Point/Counterpoint: Should Nebulized Hypertonic Saline Be Used in the Treatment of Acute Viral Bronchiolitis?

Nebulized hypertonic saline is an emerging therapy for this indication.

Viral bronchiolitis is the most common diagnosis at hospitalization for infants younger than 1 year of age.

It results in approximately 150,000 hospitalizations each year at a cost of more than $500 million, according to a study published in 2006 (Pediatrics 2006;118:2418-23). Yet so far, nothing we give our patients really works.

Nebulized hypertonic saline is garnering enthusiasm because there is a consistent set of papers and a theory of physiology supporting its efficacy in the treatment of acute viral bronchiolitis.

The very first hypertonic saline study came from a group of Israeli pulmonologists who reported an improvement in symptoms and respiratory scores on day 2 of inhaled nebulized 3% saline solution plus 5-mg terbutaline in 33 outpatient infants with viral bronchiolitis, compared with 32 control infants who received 0.9% saline plus 5 mg terbutaline (Chest 2002;122:2015-20).

The findings led the researchers to conduct a second randomized, controlled study, this time combining 3% hypertonic saline with 1.5-mg epinephrine three times a day until discharge among 27 hospitalized infants. Clinical severity scores improved significantly after 24 hours of therapy and almost a full day was shaved off the length of stay (LOS), compared with normal saline plus epinephrine in 25 infants (Chest 2003;123:481-7).

The group came back a year later with a second year of follow-up in 41 inpatients and essentially replicated their findings (Isr. Med. Assoc. J. 2006;8:169-73).

The study that caught most hospitalists’ eyes, however, was a multicenter, double-blind Canadian trial that left the concomitant use of beta-agonists up to the discretion of the physicians who treated 96 infants hospitalized with moderately severe viral bronchiolitis (J. Pediatr. 2007;151:266-70). Even though 30% of the infants did not receive beta-agonists, the use of hypertonic saline resulted in a clinically relevant 26% reduction in LOS (from 3.5 days to 2.6 days) with normal saline. Symptoms diverged the longer the infants were treated.

Short-term improvement was not really expected, based on the theory that hypertonic saline works by rehydrating the airway surface liquid (ASL), as well as inducing cough and improving sputum mobility. The Israelis theorized that mucociliary failure, such as occurs in cystic fibrosis, also occurs in severe bronchiolitis because of dehydration of the ASL, the thin layer of fluid that covers the luminal surface of the airway.

In vitro, hypertonic saline increases airway surface thickness, decreases epithelial edema, and improves mucus rheology and transport rates. In vivo, it increases mucociliary transport in healthy subjects.

Thus, it makes sense that short-term studies have found no difference in outcomes, and that studies demonstrating positive effects on LOS and respiratory scores do so only after 24 hours of therapy. Fluid shifts take time, and cilia can only do so much.

Chinese investigators have reported similar positive outcomes, including a reduction in LOS from 7.4 to 6 days with hypertonic saline plus salbutamol in hospitalized infants (Pediatr. Int. 2010;52:199-202). Moreover, these findings were replicated in a second study, this time using nebulized 3% hypertonic saline without concomitant bronchodilators (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

We’ve never seen this level of consistently positive results in the data on bronchiolitis treatment in the past, and it’s exciting – particularly as we have so little in our therapeutic armamentarium. It’s also very interesting to have a theory of mechanism of action that meshes with the known pathology in bronchiolitis. After years of repeatedly studying beta-agonists, even though we knew that airway smooth muscle reactivity was not the major pathology, it is refreshing to see a different approach emerging.

Dr. Ralston is chief of inpatient pediatrics at the University of Texas Health Science Center in San Antonio. She said she had no relevant financial disclosures.

It is too early to say if hypertonic saline is an appropriate therapy.

Much of the evidence supporting the use of nebulized hypertonic saline for acute bronchiolitis rests on changes in respiratory scores that are not likely to have clinical relevance. The true test is whether hypertonic saline can really reduce length of stay (LOS), the hard outcome that hospitalists and parents care about. That question remains unanswered.

No fewer than five short-term emergency department (ED) studies have failed to find a difference in outcomes between nebulized hypertonic saline and normal saline. One of those trials was by the same group of Canadian researchers that helped put nebulized hypertonic saline on the radar of many hospitalists and pediatricians (J. Pediatr. 2007;151:266-70).

