Editorial Opinion
prehensive insurance, like that had by many people earning more than 400% of the federal poverty line (FPL), also has lower levels of cost sharing. However, cheaper commercial insurance, like that which lower-income Americans might purchase, has higher out-of-pocket expenses. Commercially insured children in families who earned less than 250% of the FPL and who had higher levels of cost sharing were more likely to avoid or delay care than those who had better commercial insurance and those with Medicaid.4 Medicaid also provided more financial protection than commercial insurance from higher levels of cost sharing. These findings have specific implications for health care reform. Although some people will find it easier to get insurance in the state exchanges than they might on the individual market before this year, many of the less expensive plans have particularly high levels of cost sharing. Silver level plans, or those that are required for many to obtain subsidies to help defray the costs of premiums, have an actuarial value of 70%, meaning that 30% of care will be paid for by individuals themselves.
Conflict of Interest Disclosures: None reported.
ARTICLE INFORMATION Author Affiliations: Center for Pediatric and Adolescent Comparative Effectiveness Research, Indiana University School of Medicine, Indianapolis; Center for Health Policy and Professionalism Research, Indiana University School of Medicine, Indianapolis. Corresponding Author: Aaron E. Carroll, MD, MS, Indiana University School of Medicine, 410 W 10th St, Health Information and Translational Sciences Bldg 4099C, Indianapolis, IN 46202 (aaecarro @iupui.edu). Published Online: May 19, 2014. doi:10.1001/jamapediatrics.2014.449.
In many areas, including California, where this study took place, the cost-sharing copayments, coinsurance, deductibles, and out-of-pocket maximums will likely be higher than the threshold set in this study. In other words, we have good reason to believe that families making less than 250% of the FPL who obtain insurance in the exchanges will avoid or delay more care and face greater financial stress than those in this study. In addition, states that forgo the Medicaid expansion or even amend it to move the poorest among us into commercial insurance with high levels of cost sharing will leave those families at increased risk for difficulty getting care or higher levels of financial stress. The Affordable Care Act will do a great deal to reduce the numbers of the uninsured in the United States. However, having insurance is just the first step toward improved access.6 Health care is still expensive, and obtaining it is still difficult for many in the United States. As Fung and colleagues4 have shown us, we cannot ignore cost sharing, especially with respect to lower-income individuals obtaining commercial insurance through the exchanges.
REFERENCES 1. Brook RH, Ware JE Jr, Rogers WH, et al. Does free care improve adults’ health? results from a randomized controlled trial. N Engl J Med. 1983;309 (23):1426-1434. 2. Nyman JA. American health policy: cracks in the foundation. J Health Polit Policy Law. 2007;32(5): 759-783. 3. Chernew ME, Newhouse JP. What does the RAND Health Insurance Experiment tell us about the impact of patient cost sharing on health outcomes? Am J Manag Care. 2008;14(7):412-414.
4. Fung V, Graetz I, Galbraith A, et al. Financial barriers to care among low-income children with asthma: health care reform implications [published online May 19, 2014]. JAMA Pediatr. doi:10.1001 /jamapediatrics.2014.79. 5. Frakt A, Carroll AE, Pollack HA, Reinhardt U. Our flawed but beneficial Medicaid program. N Engl J Med. 2011;364(16):e31. doi:10.1056/NEJMp1103168. 6. Allen H, Wright BJ, Baicker K. New Medicaid enrollees in Oregon report health care successes and challenges. Health Aff (Millwood). 2014;33(2): 292-299.
