SGEM#157: Nebulized Hypertonic Saline for Acute Bronchiolitis

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Date: June 6th, 2016

Guest Skeptic: Dr. Chantal Guimont. Chantal is a Family Doctor who works in a in a mixed pediatric and adults tertiary care center in Quebec City. She has a PhD in epidemiology and is on faculty at Laval University.

Case: You are working in the emergency department when an eight months old presents with nasal congestion, tachypnea, and retractions. You suspect he suffers from a acute bronchiolitis. You wonder about the most accurate and up to date treatment options.

Dr. Chantal Guimont

Background: During winter months in Quebec, and I suspect it is the same in many other places, bronchiolitis is one of the most frequent emergency department complaints.

Bronchiolitis is the most common disease of the lower respiratory tract infection seen in children less than one year of age. They tend to present similar to an asthma exacerbation (coughing and wheezing). It is usually a mild illness needing only supportive care. However, it can be a more serious illness requiring hospitalization and rarely causes death.

A good history and physical exam are sufficient to confirm the diagnosis. Treatment usually involves supportive care and supplemental oxygen if oxygen saturations are below 90%.

Many treatments similar to those given to asthmatic children have been tried (example: beta-agonists, ipratropium, oral and inhaled steroids). These asthma treatments and antibiotics have been shown not to be effective for the treatment of bronchiolitis.

3% hypertonic saline (HS) is a newer treatment option. In theory, it rehydrates the respiratory tract, thins the epithelial edema and enhances secretion clearance.

In 2013, Zhang and colleagues published a meta-analysis on acute bronchiolitis. In this systematic review, there were 1,090 children aged up to 24 months with mild to moderate viral bronchiolitis. According to their analyses, they concluded that even if a tendency to reduce hospital admission was observed, there was no statistical evidence of an effect of nebulized hypertonic saline on hospital admission.

In November 2014, the American Academy of Pediatrics Clinical Practice Guidelines recommended that “Nebulized hypertonic saline should not be administered to infants with a diagnosis of bronchiolitis in the emergency department” (AAP 2014).

Also in 2014, the Canadian Paediatric Society declared that “Evidence does not currently support its routine use in the outpatient setting” (CPS 2014) .

In June 2015 the National Institute for Health and Care Excellence (NICE) put out their guidelines for the diagnosis and management of bronchiolitis. They too do not recommend hypertonic saline to treat children with bronchiolitis.

Clinical Question: Is nebulized hypertonic saline safe and effective for acute bronchiolitis?

Reference: Zhang et al. Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review. Pediatrics 2015.

Population: RCTs or quasi-RCTs of infants up to 24 months of age with diagnosis of acute bronchiolitis
- Exclusions: Studies that included patients who had had recurrent wheezing or were intubated and ventilated, and studies that assessed pulmonary function alone.
Intervention: Nebulized hypertonic saline (≥ 3%) alone or mixed with bronchodilator
Comparison: Nebulized normal saline alone or mixed with same bronchodilator or standard care.
Outcome:
- Primary outcomes: Length of stay for hospitalized patients and admission rates for outpatients.
- Secondary outcomes: Clinical severity score (CSS), rate of readmission to hospital or emergency department, oxygen saturation, respiratory rate, heart rate, time for the resolution of symptoms/signs, duration of oxygen supplementation, results of pulmonary function tests, radiologic findings, and adverse events.

Author’s Conclusions: “Nebulized HS is a safe and potentially effective treatment of infants with acute bronchiolitis.”

Quality Checklist for Therapeutic Systematic Reviews:

The clinical question is sensible and answerable. Yes
The search for studies was detailed and exhaustive. Yes. They made an effort to minimize publication bias by contacting the authors of finished but unpublished studies.
The primary studies were of high methodological quality. No. The majority of studies included had small sample sizes and were subject to selection bias. Three of the included studies were not blinded, 11 studies did not describe the randomization process and three studies showed a high and unbalanced withdrawal rate.
The assessment of studies were reproducible. Yes
The outcomes were clinically relevant. Yes
There was low statistical heterogeneity for the primary outcomes. Yes. There was no significant heterogeneity in results in the outpatient studies.
The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: 24 trials involving 3,209 patients

Decrease LOS (0.45d) and reduced risk of hospitalization (20%)

Primary Outcomes:
- Length of stay mean reduction of 0.45 days (95% CI: -0.82 to -0.08) 15 trials involving 1956 patients
- Risk of hospitalization reduced by 20% RR 0.80 (95% CI: 0.67 to 0.96) 7 trials involving 951 patients
Secondary Outcomes:
- Post-treatment clinical severity score first three days
  - Day 1: MD -0.99 (95% CI: -1.48 to -0.50)
  - Day 2: MD 21.45 (95% CI: 22.06 to 20.85)
  - Day 3: MD 21.44 (95% CI: 21.78 to 21.11) (5 trials, 404 inpatients);
Adverse Events:
- 21 out of the 24 trials assessed adverse events associated with hypertonic saline.
- Only one significant event occurred in which self-limited desaturation and bradycardia occurred following hypertonic saline treatment. Most studies noted that hypertonic saline treatment was associated with coughing and hoarse voice.

