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Is Nebulized Hypertonic Saline Solution an Effective Treatment for Bronchiolitis in Infants?

2009; Elsevier BV; Volume: 55; Issue: 1 Linguagem: Inglês

10.1016/j.annemergmed.2009.04.006

1097-6760

Kanwal Chaudhry, Richard Sinert,

Respiratory Support and Mechanisms

[Ann Emerg Med. 2010;55:120-122.]Systematic Review SourceThis is a systematic review abstract, a regular feature of the Annals' Evidence-Based Emergency Medicine (EBEM) series. Each features an abstract of a systematic review from the Cochrane Database of Systematic Reviews and a commentary by an emergency physician knowledgeable in the subject area.The source of this systematic review abstract is: Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2008;(4):CD006458.1Zhang L. Mendoza-Sassi R.A. Wainwright C. et al.Nebulized hypertonic saline solution for acute bronchiolitis in infants.Cochrane Database Syst Rev. 2008; (CD006458)Google ScholarThe Annals' EBEM editors assisted in the preparation of the abstract of this Cochrane systematic review.ObjectivesTo assess the effects of nebulized hypertonic saline solution in infants with acute viral bronchiolitis.Data SourcesThe authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2007, issue 4), which contains the Cochrane Acute Respiratory Infections Group Specialized Register; OLDMEDLINE (1951 to 1965); MEDLINE (1966 to November 2007); EMBASE (1974 to November 2007); and LILACS (November 2007).Study SelectionThe authors included randomized controlled trials and quasi–randomized controlled trials using nebulized hypertonic saline solution alone or in conjunction with bronchodilators as an active intervention in infants up to 24 months of age who had acute bronchiolitis distinguished from asthma by being their first episode of wheezing associated with cough, coryza, and fever.The primary outcomes were hospital length of stay and admission rates. Secondary outcomes included clinical severity scores, readmission rate, oxygen saturation level, pulse and respiratory rates, time for symptom resolution, duration of oxygen therapy, pulmonary function test results, and radiologic findings. Known and expected adverse events of medications used were recorded, such as tachycardia, hypertension, pallor, tremors, nausea, vomiting, and acute urinary retention.Data Extraction and AnalysisTwo authors independently selected trials for the review. When relevant articles were identified, the authors assessed each independently for satisfaction of inclusion criteria. The methodological quality of all included trials was judged by using the 5-point scoring system of Jadad.2Jadad A. Moore A.R. Carroll D. et al.Assessing the quality of reports of randomized clinical trials: Is blinding necessary?.Controlled Clinical Trials. 1996; 17: 1-12Abstract Full Text PDF PubMed Scopus (13367) Google Scholar Disagreements between the authors for inclusion/exclusion of trials and quality were resolved by discussion.The authors combined outcomes from individual trials by using the Cochrane statistical package RevMan 5 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Norway). Meta-analysis was conducted for hospital length of stay and clinical severity scores; pooled treatment effects were estimated with relative risk for hospitalization rates and mean difference for clinical severity scores and hospital length of stay. Heterogeneity was assessed by visual inspection of graphic presentations and the I2 statistic. Tests of heterogeneity seek to determine whether the variety of results from different trials in the meta-analysis are due to chance or the result of significant differences in study design such as sampling methods, variations in treatment, or variations in study quality. The I2 statistic describes the percentage of variation in effect estimates across studies beyond that expected by chance. When I2=0%, any differences between the study results are probably not important; on the other hand, when I2 is greater than 50%, substantial heterogeneity may be present and sources of the heterogeneity require exploration. The final decision of an acceptable level of study heterogeneity in a meta-analysis is still a matter of debate.3Higgins J.P. Thompson S.G. Deeks J.J. et al.Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560Crossref PubMed Scopus (38377) Google ScholarMain ResultsThere were 4 double-blind randomized controlled trials involving 254 infants in the review, which included 1 outpatient (n=65) and 3 inpatient (n=189) studies. Participants were between a mean age of 2.6 and 12.5 months, with a range of 10 days to 24 months. Respiratory syncytial virus was found in 69% to 87% of subjects. All the trials used the same intervention of nebulized 3% saline solution, 2 mL in 1 trial and 4 mL in the other 3 trials. Although all 4 trials used 0.9% saline solution in control inhalations, the other components of standard therapy administered to both the control and intervention groups differed among the individual studies. Two trials included 1.5 mg of nebulized epinephrine, 1 trial used 5 mg of