The Tale of 2 Trials Disentangling Contradictory Evidence on Hypertonic Saline for Acute Bronchiolitis Sim Grewal, MD; Terry P. Klassen, MD
For pediatricians looking for answers on how best to provide treatment for their patients, nothing can be more frustrating than 2 randomized clinical trials (RCTs) with contradictory results. It may encourage nihilism and a throwing up of Related articles pages 657 one’s hands, thinking cliniand 664 cal researchers have no idea what they are doing by producing data and gaining publications but not shedding light on the tough management issues that pediatricians face day to day. These 2 RCTs1,2 on the use of nebulized hypertonic saline for the management of bronchiolitis could potentially lead practitioners to despair in this way. One RCT1 indicates that hyjamapediatrics.com
pertonic saline is very helpful, can improve a patient’s condition clinically, and can lead to reduced hospitalizations. The other RCT2 comes to the opposite conclusion. Yet ultimately, pediatricians need some guidance as to what to do with the next patient with bronchiolitis whom they will assess and provide with treatment. Fortunately, we have made great progress and gained much understanding as to how to develop and evaluate evidence for clinical decision making in the past 60 years, and these advances can help guide us in disentangling this confusion. In the 1950s, medicine imported the RCT from the agricultural field as a useful tool to evaluate the effectiveness of new therapies.3 Over time, this process became increasingly used JAMA Pediatrics July 2014 Volume 168, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
607
Opinion Editorial
by child health researchers to build the evidence base.3 The challenge then became how to deal with this growing number of RCTs with results that were sometimes contradictory. In addition, individually the RCTs lacked statistical power and therefore had imprecise estimates of effectiveness. Hence, the meta-analysis or systematic review became an important advance in health in the mid-1970s, with Thomas C. Chalmers, MD, as one of the early advocates.4 This method was imported from the fields of psychology and education. Most recently, network meta-analysis has started to gain momentum, this being a method of combining all options for a particular health problem.5 So, back to these 2 RCTs1,2: how is it possible for 2 studies like these to arrive at such differing conclusions? It is possible that chance alone could account for this. There is always some degree of fluctuation in estimates derived from trials, and the smaller the studies, the greater will be the fluctuation. As the sample size grows, the estimates become more stable and there is less fluctuation.6 In the study by Florin et al,2 patients with bronchiolitis and persistent respiratory distress after a trial of nebulized albuterol were randomized to receive either 3% hypertonic saline or normal saline. The primary outcome was the change in respiratory distress at 1 hour after the intervention, as determined by the Respiratory Assessment Change Score (RACS). There were 31 patients in each treatment arm, and at 1 hour after the intervention, the hypertonic saline group had less improvement in median RACS compared with the normal saline group. However, this study examined only a single dose of hypertonic saline, and the treatment groups were small. In the study by Wu et al,1 patients with bronchiolitis were randomized to receive either 3% hypertonic saline or normal saline up to 3 times in the emergency department. All children received nebulized albuterol before the saline intervention. The primary outcomes were rate of hospital admission, length of stay for admitted patients, and the Respiratory Distress Assessment Instrument (RDAI) score. A total of 408 patients were enrolled in the study. The authors found a lower rate of admission in the hypertonic saline group (28.9%) vs the normal saline group (42.6%), but there was no significant difference in length of stay or RDAI score between the 2 groups. The number needed to treat to prevent 1 hospitalization was 8. However, this study failed to recruit the planned sample size of patients, thereby limiting some of the statistical analyses. In addition, there was no minimum or maximum severity criteria established for study entry, thus affecting the applicability of the results to patients with moderate or severe disease.
ARTICLE INFORMATION Author Affiliations: Division of Pediatric Emergency Medicine, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada (Grewal); Translating Emergency Knowledge for Kids, Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada (Klassen); Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada (Klassen).
