Doi:10.1016/j.jpeds.2007.04.010

Nebulized Hypertonic Saline in the Treatment of Viral
Bronchiolitis in Infants
BRIAN A. KUZIK, MD, MSC, FRCP(C), SAMIM A. AL QADHI, MD, MBCHB, STEVEN KENT, BSC(MED), MD, FRCP(C), MICHAEL P. FLAVIN, MB, MRCP(UK), FRCP(C), WILMA HOPMAN, MA, SIMON HOTTE, MD, AND SARAH GANDER, MD Objective
To investigate the use of nebulized 3% hypertonic saline (HS) for treating viral bronchiolitis in moderately ill
hospitalized infants by a prospective, randomized, double-blinded, controlled, multicenter trial.
Study design
A total of 96 infants (mean age, 4.7 months; range, 0.3 to 18 months) admitted to the hospital for treatment
of viral bronchiolitis were recruited from 3 regional pediatric centers over 3 bronchiolitis seasons (December 2003 to May
2006). Patients were randomized to receive, in a double-blind fashion, repeated doses of nebulized 3% HS (treatment group)
or 0.9% normal saline (NS; control group), in addition to routine therapy ordered by the attending physician. The principal
outcome measure was hospital length of stay (LOS).
On an intention-to-treat basis, the infants in the HS group had a clinically relevant 26% reduction in LOS to 2.6 ؎
1.9 days, compared with 3.5 ؎ 2.9 days in the NS group (P ؍ .05). The treatment was well tolerated, with no adverse effects
attributable to the use of HS.
Conclusions
The use of nebulized 3% HS is a safe, inexpensive, and effective treatment for infants hospitalized with
moderately severe viral bronchiolitis. (J Pediatr 2007;151:266-70)
Respiratorysyncytialvirus(RSV)accountsforthemajorityofviralbronchiolitiscases,althoughotherviruses,including
human metapneumovirus, adenovirus, parainfluenza, rhinovirus, and influenza,also play important Given that virtually all children become infected with RSV by age 2 years and that at least 1% of these children will develop bronchiolitis sufficient to require the burden of this disease is high, accounting for upto 17% of all infant at an annual cost of more than $500 million in theUnited States From the Department of Paediatrics,Sheikh Khalifa Medical City, Abu Dhabi, Despite the high prevalence and morbidity of bronchiolitis, therapy remains con- United Arab Emirates (B.K., S.Q.); Depart- troversial and without widely accepted therapeutic guidelines other than supportive ment of Paediatrics, University of BritishColumbia, Victoria General Hospital, Victo- Bronchiolitis is characterized by airway plugging with sloughed epithelium, ria, British Columbia, Canada (S.K.); Depart- mucus, and edema rather than Nevertheless, the use of nebulized ment of Paediatrics, Queen’s University, bronchodilators continues to be despite extensive evidence supported by 3 Kingston General Hospital, Kingston, On-tario, Canada (M.F., S.H., S.G.); Clinical Re- meta-analyses that the benefits are limited, short term, and do not justify routine Similarly, although steroids might reasonably be expected to decrease the inflammatory response in bronchiolitis, published data are conflicting, with equally well-designed Supported by the Queen Alexandra Foun-dation for Children, British Columbia, Can- studies concluding that steroids may be either or The primary treatment, therefore, remains largely supportive, with administration of fluids and Youth and Maternal Programme, BritishColumbia, Canada; and an Ontario Tho- supplemental oxygen, observation, and mechanical ventilatory support as Several reports over the last decade have demonstrated that inhalation of nebulized No reprint requests are available from the 6% to 10% hypertonic saline (HS) improves both immediate and long-term clearance of small airways in patients with cystic The exact mechanism is unknown but Submitted for publication Aug 17, 2006;last revision received Mar 7, 2007; accepted is thought to facilitate removal of inspissated mucus through osmotic hydration, disrup- tion of mucus strand cross-linking, and reduction of mucosal In otherwise Reprint requests: Brian A. Kuzik, MD, MSc,FRCP(C), Department of Paediatrics, RoyalVictoria Hospital of Barrie, 208-1 QuarryRidge Road, Barrie, Ontario, Canada L4M Respiratory Distress Assessment Instrument 6M2. E-mail: briankuzik@hotmail.com.