When the Canadians studied hypertonic saline in the ED setting, there were no significant differences in hospital admission rates or respiratory scores after three consecutive 4-mL doses of nebulized 3% hypertonic saline in children younger than age 2 years who presented to the ED with moderately severe bronchiolitis (CJEM 2010;12:477-84).

In addition, no large randomized trials from the United States have been conducted using our criteria for hospitalization. A recent Chinese study demonstrated a reduction in LOS with the use of hypertonic saline plus salbutamol in 93 infants hospitalized with mild to moderate bronchiolitis (Pediatr. Int. 2010;52:199-202). The reduction, however, was from 7.4 days to 6.0 days – an LOS that was more than double the U.S. average LOS of 2.5 days.

The same researchers evaluated nebulized 3% hypertonic saline without bronchodilators, and reported a similar reduction in LOS from an average of 6.4 days with normal saline to a full 4.8 days with hypertonic saline (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

Dr. Susan Wu and her colleagues at Childrens Hospital Los Angeles presented data, however, at the recent Pediatric Hospital Medicine 2011 meeting that contradicts these findings. Although the preliminary analysis includes subjects from only the first 2 years of the study and was not fully powered for the LOS outcome, hypertonic saline was no better than normal saline for respiratory distress, and actually resulted in a longer LOS of 3.46 days compared with 2.74 days with normal saline (Pediatric Hospital Medicine 2011;1 [poster session B, July 29] abstract 4).

One also has to question whether the cost of respiratory therapy labor to provide such a potentially ineffective therapy can be justified in the current health care environment, when hypertonic saline hasn’t been established as being superior to the guideline recommendation of supportive care only.

Some may argue that the cost of hypertonic saline is free, but a quick back-of-the-envelope calculation would suggest otherwise. If you practice in a 90-bed hospital, see 500 bronchiolitis patients per year, and have a 3-day LOS using hypertonic saline every 4 hours, that works out to 12,000 nebulizations and 400 hours of respiratory time, which ends up costing $300,000 per year. At that price tag, one could hire a full-time employee for your hospitalist team.

Many administrations may also insist that hypertonic saline be given with albuterol, which one could argue may in some cases actually extend LOS because of the potential for patients to desaturate.

Finally, if you’re a fee-for-service hospital, there’s a financial disincentive for your administration to spend $300,000 for a therapy that could actually reduce profits by shortening LOS. Hospitals adopt measures that shorten LOS, but few would be willing to implement such a strategy until a large, randomized, controlled trial conducted in the United States has proved that hypertonic saline, likely without albuterol, is both clinically and cost effective.

Dr. Alverson is director of pediatric hospital medicine at Hasbro Children’s Hospital in Providence, R.I. He said that he had no relevant financial disclosures.

This column, Point/Counterpoint, regularly appears in Pediatric News, an Elsevier publication.

Nebulized hypertonic saline is an emerging therapy for this indication.

Viral bronchiolitis is the most common diagnosis at hospitalization for infants younger than 1 year of age.

It results in approximately 150,000 hospitalizations each year at a cost of more than $500 million, according to a study published in 2006 (Pediatrics 2006;118:2418-23). Yet so far, nothing we give our patients really works.

Nebulized hypertonic saline is garnering enthusiasm because there is a consistent set of papers and a theory of physiology supporting its efficacy in the treatment of acute viral bronchiolitis.

The very first hypertonic saline study came from a group of Israeli pulmonologists who reported an improvement in symptoms and respiratory scores on day 2 of inhaled nebulized 3% saline solution plus 5-mg terbutaline in 33 outpatient infants with viral bronchiolitis, compared with 32 control infants who received 0.9% saline plus 5 mg terbutaline (Chest 2002;122:2015-20).

The findings led the researchers to conduct a second randomized, controlled study, this time combining 3% hypertonic saline with 1.5-mg epinephrine three times a day until discharge among 27 hospitalized infants. Clinical severity scores improved significantly after 24 hours of therapy and almost a full day was shaved off the length of stay (LOS), compared with normal saline plus epinephrine in 25 infants (Chest 2003;123:481-7).