608
When we consider study design and risk of bias,7 these 2 RCTs appear to be well designed. We had access to their protocols, and the studies seemed to be well implemented. Differences in populations, interventions, control, and outcome measures may also result in study results being different; however, when examining these 2 studies, there are no obvious reasons for their results to differ because of these factors. It remains to be seen whether the way in which albuterol was used in reference to hypertonic saline has an effect on the outcome. Evaluating the efficacy of hypertonic saline in the treatment of bronchiolitis is not an easy task. As seen in these 2 RCTs as well as in other studies to date, the optimal concentration, dosing frequency, and duration of therapy of hypertonic saline still need to be determined. One of the most significant limitations in the published data thus far is the small sample size. In addition, we still are unsure of what is the best outcome measure. Does a respiratory assessment tool actually translate to a clinically relevant outcome?8 Evidently, it is difficult to base treatment decisions on the result of a single study. There is, of course, some debate about what is the best evidence: a large RCT (networks) or a welldone meta-analysis? But neither of these RCTs is what one would call large. Therefore, we believe we are left with examining the totality of evidence and finding a well-designed systematic review or meta-analysis. To do this, we need to look no further than the Cochrane Database of Systematic Reviews, where an updated systematic review on the role of hypertonic saline for the treatment of bronchiolitis was published in 2013.9 The summary is that there is probably not a role for hypertonic saline for patients with bronchiolitis treated in the emergency department, but it may be helpful for inpatients by decreasing their length of hospital stay by 1.15 days. The 2 just-published RCTs1,2 now need to be incorporated into an updated systematic review to see whether the overall findings will change. An exciting proposal for the future to reduce the evidence-practice gap is to develop the “living systematic review” so that these entities would be updated almost in real time as new trials are available for inclusion.10 Therefore, rather than despair, we believe these 2 trials point us to the importance of using scientifically developed systematic reviews and meta-analyses to get the best sense of optimal treatment for children. From our read of the current systematic review (which now will need to be updated) and our read of these 2 individual trials, we would not start using hypertonic saline in the emergency department on a routine basis. However, nebulized hypertonic saline may have a role to play for children hospitalized with bronchiolitis.
Corresponding Author: Terry P. Klassen, MD, Translating Emergency Knowledge for Kids, Manitoba Institute of Child Health, 513-715 McDermot Ave, Winnipeg, MB R3E 3P4, Canada ([email protected]).
REFERENCES
Published Online: May 26, 2014. doi:10.1001/jamapediatrics.2014.423.
2. Florin TA, Shaw KN, Kittick M, Yackscoe S, Zorc JJ. Nebulized hypertonic saline for bronchiolitis in the emergency department: a randomized clinical trial [published online May 26, 2014]. JAMA Pediatr. doi:10.1001/jamapediatrics.2013.5306.
Conflict of Interest Disclosures: None reported.
1. Wu S, Baker C, Lang ME, et al. Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial [published online May 26, 2014]. JAMA Pediatr. doi:10.1001/jamapediatrics.2014.301.
JAMA Pediatrics July 2014 Volume 168, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
jamapediatrics.com
Editorial Opinion
3. Thomson D, Hartling L, Cohen E, Vandermeer B, Tjosvold L, Klassen TP. Controlled trials in children: quantity, methodological quality and descriptive characteristics of pediatric controlled trials published 1948-2006. PLoS One. 2010;5(9):e13106. doi:10.1371/journal.pone.0013106. 4. Rennie D, Chalmers I. Exposing the dangers to patients of medical reviews and textbooks that ignore scientific principles. JLL Bulletin: Commentaries on the History of Treatment Evaluation; 2009. http://www.jameslindlibrary.org /illustrating/articles/exposing-the-dangers-to -patients-of-medical-reviews-and-textbook.pdf. Accessed April 9, 2014.
jamapediatrics.com
5. Hartling L, Fernandes RM, Bialy L, et al. Steroids and bronchodilators for bronchiolitis in the first two years of life: systematic review and meta-analysis. BMJ. 2011;342:d1714. doi:10.1136/bmj.d1714.
enough benefit to warrant adoption into clinical practice? Arch Pediatr Adolesc Med. 1996;150(11): 1120-1121.
6. Ioannidis J, Lau J. Evolution of treatment effects over time: empirical insight from recursive cumulative metaanalyses. Proc Natl Acad Sci U S A. 2001;98(3):831-836.
9. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;7(4):CD006458. doi:10.1002 /14651858.CD006458.pub3.
7. Hartling L, Ospina M, Liang Y, et al. Risk of bias versus quality assessment of randomised controlled trials: cross sectional study. BMJ. 2009;339:b4012. doi:10.1136/bmj.b4012.
10. Elliott JH, Turner T, Clavisi O, et al. Living systematic reviews: an emerging opportunity to narrow the evidence-practice gap. PLoS Med. 2014; 11(2):e1001603. doi:10.1371/journal.pmed.1001603.