healthy infants hospitalized with viral bronchiolitis, the reg- Study Design
ular administration of nebulized 3% HS combined with epi- Patients admitted to hospital with bronchiolitis were nephrine decreased length of stay (LOS) by approximately assessed within 12 hours for entry into the study. If inclusion/ 22% compared with infants receiving the same dose of epi- exclusion criteria were satisfied, then informed consent was nephrine mixed in 0.9% normal saline Similarly, in obtained, and the patient was randomized to receive treat- ambulatory infants with mild bronchiolitis, inhalation of neb- ment with 4 mL of nebulized study solution containing either ulized 3% HS (with terbutaline) improved clinical scores but 3% HS (study group) or NS (control group). The study did not produce a decrease in hospital admission rate.Both solution was administered in a double-blind fashion every 2 of the aforementioned studies used 3 times per day dosing, hours for 3 doses, followed by every 4 hours for 5 doses, which is significantly less than the 3 to 6 times per hour followed by every 6 hours until discharge. After study enroll- regimens often used to deliver nebulized medication to chil- ment, any additional (nonprotocol) treatments were at the sole discretion of the attending physician, who was blinded to The purpose of the present study was to investigate the the study treatment. If additional treatments included nebu- addition of frequently nebulized 3% HS to standard therapy lized medication, the medication was nebulized in 4 mL of of moderately ill infants hospitalized with typical viral bron- the assigned study solution (ie, HS or NS). All inhaled chiolitis in a prospective, randomized, double-blind, con- therapies were delivered to a settled infant from a standard trolled fashion. The primary objective was to compare the oxygen-driven hospital nebulizer through a tight-fitting face-mask, or head box, whichever was better tolerated by the LOS of these infants with that of a control group of infants receiving standard therapy plus frequently nebulized NS.
Patients were randomized independently at each study site to receive either HS or NS using a computer-based randomization program. Study solutions were prepared by aresearch pharmacist and were identical in appearance and Patients
odor. The identity of the study solutions was blinded to all Infants up to age 18 months who were admitted to the participants, care providers, and investigators. Clinical re- hospital for the treatment of moderately severe viral bronchi- sponse was determined by the designated study physicianusing RDAI scores and SaO olitis were eligible for study. The diagnosis of moderately severe bronchiolitis required a history of a preceding viralupper respiratory infection, the presence of wheezing orcrackles on chest auscultation, plus either an oxygen satura- Determination of LOS
LOS was defined as the time between study entry 2) of Ͻ94% in room air or significant respiratory distress as measured by a Respiratory Distress Assessment (within 12 hours of admission to the hospital) and the time at Instrument score of Ն4. In brief, 6 separate assess- which the infant either reached protocol-defined discharge ments of retractions and auscultatory findings are made and criteria as measured by the study physician or was discharged assigned a numerical score; the sum of these scores provides from the hospital on independent clinical grounds by the the RDAI score ranging from 0 to 17, with increasing scores attending physician, whichever came first. Protocol-defined indicating increasing respiratory distress.
discharge criteria required both an RDAI score Ͻ4 and an Exclusion criteria included a history of any of the fol- SaO2 of at least 95% in room air for 4 hours.
lowing: previous episode of wheezing, chronic cardiopulmo-nary disease or immunodeficiency; critical illness at presenta- tion requiring admission to intensive care; the use of The study was approved by the ethics and human nebulized HS within the previous 12 hours; or premature research committees of the 3 participating hospitals. In- birth (gestational age Յ 34 weeks).
formed written consent was obtained from at least 1 parent ofeach infant before enrollment.
Statistical Strategy
The study was conducted at 3 regional tertiary care A reduction in LOS of 1 day was previously proposed as hospitals: Sheikh Khalifa Medical City (SKMC), Abu Dhabi, being clinically and was adopted in this study. It United Arab Emirates; Victoria General Hospital (VGH), was anticipated that this would require a sample size of Victoria, British Columbia, Canada, and Kingston General approximately 46 patients per trial arm, for 80% power, to Hospital (KGH), Kingston, Ontario, Canada. VGH and show a P value Յ .05. This number is based on a prestudy KGH serve multiethnic populations in the west coast and mean LOS at the largest study hospital (SKMC) of 4.1 Ϯ 1.7 central regions of Canada, respectively. Data were collected days (unpublished data). Data were entered into an Excel during the winter bronchiolitis seasons between December spreadsheet (Microsoft Corp, Redmond, WA) and imported into SPSS version 12.0.1 software (SPSS Inc, Chicago, IL) Nebulized Hypertonic Saline in the Treatment of Viral Bronchiolitis in Infants Table I. Patient demographics and illness status at
Table III. Treatments received during the study
baseline
Treatment
(n ؍ 47)*
(n ؍ 49)*
P
(n ؍ 47)*
(n ؍ 49)*
P
*Sample sizes vary slightly for the individual comparisons due to missing data.