nebulized terbutaline, and 1 trial did not require or encourage the addition of any bronchodilators. This clinical heterogeneity as a result of the difference in bronchodilators could not be adjusted for in the analysis. Clinical heterogeneity among the trials was also evident, given that 3 trials delivered inhalations every 8 hours, whereas 1 trial prescribed nebulizers every 2 hours for 3 treatments.All 3 inpatient studies measured length of stay as the primary outcome, but only 2 trials used the same clinical severity score. The single outpatient trial used hospital admission rate and clinical severity score as outcome measures. All 4 trials were deemed adequate with respect to concealment, blinding, and follow-up; however, only 1 trial reported results by using an intention-to-treat analysis.Hypertonic saline solution compared with normal saline solution nebulizers significantly reduced hospital length of stay by 25.9%, with a mean decrease of 0.94 days (95% confidence interval 0.40 to 1.48 days), with minimal heterogeneity (I2=0.0%) identified between the 3 inpatient trials. Admission rate was not significantly (P=.65) different between the hypertonic and normal saline solution group in the outpatient study. Pretreatment clinical severity scores were comparable between the intervention and control groups for all trials. Pooled clinical severity scores for all trials showed significant improvement for the nebulized hypertonic saline solution groups compared with normal saline solution groups during the first 3 days of treatment. Subgroup analysis of the improvements of clinical severity scores showed substantial heterogeneity (I2=59%) between the in- and outpatient trials. The outpatient trial patients had significantly greater improvement in clinical severity scores compared with the inpatient trial patients, a result that persisted throughout the study period. No adverse events were reported for the hypertonic saline solution group in any of the reviewed trials.ConclusionsNebulized 3% saline solution in combination with β-agonists used in infants with bronchiolitis appears to reduce clinical severity scores and hospital lengths of stay without adverse effects.Systematic Review Author ContactLinjie Zhang, MD, PhDDepartment of Maternal and Child HealthFederal University of Rio Grande, Rua Visconde ParanaguáRio Grande, BrazilE-mail[email protected]Commentary: Clinical ImplicationBronchiolitis is a common, occasionally severe, viral infection of the lower respiratory tract that affects children younger than 2 years, with a peak incidence between 3 and 6 months. In the United States, the Centers for Disease Control and Prevention estimates that 25 of 1,000 children with bronchiolitis will require hospitalization, and 1% to 2% of these children will require ventilatory support.4Greensill J. McNamara P.S. Dove W. et al.Human metapneumovirus in severe respiratory syncytial virus bronchiolitis.Emerg Infect Dis. 2003; 9: 372-375Crossref PubMed Scopus (274) Google Scholar The US economic effect of bronchiolitis approaches $700 million per year.5Stang P. Brandenburg N. Carter B. The economic burden of respiratory syncytial virus-associated bronchiolitis hospitalizations.Arch Pediatr Adolesc Med. 2001; 155: 95-96PubMed Google Scholar Worldwide, the World Health Organization estimates that bronchiolitis is responsible for 18,000 to 75,000 hospitalizations, with 90 to 1,900 deaths annually.6Girard M.P. Cherian T. Pervikov Y. et al.A review of vaccine research and development: human acute respiratory infections.Vaccine. 2005; 23: 5708-5724Crossref PubMed Scopus (132) Google ScholarCurrently, the emergency department (ED) treatment for bronchiolitis is variable and typically consists of a trial of nebulized β2-agonists (albuterol, terbutaline, epinephrine) diluted in normal saline solution.7Mansbach J.M. Emond J.A. Camargo Jr, C.A. Bronchiolitis in US emergency departments, 1992 to 2000: epidemiology and practice variation.Pediatr Emerg Care. 2005; 21: 242-247Crossref PubMed Scopus (97) Google Scholar The addition of nebulized or oral corticosteroids does not offer any short- or long-term clinical benefits.8Cade A. Brownlee K.G. Conway S.P. et al.Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis.Arch Dis Child. 2000; 82: 126-130Crossref PubMed Scopus (129) Google Scholar, 9Corneli H.M. Zorc J.J. Mahajan P. et al.A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis.N Engl J Med. 2007; 357: 331-339Crossref PubMed Scopus (228) Google ScholarThis Cochrane review assessing the effectiveness of nebulized hypertonic saline solution (3%) for bronchiolitis provides some support for use in the inpatient setting, but there was significant statistical (I2=59%) and clinical heterogeneity identified with respect to improvements in clinical severity scores between in- and outpatient trials. Unfortunately, the applicability of the results of this Cochrane review to the acute care setting is limited by the fact that only a single small clinic-based study (n=65) was designed to address the ED-relevant outcome of admission rate and failed to show any difference with nebulized hypertonic saline solution.10Sarrell E.M. Tal G. Witzling M. et al.Nebulized 3% hypertonic saline solution treatment in ambulatory children with viral bronchiolitis decreases symptoms.Chest. 