8. Klassen TP. Determining the benefit of bronchodilators in bronchiolitis: when is there
JAMA Pediatrics July 2014 Volume 168, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
609
prehensive insurance, like that had by many people earning more than 400% of the federal poverty line (FPL), also has lower levels of cost sharing. However, cheaper commercial insurance, like that which lower-income Americans might purchase, has higher out-of-pocket expenses. Commercially insured children in families who earned less than 250% of the FPL and who had higher levels of cost sharing were more likely to avoid or delay care than those who had better commercial insurance and those with Medicaid.4 Medicaid also provided more financial protection than commercial insurance from higher levels of cost sharing. These findings have specific implications for health care reform. Although some people will find it easier to get insurance in the state exchanges than they might on the individual market before this year, many of the less expensive plans have particularly high levels of cost sharing. Silver level plans, or those that are required for many to obtain subsidies to help defray the costs of premiums, have an actuarial value of 70%, meaning that 30% of care will be paid for by individuals themselves.
Conflict of Interest Disclosures: None reported.
ARTICLE INFORMATION Author Affiliations: Center for Pediatric and Adolescent Comparative Effectiveness Research, Indiana University School of Medicine, Indianapolis; Center for Health Policy and Professionalism Research, Indiana University School of Medicine, Indianapolis. Corresponding Author: Aaron E. Carroll, MD, MS, Indiana University School of Medicine, 410 W 10th St, Health Information and Translational Sciences Bldg 4099C, Indianapolis, IN 46202 (aaecarro @iupui.edu). Published Online: May 19, 2014. doi:10.1001/jamapediatrics.2014.449.
In many areas, including California, where this study took place, the cost-sharing copayments, coinsurance, deductibles, and out-of-pocket maximums will likely be higher than the threshold set in this study. In other words, we have good reason to believe that families making less than 250% of the FPL who obtain insurance in the exchanges will avoid or delay more care and face greater financial stress than those in this study. In addition, states that forgo the Medicaid expansion or even amend it to move the poorest among us into commercial insurance with high levels of cost sharing will leave those families at increased risk for difficulty getting care or higher levels of financial stress. The Affordable Care Act will do a great deal to reduce the numbers of the uninsured in the United States. However, having insurance is just the first step toward improved access.6 Health care is still expensive, and obtaining it is still difficult for many in the United States. As Fung and colleagues4 have shown us, we cannot ignore cost sharing, especially with respect to lower-income individuals obtaining commercial insurance through the exchanges.
REFERENCES 1. Brook RH, Ware JE Jr, Rogers WH, et al. Does free care improve adults’ health? results from a randomized controlled trial. N Engl J Med. 1983;309 (23):1426-1434. 2. Nyman JA. American health policy: cracks in the foundation. J Health Polit Policy Law. 2007;32(5): 759-783. 3. Chernew ME, Newhouse JP. What does the RAND Health Insurance Experiment tell us about the impact of patient cost sharing on health outcomes? Am J Manag Care. 2008;14(7):412-414.
4. Fung V, Graetz I, Galbraith A, et al. Financial barriers to care among low-income children with asthma: health care reform implications [published online May 19, 2014]. JAMA Pediatr. doi:10.1001 /jamapediatrics.2014.79. 5. Frakt A, Carroll AE, Pollack HA, Reinhardt U. Our flawed but beneficial Medicaid program. N Engl J Med. 2011;364(16):e31. doi:10.1056/NEJMp1103168. 6. Allen H, Wright BJ, Baicker K. New Medicaid enrollees in Oregon report health care successes and challenges. Health Aff (Millwood). 2014;33(2): 292-299.