The group came back a year later with a second year of follow-up in 41 inpatients and essentially replicated their findings (Isr. Med. Assoc. J. 2006;8:169-73).

The study that caught most hospitalists’ eyes, however, was a multicenter, double-blind Canadian trial that left the concomitant use of beta-agonists up to the discretion of the physicians who treated 96 infants hospitalized with moderately severe viral bronchiolitis (J. Pediatr. 2007;151:266-70). Even though 30% of the infants did not receive beta-agonists, the use of hypertonic saline resulted in a clinically relevant 26% reduction in LOS (from 3.5 days to 2.6 days) with normal saline. Symptoms diverged the longer the infants were treated.

Short-term improvement was not really expected, based on the theory that hypertonic saline works by rehydrating the airway surface liquid (ASL), as well as inducing cough and improving sputum mobility. The Israelis theorized that mucociliary failure, such as occurs in cystic fibrosis, also occurs in severe bronchiolitis because of dehydration of the ASL, the thin layer of fluid that covers the luminal surface of the airway.

In vitro, hypertonic saline increases airway surface thickness, decreases epithelial edema, and improves mucus rheology and transport rates. In vivo, it increases mucociliary transport in healthy subjects.

Thus, it makes sense that short-term studies have found no difference in outcomes, and that studies demonstrating positive effects on LOS and respiratory scores do so only after 24 hours of therapy. Fluid shifts take time, and cilia can only do so much.

Chinese investigators have reported similar positive outcomes, including a reduction in LOS from 7.4 to 6 days with hypertonic saline plus salbutamol in hospitalized infants (Pediatr. Int. 2010;52:199-202). Moreover, these findings were replicated in a second study, this time using nebulized 3% hypertonic saline without concomitant bronchodilators (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

We’ve never seen this level of consistently positive results in the data on bronchiolitis treatment in the past, and it’s exciting – particularly as we have so little in our therapeutic armamentarium. It’s also very interesting to have a theory of mechanism of action that meshes with the known pathology in bronchiolitis. After years of repeatedly studying beta-agonists, even though we knew that airway smooth muscle reactivity was not the major pathology, it is refreshing to see a different approach emerging.

Dr. Ralston is chief of inpatient pediatrics at the University of Texas Health Science Center in San Antonio. She said she had no relevant financial disclosures.

It is too early to say if hypertonic saline is an appropriate therapy.

Much of the evidence supporting the use of nebulized hypertonic saline for acute bronchiolitis rests on changes in respiratory scores that are not likely to have clinical relevance. The true test is whether hypertonic saline can really reduce length of stay (LOS), the hard outcome that hospitalists and parents care about. That question remains unanswered.

No fewer than five short-term emergency department (ED) studies have failed to find a difference in outcomes between nebulized hypertonic saline and normal saline. One of those trials was by the same group of Canadian researchers that helped put nebulized hypertonic saline on the radar of many hospitalists and pediatricians (J. Pediatr. 2007;151:266-70).

When the Canadians studied hypertonic saline in the ED setting, there were no significant differences in hospital admission rates or respiratory scores after three consecutive 4-mL doses of nebulized 3% hypertonic saline in children younger than age 2 years who presented to the ED with moderately severe bronchiolitis (CJEM 2010;12:477-84).

In addition, no large randomized trials from the United States have been conducted using our criteria for hospitalization. A recent Chinese study demonstrated a reduction in LOS with the use of hypertonic saline plus salbutamol in 93 infants hospitalized with mild to moderate bronchiolitis (Pediatr. Int. 2010;52:199-202). The reduction, however, was from 7.4 days to 6.0 days – an LOS that was more than double the U.S. average LOS of 2.5 days.

The same researchers evaluated nebulized 3% hypertonic saline without bronchodilators, and reported a similar reduction in LOS from an average of 6.4 days with normal saline to a full 4.8 days with hypertonic saline (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

Dr. Susan Wu and her colleagues at Childrens Hospital Los Angeles presented data, however, at the recent Pediatric Hospital Medicine 2011 meeting that contradicts these findings. Although the preliminary analysis includes subjects from only the first 2 years of the study and was not fully powered for the LOS outcome, hypertonic saline was no better than normal saline for respiratory distress, and actually resulted in a longer LOS of 3.46 days compared with 2.74 days with normal saline (Pediatric Hospital Medicine 2011;1 [poster session B, July 29] abstract 4).