Target Population: Do you think the patients represented the target population?
- The assessment of bronchiolitis and its definition were appropriate. However, it is possible that by including infants aged more than 12 months old, asthmatic children were included, thus limiting the effect of hypertonic saline.
- Also, although most studies included infants with mild to moderate acute bronchiolitis, some trials, namely Evergard et al included infants with severe disease presenting saturation rates lower than 92%. Patients with severe bronchiolitis are usually not the ones that are treated to prevent hospital admission.
- It is interesting to note that the authors of one of the included but unpublished study (Silver et al.) pointed out that their study was included in the systematic review, even though they included children who presented with recurrent wheezing. This was supposedly an exclusion criteria for the systematic review.
Parent Oriented Outcomes: We usually ask about patient oriented outcomes but what about all “parent” oriented outcomes in this study?
- I think that all clinically important issues were considered. However, acute bronchiolitis is a disease that lasts a few weeks and is thus associated with parental leave from work. The economic burdens was not studied.
Treatment Comparisons: Were the treatments being compared correctly chosen?
- There was some heterogeneity in treatments given, for example the presence or absence of a bronchodilator. The inclusion of a bronchodilator in asthmatic infants might induce a bias by treating the asthma exacerbation. This bias might underestimate the real effect of hypertonic saline.
- Also, the comparison of different hypertonic saline concentration has to be taken into account, along with the inclusion of variable control groups, mostly normal saline nebs but some without nebs (Evergard). Normal saline might not be a real placebo, having some potential therapeutic effect. That being said, it is the most appropriate control in our opinion to assure blinding.
- Finally, we noted that one of the outpatients trials, Sarrel et al (2002), included patients treated daily for five days, which is quite different from the usual emergency department setting. Is this really an outpatient trial?
Quality of Included Studies: They used the GRADE criteria and found the studies included to be of moderate quality. How do you think that impacted the results and our interpretation of the results?
- “the quality of evidence could be graded only as moderate, mainly due to inconsistency in the results between studies and risk of bias in some trials, according to  the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria.”
- In my opinion, in view of the amount of small studies with inconsistency in the results, there is still place for a bigger and well-designed randomized control trial to assess the question of hypertonic saline in acute bronchiolitis.
Safety: They claim safety of nebulized hypertonic saline in their conclusions but there is a difference between safety and adverse events?
- This was not a randomized control trial with the primary outcome of safety. A more accurate conclusion would be that there were no increased adverse events or harms observed.
  - In the results section the state: “Variation in reporting and in outcomes precluded the possibility of conducting meta-analysis of safety data.”
  - Their comment about safety was softened in the discussion. “These results suggest that nebulized HS is a safe treatment in infants with bronchiolitis, especially when administered in conjunction with a bronchodilator.”

Comment on author’s conclusion compared to SGEM Conclusion: We agree that the data demonstrates a decrease hospital length of stay and lowers the risk of admission. We do not agree with the conclusion of safety but rather no evidence of harm.

SGEM Bottom Line: Routine use of hypertonic saline cannot be recommended at this time for mild to moderate acute bronchiolitis.

Case Resolution: I would explain the diagnosis to the parents, explain the standard care and discharge them without further treatment and provide then with clear data on when to return to the emergency department.

Clinically Application: It is difficult to define a practice guideline for the emergency department due to the great variability in treatment regiments used, namely the different hypertonic saline concentration and the number and recurrence of administered doses.

In light of the results of this new meta-analysis, the exact place of hypertonic saline in the emergency department for treating viral bronchiolitis remains uncertain, as is the exact recipe to be used. A randomized clinical trial with more patients, using repeated 3% hypertonic saline in the first hour of the emergency department visit, compared with nebulizer normal saline, along with a more appropriate selection of patients with viral bronchiolitis (less then 12 months old, no previous wheezing and no history of atopia) would help to clarify the exact place of hypertonic saline in treating viral bronchiolitis.

What do I tell my patient? I explain viral bronchiolitis, its symptoms, its risks and its duration. If it’s a mild episode, I discharge without treatment but with appropriate documentation explaining when to return to the emergency department. If it’s a moderate episode, I decide with the parents if the hypertonic saline treatment might help their child and prevent hospitalization. My impression is that hypertonic saline works mostly in the secretory phase of the disease, when the infant has a lot of crackles. I thus sometimes use it. In the majority of moderate cases, it is useless and standard care, clearing the nose and hydration, is sufficient.

I strongly believe that for most cases of viral bronchiolitis, less is more. The parents leave the emergency department with clear instructions on when to return: signs of dehydration and disease severity. Since viral bronchiolitis lasts a few weeks, it is essential to adequately inform the parents.

Keener Kontest: Last weeks’ winner was David Calcara a PGY3 EM resident from Ohio State University. He knew cobblestoning is the classic, descriptive finding present on ultrasound for cellulitis, which help differentiate cellulitis from an abscess.

Listen to the podcast for this weeks’ question. If you know the answer, send it to TheSGEM@gmail.com with Keener in the subject line. The first correct answer will receive a cool skeptical prize.