The Tale of 2 Trials Disentangling Contradictory Evidence on Hypertonic Saline for Acute Bronchiolitis Sim Grewal, MD; Terry P. Klassen, MD
For pediatricians looking for answers on how best to provide treatment for their patients, nothing can be more frustrating than 2 randomized clinical trials (RCTs) with contradictory results. It may encourage nihilism and a throwing up of Related articles pages 657 one’s hands, thinking cliniand 664 cal researchers have no idea what they are doing by producing data and gaining publications but not shedding light on the tough management issues that pediatricians face day to day. These 2 RCTs1,2 on the use of nebulized hypertonic saline for the management of bronchiolitis could potentially lead practitioners to despair in this way. One RCT1 indicates that hyjamapediatrics.com
pertonic saline is very helpful, can improve a patient’s condition clinically, and can lead to reduced hospitalizations. The other RCT2 comes to the opposite conclusion. Yet ultimately, pediatricians need some guidance as to what to do with the next patient with bronchiolitis whom they will assess and provide with treatment. Fortunately, we have made great progress and gained much understanding as to how to develop and evaluate evidence for clinical decision making in the past 60 years, and these advances can help guide us in disentangling this confusion. In the 1950s, medicine imported the RCT from the agricultural field as a useful tool to evaluate the effectiveness of new therapies.3 Over time, this process became increasingly used JAMA Pediatrics July 2014 Volume 168, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
607
Opinion Editorial
by child health researchers to build the evidence base.3 The challenge then became how to deal with this growing number of RCTs with results that were sometimes contradictory. In addition, individually the RCTs lacked statistical power and therefore had imprecise estimates of effectiveness. Hence, the meta-analysis or systematic review became an important advance in health in the mid-1970s, with Thomas C. Chalmers, MD, as one of the early advocates.4 This method was imported from the fields of psychology and education. Most recently, network meta-analysis has started to gain momentum, this being a method of combining all options for a particular health problem.5 So, back to these 2 RCTs1,2: how is it possible for 2 studies like these to arrive at such differing conclusions? It is possible that chance alone could account for this. There is always some degree of fluctuation in estimates derived from trials, and the smaller the studies, the greater will be the fluctuation. As the sample size grows, the estimates become more stable and there is less fluctuation.6 In the study by Florin et al,2 patients with bronchiolitis and persistent respiratory distress after a trial of nebulized albuterol were randomized to receive either 3% hypertonic saline or normal saline. The primary outcome was the change in respiratory distress at 1 hour after the intervention, as determined by the Respiratory Assessment Change Score (RACS). There were 31 patients in each treatment arm, and at 1 hour after the intervention, the hypertonic saline group had less improvement in median RACS compared with the normal saline group. However, this study examined only a single dose of hypertonic saline, and the treatment groups were small. In the study by Wu et al,1 patients with bronchiolitis were randomized to receive either 3% hypertonic saline or normal saline up to 3 times in the emergency department. All children received nebulized albuterol before the saline intervention. The primary outcomes were rate of hospital admission, length of stay for admitted patients, and the Respiratory Distress Assessment Instrument (RDAI) score. A total of 408 patients were enrolled in the study. The authors found a lower rate of admission in the hypertonic saline group (28.9%) vs the normal saline group (42.6%), but there was no significant difference in length of stay or RDAI score between the 2 groups. The number needed to treat to prevent 1 hospitalization was 8. However, this study failed to recruit the planned sample size of patients, thereby limiting some of the statistical analyses. In addition, there was no minimum or maximum severity criteria established for study entry, thus affecting the applicability of the results to patients with moderate or severe disease.
ARTICLE INFORMATION Author Affiliations: Division of Pediatric Emergency Medicine, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada (Grewal); Translating Emergency Knowledge for Kids, Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada (Klassen); Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada (Klassen).