One also has to question whether the cost of respiratory therapy labor to provide such a potentially ineffective therapy can be justified in the current health care environment, when hypertonic saline hasn’t been established as being superior to the guideline recommendation of supportive care only.

Some may argue that the cost of hypertonic saline is free, but a quick back-of-the-envelope calculation would suggest otherwise. If you practice in a 90-bed hospital, see 500 bronchiolitis patients per year, and have a 3-day LOS using hypertonic saline every 4 hours, that works out to 12,000 nebulizations and 400 hours of respiratory time, which ends up costing $300,000 per year. At that price tag, one could hire a full-time employee for your hospitalist team.

Many administrations may also insist that hypertonic saline be given with albuterol, which one could argue may in some cases actually extend LOS because of the potential for patients to desaturate.

Finally, if you’re a fee-for-service hospital, there’s a financial disincentive for your administration to spend $300,000 for a therapy that could actually reduce profits by shortening LOS. Hospitals adopt measures that shorten LOS, but few would be willing to implement such a strategy until a large, randomized, controlled trial conducted in the United States has proved that hypertonic saline, likely without albuterol, is both clinically and cost effective.

Dr. Alverson is director of pediatric hospital medicine at Hasbro Children’s Hospital in Providence, R.I. He said that he had no relevant financial disclosures.

This column, Point/Counterpoint, regularly appears in Pediatric News, an Elsevier publication.

Nebulized hypertonic saline is an emerging therapy for this indication.

Viral bronchiolitis is the most common diagnosis at hospitalization for infants younger than 1 year of age.

It results in approximately 150,000 hospitalizations each year at a cost of more than $500 million, according to a study published in 2006 (Pediatrics 2006;118:2418-23). Yet so far, nothing we give our patients really works.

Nebulized hypertonic saline is garnering enthusiasm because there is a consistent set of papers and a theory of physiology supporting its efficacy in the treatment of acute viral bronchiolitis.

The very first hypertonic saline study came from a group of Israeli pulmonologists who reported an improvement in symptoms and respiratory scores on day 2 of inhaled nebulized 3% saline solution plus 5-mg terbutaline in 33 outpatient infants with viral bronchiolitis, compared with 32 control infants who received 0.9% saline plus 5 mg terbutaline (Chest 2002;122:2015-20).

The findings led the researchers to conduct a second randomized, controlled study, this time combining 3% hypertonic saline with 1.5-mg epinephrine three times a day until discharge among 27 hospitalized infants. Clinical severity scores improved significantly after 24 hours of therapy and almost a full day was shaved off the length of stay (LOS), compared with normal saline plus epinephrine in 25 infants (Chest 2003;123:481-7).

The group came back a year later with a second year of follow-up in 41 inpatients and essentially replicated their findings (Isr. Med. Assoc. J. 2006;8:169-73).

The study that caught most hospitalists’ eyes, however, was a multicenter, double-blind Canadian trial that left the concomitant use of beta-agonists up to the discretion of the physicians who treated 96 infants hospitalized with moderately severe viral bronchiolitis (J. Pediatr. 2007;151:266-70). Even though 30% of the infants did not receive beta-agonists, the use of hypertonic saline resulted in a clinically relevant 26% reduction in LOS (from 3.5 days to 2.6 days) with normal saline. Symptoms diverged the longer the infants were treated.

Short-term improvement was not really expected, based on the theory that hypertonic saline works by rehydrating the airway surface liquid (ASL), as well as inducing cough and improving sputum mobility. The Israelis theorized that mucociliary failure, such as occurs in cystic fibrosis, also occurs in severe bronchiolitis because of dehydration of the ASL, the thin layer of fluid that covers the luminal surface of the airway.

In vitro, hypertonic saline increases airway surface thickness, decreases epithelial edema, and improves mucus rheology and transport rates. In vivo, it increases mucociliary transport in healthy subjects.

Thus, it makes sense that short-term studies have found no difference in outcomes, and that studies demonstrating positive effects on LOS and respiratory scores do so only after 24 hours of therapy. Fluid shifts take time, and cilia can only do so much.