tested infants were positive for RSV. Subset comparison of the SKMC and Canadian sites revealed minimal differences *Sample sizes vary slightly for the individual comparisons due to missing data.
the Arab infants tended to be sicker (RDAI 8.9 Ϯ 2.9 vs6.2 Ϯ 1.9; P Ͻ .001) and more likely to receive previoustreatment with a bronchodilator (98% vs 70%; P Ͻ .001), all for analysis on an intention-to-treat basis. Descriptive analy- ses were completed overall and also for the control and studygroups separately. The ␹2 test (Fisher’s exact) was used to Treatment Received
examine the association between categorical variables and After enrollment, all treatments (protocol and add-on) group, and independent sample t tests and Levene’s test for received by infants in the HS and NS groups were comparable equality of variance were used to assess the association be- The infants received a mean of 9 nebulizations of tween numeric variables and group. One-way analysis of study solution per day delivered alone (38% of treatments) or variance (ANOVA) was used to compare data from the 3 co-administered with albuterol (salbutamol; 37%), racemic study sites. To test for the potential effect of age on the epinephrine (racepinephrine; 23%), or inhaled steroid (3%).
results, the patients were divided into 3 age groups (0 to 6 Subset comparison of the SKMC and Canadian sites revealed months, 7 to 12 months, and 13 to 18 months), and the minimal differences in the treatments received effects of age and treatment were tested in a 2-way ANOVA.
available at Treatment at SKMC was morelikely to include antibiotics (P ϭ .002) as well as the addition of racemic epinephrine to the inhaled study solution (P ϭ Study Population
A total of 96 previously well infants (mean age, 4.7 Ϯ 4.2 months; range, 10 days to 18 months) with viral bron- Adverse Effects of HS
chiolitis were enrolled from 3 centers during the bronchiolitis All participants tolerated therapy without apparent ad- seasons from December 2003 to May 2006. Thirty-two in- verse effects and were eventually discharged after achieving fants were enrolled from the 2 Canadian sites (VGH and full recovery. No infants were withdrawn by the medical staff KGH), and 64 infants were enrolled from SKMC. Forty- due to clinical deterioration or the need for intensive care seven infants were randomized to the HS treatment group, support. Although 5 infants were withdrawn at parents’ re- and 49 were randomized to the NS control group. Five infants quest because of perceived adverse effects of therapy, only 2 of (2 from the HS group and 3 from the NS group) were these infants were receiving HS. One of these infants (a withdrawn at parental request before study completion but 2-month-old male) cried very vigorously during his third were included in the final intention-to-treat analysis.
inhalation (HS alone) and again with his fifth inhalation (HS The HS and NS groups were comparable at baseline with racemic epinephrine) and was withdrawn at that time.
and typically presented on the fifth day of illness (range, 1 to This was not associated with any significant acute change in 14 days) with borderline hypoxia (mean SaO2, 95%; range, his clinical condition, and he was eventually discharged on 85% to 100%) and moderate respiratory distress (mean clinical day 6. The second infant (a 3-month-old female) was with- score, 8 out of 17; range, 4 to 17) Some 69% of all drawn because of agitation after her second inhalation (HS The Journal of Pediatrics • September 2007 bronchiolitis studies, with a slight male predominance (62%),primary infection with RSV (69%), mean age of 4.7 months,and LOS in the control group of 3.5 to 4 Strictinclusion and discharge criteria were used to minimize pos-sible confounding effects of uncharacterized and evolvingwheezing phenotypes and to minimize between-site variabil-ity. The clinical scoring system chosen has been widely usedin other studies on and has been proposedto be the scoring system of choice for further studies.Therefore, our findings should be universally applicable toother previously healthy infants hospitalized with moderatelysevere viral bronchiolitis.