608
When we consider study design and risk of bias,7 these 2 RCTs appear to be well designed. We had access to their protocols, and the studies seemed to be well implemented. Differences in populations, interventions, control, and outcome measures may also result in study results being different; however, when examining these 2 studies, there are no obvious reasons for their results to differ because of these factors. It remains to be seen whether the way in which albuterol was used in reference to hypertonic saline has an effect on the outcome. Evaluating the efficacy of hypertonic saline in the treatment of bronchiolitis is not an easy task. As seen in these 2 RCTs as well as in other studies to date, the optimal concentration, dosing frequency, and duration of therapy of hypertonic saline still need to be determined. One of the most significant limitations in the published data thus far is the small sample size. In addition, we still are unsure of what is the best outcome measure. Does a respiratory assessment tool actually translate to a clinically relevant outcome?8 Evidently, it is difficult to base treatment decisions on the result of a single study. There is, of course, some debate about what is the best evidence: a large RCT (networks) or a welldone meta-analysis? But neither of these RCTs is what one would call large. Therefore, we believe we are left with examining the totality of evidence and finding a well-designed systematic review or meta-analysis. To do this, we need to look no further than the Cochrane Database of Systematic Reviews, where an updated systematic review on the role of hypertonic saline for the treatment of bronchiolitis was published in 2013.9 The summary is that there is probably not a role for hypertonic saline for patients with bronchiolitis treated in the emergency department, but it may be helpful for inpatients by decreasing their length of hospital stay by 1.15 days. The 2 just-published RCTs1,2 now need to be incorporated into an updated systematic review to see whether the overall findings will change. An exciting proposal for the future to reduce the evidence-practice gap is to develop the “living systematic review” so that these entities would be updated almost in real time as new trials are available for inclusion.10 Therefore, rather than despair, we believe these 2 trials point us to the importance of using scientifically developed systematic reviews and meta-analyses to get the best sense of optimal treatment for children. From our read of the current systematic review (which now will need to be updated) and our read of these 2 individual trials, we would not start using hypertonic saline in the emergency department on a routine basis. However, nebulized hypertonic saline may have a role to play for children hospitalized with bronchiolitis.
Corresponding Author: Terry P. Klassen, MD, Translating Emergency Knowledge for Kids, Manitoba Institute of Child Health, 513-715 McDermot Ave, Winnipeg, MB R3E 3P4, Canada ([email protected]).
REFERENCES
Published Online: May 26, 2014. doi:10.1001/jamapediatrics.2014.423.
2. Florin TA, Shaw KN, Kittick M, Yackscoe S, Zorc JJ. Nebulized hypertonic saline for bronchiolitis in the emergency department: a randomized clinical trial [published online May 26, 2014]. JAMA Pediatr. doi:10.1001/jamapediatrics.2013.5306.
Conflict of Interest Disclosures: None reported.
1. Wu S, Baker C, Lang ME, et al. Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial [published online May 26, 2014]. JAMA Pediatr. doi:10.1001/jamapediatrics.2014.301.
JAMA Pediatrics July 2014 Volume 168, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
jamapediatrics.com
Editorial Opinion
3. Thomson D, Hartling L, Cohen E, Vandermeer B, Tjosvold L, Klassen TP. Controlled trials in children: quantity, methodological quality and descriptive characteristics of pediatric controlled trials published 1948-2006. PLoS One. 2010;5(9):e13106. doi:10.1371/journal.pone.0013106. 4. Rennie D, Chalmers I. Exposing the dangers to patients of medical reviews and textbooks that ignore scientific principles. JLL Bulletin: Commentaries on the History of Treatment Evaluation; 2009. http://www.jameslindlibrary.org /illustrating/articles/exposing-the-dangers-to -patients-of-medical-reviews-and-textbook.pdf. Accessed April 9, 2014.
jamapediatrics.com
5. Hartling L, Fernandes RM, Bialy L, et al. Steroids and bronchodilators for bronchiolitis in the first two years of life: systematic review and meta-analysis. BMJ. 2011;342:d1714. doi:10.1136/bmj.d1714.
enough benefit to warrant adoption into clinical practice? Arch Pediatr Adolesc Med. 1996;150(11): 1120-1121.
6. Ioannidis J, Lau J. Evolution of treatment effects over time: empirical insight from recursive cumulative metaanalyses. Proc Natl Acad Sci U S A. 2001;98(3):831-836.
9. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;7(4):CD006458. doi:10.1002 /14651858.CD006458.pub3.
7. Hartling L, Ospina M, Liang Y, et al. Risk of bias versus quality assessment of randomised controlled trials: cross sectional study. BMJ. 2009;339:b4012. doi:10.1136/bmj.b4012.
10. Elliott JH, Turner T, Clavisi O, et al. Living systematic reviews: an emerging opportunity to narrow the evidence-practice gap. PLoS Med. 2014; 11(2):e1001603. doi:10.1371/journal.pmed.1001603.
8. Klassen TP. Determining the benefit of bronchodilators in bronchiolitis: when is there
JAMA Pediatrics July 2014 Volume 168, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
609
