in mucus layer which reduces cross linking Increases ciliary beat frequency by release of PGE2 (note higher conc. may decrease cbf) Causes conformational change in mucus by shielding negative charges thereby reducing repulsion Theoretically reduces edema in airway wall through flow of free water into the ASL Induces cough and moves out the sputum which is now better able to flow

4 Nebulized distilled water makes a bad placebo Initial Ribavirin studies were done with distilled water as placebo, and then were not repeatable, ultimate conclusion was that the placebo was harmful whereas the medicine wasn t very useful.. NS may not be a placebo Many authors of negative studies have made this conjecture, everybody in these studies gets significantly better which makes them awfully hard to power when you are using respiratory scores as the outcome Sood N. Am J Respir Crit Care Med. 2003; 167: (proposed effects on ASL not concentration dependent but function of total NaCl delivered) Further hypothesized by both Anil and Mandelberg But is it safe? Major concern was with bronchospasm In asthma studies HS has been used to demonstrate that a patient has asthma (i.e. suffers from a repeated pattern of reversible airway obstruction) Doses are generally much higher in asthma studies (concentrations of at least 4.5% and clear dose-response curve seen with increasing volumes) From Anderson Chest - Volume 138, Issue 2 Suppl 1 (August 2010) Direct Evidence of Safety? Kuzik was the first to administer in bronchiolitis without beta-agonists but did not report clearly on this question Ralston and Hill retrospectively reported on safety profile with clear data on timing of doses of HS vs. beta-agonists Luo did a full RCT without beta-agonists Favorable safety profile for nebulized 3% in bronchiolitis is likely established

5 So what s next? Currently a multicenter study in the US at CHLA and Oakland Children s (with albuterol) Undoubtedly there will be more studies without albuterol in both the US and Canada Only in inpatients, outpatients, at home? Could you just use enough NS? No safety concerns, cheap, easy.