The majority of our patients received bronchodilators before study entry. In addition, although our study protocoldid not require or encourage the co-administration of bron-chodilator with the study solution, blinded attending physi-cians prescribed bronchodilators approximately 5 times perday. This finding was not unexpected, because the use ofbronchodilators in bronchiolitis remains widespread, withsome reporting it in more than 80% of It is alsopossible that attending physicians prescribed bronchodilatorsto prevent possible adverse effects of HS. Although inhalationof HS may cause bronchoconstriction in and Figure. Percentage of patients in each group remaining in the hospital.
co-administration with a bronchodilator is often recom- with albuterol), which was not associated with a significant mended,others have reported that inhalation of 4.5% to change in her respiratory status. She was eventually dis- 7% HS (without a bronchodilator) can be performed safely in healthy nonasthmatic childrenor in children with mod-erately severe small airway obstruction secondary to cystic Response to Therapy
In our study, there were no apparent adverse effects The endpoint of LOS was identified by the attending attributable to the use of HS without a bronchodilator, al- physician using clinical grounds alone (45% of patients) or by though the numbers were insufficient to allow further explo- reaching protocol-established discharge criteria as measured ration of this issue. However, there was no increase in add-on by the study physician (55% of patients), whichever came first.
bronchodilator therapy in the treatment group, suggesting One-way ANOVA confirmed that the LOS did not differ that the use of HS in this setting was not associated with a significantly between study sites for either the NS group (P ϭ clinically significant increase in lower airway obstruction.
.12) or the HS group (P ϭ .44).
The use of inhaled HS in the treatment of viral bron- Infants in the control group had a mean LOS of 3.5 Ϯ chiolitis in hospitalized infants is a novel therapy that was first 2.9 days, whereas infants treated with nebulized 3% HS were reported in and recently strengthened with the pub- discharged on average 1 day sooner, with a 26% reduction in lication of a 2-year extension of the original These LOS to 2.6 Ϯ 1.9 days (P ϭ .05). There was a trend toward authors demonstrated that 3 times a day dosing with 4 mL of greater improvement in infants under age 6 months, but this 3% HS containing 1.5 mg of epinephrine compared with the difference did not attain statistical significance (P ϭ .17). The same dose of epinephrine in NS reduced the LOS from 3.6 Ϯ percentage of patients from each group remaining in hospital 1.6 days to 2.8 Ϯ 1.3 days, a 22% improvement (P Ͻ .05).
They included epinephrine to prevent possible adverse effectsof HS and attributed the beneficial effects in the treatment group to the presence of HS. Our study was very similar but This study demonstrates that inhaled 3% HS is an differed primarily in the inclusion of slightly older infants (up effective treatment for infants up to age 18 months hospital- to age 18 months), plus the much more frequent dosing of HS ized with viral bronchiolitis. Repeated inhalations of nebu- (9.1 Ϯ 3.0 inhalations/day). In our hands, increasing the lized HS reduced the LOS by approximately 1 day, from frequency of inhaled HS produced a further reduction in the 3.5 Ϯ 2.9 to 2.6 Ϯ 1.9 days. This is a clinically relevant benefit LOS to 26%, but this reduction was not significant compared with the potential for widespread impact on the treatment of The routine use of 3% HS in the treatment of infants The infants that we studied came from a population hospitalized with bronchiolitis has the potential for enormous that was geographically and ethnically very diverse. Neverthe- economic benefit. A 26% reduction in LOS not only will less, these infants were very similar to those described in other return infants to home and their parents to work a day sooner, Nebulized Hypertonic Saline in the Treatment of Viral Bronchiolitis in Infants but also will also substantially reduce hospital costs. The 19. Patel H, Platt R, Lozano JM, Wang EEL. Glucocorticoids for acute viral bron-
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The Journal of Pediatrics • September 2007 Table II. Site-specific patient demographics and
Table IV. Site-specific treatments received
illness status at baseline
KGH ؉ VGH
VGH ؉ KGH
Treatment
(n ؍ 64)*
(n ؍ 32)*
P
(n ؍ 64)*
(n ؍ 32)*
P
*Sample sizes vary slightly for the individual comparisons due to missing data.
*Sample sizes vary slightly for the individual comparisons due to missing data.
Nebulized Hypertonic Saline in the Treatment of Viral Bronchiolitis in Infants

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