Chinese investigators have reported similar positive outcomes, including a reduction in LOS from 7.4 to 6 days with hypertonic saline plus salbutamol in hospitalized infants (Pediatr. Int. 2010;52:199-202). Moreover, these findings were replicated in a second study, this time using nebulized 3% hypertonic saline without concomitant bronchodilators (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

We’ve never seen this level of consistently positive results in the data on bronchiolitis treatment in the past, and it’s exciting – particularly as we have so little in our therapeutic armamentarium. It’s also very interesting to have a theory of mechanism of action that meshes with the known pathology in bronchiolitis. After years of repeatedly studying beta-agonists, even though we knew that airway smooth muscle reactivity was not the major pathology, it is refreshing to see a different approach emerging.

Dr. Ralston is chief of inpatient pediatrics at the University of Texas Health Science Center in San Antonio. She said she had no relevant financial disclosures.

It is too early to say if hypertonic saline is an appropriate therapy.

Much of the evidence supporting the use of nebulized hypertonic saline for acute bronchiolitis rests on changes in respiratory scores that are not likely to have clinical relevance. The true test is whether hypertonic saline can really reduce length of stay (LOS), the hard outcome that hospitalists and parents care about. That question remains unanswered.

No fewer than five short-term emergency department (ED) studies have failed to find a difference in outcomes between nebulized hypertonic saline and normal saline. One of those trials was by the same group of Canadian researchers that helped put nebulized hypertonic saline on the radar of many hospitalists and pediatricians (J. Pediatr. 2007;151:266-70).

When the Canadians studied hypertonic saline in the ED setting, there were no significant differences in hospital admission rates or respiratory scores after three consecutive 4-mL doses of nebulized 3% hypertonic saline in children younger than age 2 years who presented to the ED with moderately severe bronchiolitis (CJEM 2010;12:477-84).

In addition, no large randomized trials from the United States have been conducted using our criteria for hospitalization. A recent Chinese study demonstrated a reduction in LOS with the use of hypertonic saline plus salbutamol in 93 infants hospitalized with mild to moderate bronchiolitis (Pediatr. Int. 2010;52:199-202). The reduction, however, was from 7.4 days to 6.0 days – an LOS that was more than double the U.S. average LOS of 2.5 days.

The same researchers evaluated nebulized 3% hypertonic saline without bronchodilators, and reported a similar reduction in LOS from an average of 6.4 days with normal saline to a full 4.8 days with hypertonic saline (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

Dr. Susan Wu and her colleagues at Childrens Hospital Los Angeles presented data, however, at the recent Pediatric Hospital Medicine 2011 meeting that contradicts these findings. Although the preliminary analysis includes subjects from only the first 2 years of the study and was not fully powered for the LOS outcome, hypertonic saline was no better than normal saline for respiratory distress, and actually resulted in a longer LOS of 3.46 days compared with 2.74 days with normal saline (Pediatric Hospital Medicine 2011;1 [poster session B, July 29] abstract 4).

One also has to question whether the cost of respiratory therapy labor to provide such a potentially ineffective therapy can be justified in the current health care environment, when hypertonic saline hasn’t been established as being superior to the guideline recommendation of supportive care only.

Some may argue that the cost of hypertonic saline is free, but a quick back-of-the-envelope calculation would suggest otherwise. If you practice in a 90-bed hospital, see 500 bronchiolitis patients per year, and have a 3-day LOS using hypertonic saline every 4 hours, that works out to 12,000 nebulizations and 400 hours of respiratory time, which ends up costing $300,000 per year. At that price tag, one could hire a full-time employee for your hospitalist team.

Many administrations may also insist that hypertonic saline be given with albuterol, which one could argue may in some cases actually extend LOS because of the potential for patients to desaturate.

Finally, if you’re a fee-for-service hospital, there’s a financial disincentive for your administration to spend $300,000 for a therapy that could actually reduce profits by shortening LOS. Hospitals adopt measures that shorten LOS, but few would be willing to implement such a strategy until a large, randomized, controlled trial conducted in the United States has proved that hypertonic saline, likely without albuterol, is both clinically and cost effective.

Dr. Alverson is director of pediatric hospital medicine at Hasbro Children’s Hospital in Providence, R.I. He said that he had no relevant financial disclosures.

This column, Point/Counterpoint, regularly appears in Pediatric News, an Elsevier publication.