2002; 122: 2015-2020Crossref PubMed Scopus (89) Google Scholar The fact that in 3 of the studies, including the clinic-based trial, the intervention was administered every 8 hours also highlights problems with application to the ED setting. On the other hand, improvements in the secondary outcomes of studies reporting clinical severity scores were most pronounced in the outpatient setting compared with inpatient settings. One argument for considering the initiation of nebulized 3% saline solution in the ED is that therapies started in the ED may be continued on an inpatient basis when the benefit of decreasing hospital length of stay might be realized. However, future studies need to establish what is a clinically relevant reduction in hospital length of stay.Take-Home MessageThere is a lack of strong evidence to support routine use of nebulized hypertonic saline solution for infants presenting to the ED with acute bronchiolitis.EBEM Commentator ContactRichard Sinert, DODepartment of Emergency MedicineState University of New York, Downstate Medical CenterBrooklyn, NYEmail[email protected] [Ann Emerg Med. 2010;55:120-122.] Systematic Review SourceThis is a systematic review abstract, a regular feature of the Annals' Evidence-Based Emergency Medicine (EBEM) series. Each features an abstract of a systematic review from the Cochrane Database of Systematic Reviews and a commentary by an emergency physician knowledgeable in the subject area.The source of this systematic review abstract is: Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2008;(4):CD006458.1Zhang L. Mendoza-Sassi R.A. Wainwright C. et al.Nebulized hypertonic saline solution for acute bronchiolitis in infants.Cochrane Database Syst Rev. 2008; (CD006458)Google ScholarThe Annals' EBEM editors assisted in the preparation of the abstract of this Cochrane systematic review. This is a systematic review abstract, a regular feature of the Annals' Evidence-Based Emergency Medicine (EBEM) series. Each features an abstract of a systematic review from the Cochrane Database of Systematic Reviews and a commentary by an emergency physician knowledgeable in the subject area. The source of this systematic review abstract is: Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2008;(4):CD006458.1Zhang L. Mendoza-Sassi R.A. Wainwright C. et al.Nebulized hypertonic saline solution for acute bronchiolitis in infants.Cochrane Database Syst Rev. 2008; (CD006458)Google Scholar The Annals' EBEM editors assisted in the preparation of the abstract of this Cochrane systematic review. ObjectivesTo assess the effects of nebulized hypertonic saline solution in infants with acute viral bronchiolitis. To assess the effects of nebulized hypertonic saline solution in infants with acute viral bronchiolitis. Data SourcesThe authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2007, issue 4), which contains the Cochrane Acute Respiratory Infections Group Specialized Register; OLDMEDLINE (1951 to 1965); MEDLINE (1966 to November 2007); EMBASE (1974 to November 2007); and LILACS (November 2007). The authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2007, issue 4), which contains the Cochrane Acute Respiratory Infections Group Specialized Register; OLDMEDLINE (1951 to 1965); MEDLINE (1966 to November 2007); EMBASE (1974 to November 2007); and LILACS (November 2007). Study SelectionThe authors included randomized controlled trials and quasi–randomized controlled trials using nebulized hypertonic saline solution alone or in conjunction with bronchodilators as an active intervention in infants up to 24 months of age who had acute bronchiolitis distinguished from asthma by being their first episode of wheezing associated with cough, coryza, and fever.The primary outcomes were hospital length of stay and admission rates. Secondary outcomes included clinical severity scores, readmission rate, oxygen saturation level, pulse and respiratory rates, time for symptom resolution, duration of oxygen therapy, pulmonary function test results, and radiologic findings. Known and expected adverse events of medications used were recorded, such as tachycardia, hypertension, pallor, tremors, nausea, vomiting, and acute urinary retention. The authors included randomized controlled trials and quasi–randomized controlled trials using nebulized hypertonic saline solution alone or in conjunction with bronchodilators as an active intervention in infants up to 24 months of age who had acute bronchiolitis distinguished from asthma by being their first episode of wheezing associated with cough, coryza, and fever. The primary outcomes were hospital length of stay and admission rates. Secondary outcomes included clinical severity scores, readmission rate, oxygen saturation level, pulse and respiratory rates, time for symptom resolution, duration of oxygen therapy, pulmonary function test results, and radiologic findings. Known and expected adverse events of medications used were recorded, such as tachycardia, hypertension, pallor, tremors, nausea, vomiting, and acute urinary retention. Data Extraction and AnalysisTwo authors independently selected trials for the review. When relevant articles were identified, the authors assessed each independently for satisfaction of inclusion criteria. The methodological quality of all included trials was judged by using the 5-point scoring system of Jadad.2Jadad A. Moore A.R. Carroll D. et al.Assessing the quality of reports of randomized clinical trials: Is blinding necessary?.Controlled Clinical Trials. 1996; 17: 1-12Abstract Full Text PDF PubMed Scopus (13367) Google Scholar Disagreements between the authors for inclusion/exclusion of trials and quality were resolved by discussion.The authors combined outcomes from individual trials by using the Cochrane statistical package RevMan 5 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Norway). Meta-analysis was conducted for hospital length of stay and clinical severity scores; pooled treatment effects were estimated with relative risk for hospitalization rates and mean difference for clinical severity scores and hospital length of stay. Heterogeneity was assessed by visual inspection of graphic presentations and the I2 statistic. Tests of heterogeneity seek to determine whether the variety of results from different trials in the meta-analysis are due to chance or the result of significant differences in study design such as sampling methods, variations in treatment, or variations in study quality. The I2 statistic describes the percentage of variation in effect estimates across studies beyond that expected by chance. When I2=0%, any differences between the study results are probably not important; on the other hand, when I2 is greater than 50%, substantial heterogeneity may be present and sources of the heterogeneity require exploration. The final decision of an acceptable level of study heterogeneity in a meta-analysis is still a matter of debate.3Higgins J.P. Thompson S.G. Deeks J.J. et al.Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560Crossref PubMed Scopus (38377) Google Scholar Two authors independently selected trials for the review. When relevant articles were identified, the authors assessed each independently for satisfaction of inclusion criteria. The methodological quality of all included trials was judged by using the 5-point scoring system of Jadad.2Jadad A. Moore A.R. Carroll D. et al.Assessing the quality of reports of randomized clinical trials: Is blinding necessary?.Controlled Clinical Trials. 1996; 17: 1-12Abstract Full Text PDF PubMed Scopus (13367) Google Scholar Disagreements between the authors for inclusion/exclusion of trials and quality were resolved by discussion. The authors combined outcomes from individual trials by using the Cochrane statistical package RevMan 5 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Norway). Meta-analysis was conducted for hospital length of stay and clinical severity scores; pooled treatment effects were estimated with relative risk for hospitalization rates and mean difference for clinical severity scores and hospital length of stay. Heterogeneity was assessed by visual inspection of graphic presentations and the I2 statistic. Tests of heterogeneity seek to determine whether the variety of results from different trials in the meta-analysis are due to chance or the result of significant differences in study design such as sampling methods, variations in treatment, or variations in study quality. The I2 statistic describes the percentage of variation in effect estimates across studies beyond that expected by chance. When I2=0%, any differences between the study results are probably not important; on the other hand, when I2 is greater than 50%, substantial heterogeneity may be present and sources of the heterogeneity require exploration. The final decision of an acceptable level of study heterogeneity in a meta-analysis is still a matter of debate.3Higgins J.P. Thompson S.G. Deeks J.J. et al.Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560Crossref PubMed Scopus (38377) Google Scholar Main ResultsThere were 4 double-blind randomized controlled trials involving 254 infants in the review, which included 1 outpatient (n=65) and 3 inpatient (n=189) studies. Participants were between a mean age of 2.6 and 12.5 months, with a range of 10 days to 24 months. Respiratory syncytial virus was found in 69% to 87% of subjects. All the trials used the same intervention of nebulized 3% saline solution, 2 mL in 1 trial and 4 mL in the other 3 trials. Although all 4 trials used 0.9% saline solution in control inhalations, the other components of standard therapy administered to both the control and intervention groups differed among the individual studies. Two trials included 1.5 mg of nebulized epinephrine, 1 trial used 5 mg of nebulized terbutaline, and 1 trial did not require or encourage the addition of any bronchodilators. This clinical heterogeneity as a result of the difference in bronchodilators could not be adjusted for in the analysis. Clinical heterogeneity among the trials was also evident, given that 3 trials delivered inhalations every 8 hours, whereas 1 trial prescribed nebulizers every 2 hours for 3 treatments.All 3 inpatient studies measured length of stay as the primary outcome, but only 2 trials used the same clinical severity score. The single outpatient trial used hospital admission rate and clinical severity score as outcome measures. All 4 trials were deemed adequate with respect to concealment, blinding, and follow-up; however, only 1 trial reported results by using an intention-to-treat analysis.Hypertonic saline solution compared with normal saline solution nebulizers significantly reduced hospital length of stay by 25.9%, with a mean decrease of 0.94 days (95% confidence interval 0.40 to 1.48 days), with minimal heterogeneity (I2=0.0%) identified between the 3 inpatient trials. Admission rate was not significantly (P=.65) different between the hypertonic and normal saline solution group in the outpatient study. Pretreatment clinical severity scores were comparable between the intervention and control groups for all trials. Pooled clinical severity scores for all trials showed significant improvement for the nebulized hypertonic saline solution groups compared with normal saline solution groups during the first 3 days of treatment. Subgroup analysis of the improvements of clinical severity scores showed substantial heterogeneity (I2=59%) between the in- and outpatient trials. The outpatient trial patients had significantly greater improvement in clinical severity scores compared with the inpatient trial patients, a result that persisted throughout the study period. No adverse events were reported for the hypertonic saline solution group in any of the reviewed trials. There were 4 double-blind randomized controlled trials involving 254 infants in the review, which included 1 outpatient (n=65) and 3 inpatient (n=189) studies. Participants were between a mean age of 2.6 and 12.5 months, with a range of 10 days to 24 months. Respiratory syncytial virus was found in 69% to 87% of subjects. All the trials used the same intervention of nebulized 3% saline solution, 2 mL in 1 trial and 4 mL in the other 3 trials. Although all 4 trials used 0.9% saline solution in control inhalations, the other components of standard therapy administered to both the control and intervention groups differed among the individual studies. Two trials included 1.5 mg of nebulized epinephrine, 1 trial used 5 mg of nebulized terbutaline, and 1 trial did not require or encourage the addition of any bronchodilators. This clinical heterogeneity as a result of the difference in bronchodilators could not be adjusted for in the analysis. Clinical heterogeneity among the trials was also evident, given that 3 trials delivered inhalations every 8 hours, whereas 1 trial prescribed nebulizers every 2 hours for 3 treatments. All 3 inpatient studies measured length of stay as the primary outcome, but only 2 trials used the same clinical severity score. The single outpatient trial used hospital admission rate and clinical severity score as outcome measures. All 4 trials were deemed adequate with respect to concealment, blinding, and follow-up; however, only 1 trial reported results by using an intention-to-treat analysis. Hypertonic saline solution compared with normal saline solution nebulizers significantly reduced hospital length of stay by 25.9%, with a mean decrease of 0.94 days (95% confidence interval 0.40 to 1.48 days), with minimal heterogeneity (I2=0.0%) identified between the 3 inpatient trials. Admission rate was not significantly (P=.65) different between the hypertonic and normal saline solution group in the outpatient study. Pretreatment clinical severity scores were comparable between the intervention and control groups for all trials. Pooled clinical severity scores for all trials showed significant improvement for the nebulized hypertonic saline solution groups compared with normal saline solution groups during the first 3 days of treatment. Subgroup analysis of the improvements of clinical severity scores showed substantial heterogeneity (I2=59%) between the in- and outpatient trials. The outpatient trial patients had significantly greater improvement in clinical severity scores compared with the inpatient trial patients, a result that persisted throughout the study period. No adverse events were reported for the hypertonic saline solution group in any of the reviewed trials. ConclusionsNebulized 3% saline solution in combination with β-agonists used in infants with bronchiolitis appears to reduce clinical severity scores and hospital lengths of stay without adverse effects.Systematic Review Author ContactLinjie Zhang, MD, PhDDepartment of Maternal and Child HealthFederal University of Rio Grande, Rua Visconde ParanaguáRio Grande, BrazilE-mail[email protected] Nebulized 3% saline solution in combination with β-agonists used in infants with bronchiolitis appears to reduce clinical severity scores and hospital lengths of stay without adverse effects.