OBJECTIVE: The goal was to determine an adverse event rate for nebulized hypertonic saline solution administered without adjunctive bronchodilators for infants with bronchiolitis.
METHODS: This was a retrospective cohort study of the use of nebulized 3% saline for children <2 years of age who were hospitalized with the primary diagnosis of bronchiolitis at a single academic medical center. The medical records of study participants were analyzed for the use of nebulized 3% saline solution and any documented adverse events related to this therapy. Other clinical outcomes evaluated included respiratory distress scores, timing of the use of bronchodilators in relation to 3% saline solution, transfer to a higher level of care, and readmission within 72 hours after discharge.
RESULTS: A total of 444 total doses of 3% saline solution were administered, with 377 doses (85%) being administered without adjunctive bronchodilators. Four adverse events occurred with these 377 doses, for a 1.0% adverse event rate (95% confidence interval: 0.3%–2.8%). Adverse events were generally mild. One episode of bronchospasm was documented, for a rate of 0.3% (95% confidence interval: <0.01%–1.6%).
CONCLUSIONS: The use of 3% saline solution without adjunctive bronchodilators for inpatients with bronchiolitis had a low rate of adverse events in our center. Additional clinical trials of 3% saline solution in bronchiolitis should evaluate its effectiveness in the absence of adjunctive bronchodilators.
WHAT'S KNOWN ON THIS SUBJECT:
Multiple studies evaluated nebulized hypertonic saline solution as a therapy for viral bronchiolitis in young children. However, the available studies combined hypertonic saline solution with some form of bronchodilator because of theoretical concerns that hypertonic saline solution may cause bronchospasm.
WHAT THIS STUDY ADDS:
This is the first study to investigate systematically the risk of bronchospasm or other significant adverse effects with hypertonic saline solution administered without bronchodilators for viral bronchiolitis.
Viral bronchiolitis is the most-common reason for hospital admission for infants, accounting for 20% of hospitalizations at <1 year of age.1 Meta-analyses of data on the most-used therapies, namely, nebulized albuterol and epinephrine, failed to demonstrate any effect on relevant clinical outcomes, in comparison with placebo.2,–,5 Current clinical practice guidelines do not recommend the routine use of any medication for bronchiolitis.6 Despite the evidence, use of ineffective therapies for bronchiolitis remains high.7,8
Several studies reported on the use of nebulized 3% saline solution for infants with bronchiolitis, with the majority reporting substantial benefits of therapy.9,–,12 Evidence suggests that hypertonic saline solution favorably alters mucociliary clearance in both normal and diseased lungs, in multiple clinical settings.13,–,16 Because the pathophysiologic characteristics of bronchiolitis primarily involve airway inflammation with increased mucus production and mucus plugging, it is logical to think that improved mucociliary clearance would be beneficial in bronchiolitis, although there is only indirect evidence that this is true.
The only significant adverse effect of nebulized hypertonic saline solution is the risk of bronchospasm. Use of nebulized hypertonic saline solution is established in the asthma literature as a diagnostic test to distinguish individuals with asthma from those without asthma.17 There is a fairly clear dose-response relationship for hypertonic saline solution and bronchospasm in individuals with asthma.18 Typical concentrations used in studies of individuals with asthma range from 4.5% to 7%, with widely varying volumes being required to induce bronchospasm.19 Because the vast majority of patients with bronchiolitis do not have asthma and the pathophysiologic features of typical bronchiolitis do not involve bronchial smooth muscle hyperresponsiveness, concern regarding bronchospasm resulting from the use of 3% saline solution among patients with bronchiolitis remains theoretical.
Most available studies on hypertonic saline solution in bronchiolitis are problematic because investigators coadministered 3% saline solution with bronchodilators, medications that are known to be ineffective in the disease. In only 1 study was any 3% saline solution administered without concomitant bronchodilator treatment; although only some of the patients in that study received the medication without bronchodilators, bronchospasm was not a reported adverse effect.12 No evidence has established that 3% saline solution induces bronchospasm in infants with bronchiolitis, but its safety when used without adjunctive bronchodilators also has not been established.
This study was undertaken because of the emerging popularity of nebulized 3% saline solution in our center and the variable use patterns noted. Our primary goal was to gain more information about the use of this new therapy in our center, with a specific aim of establishing a rate of adverse reactions for 3% saline solution used without adjunctive bronchodilators, to establish the safety of the intervention.
This was a retrospective cohort study of infants hospitalized with bronchiolitis between December 15, 2008, and March 15, 2009, at Christus Santa Rosa Children's Hospital. This study qualified for exempt status from the University of Texas Health Science Center at San Antonio institutional review board and was approved by the Christus Santa Rosa Children's Hospital research office.
The Christus Santa Rosa Children's Hospital is an urban, nonprofit, children's hospital in San Antonio, Texas (metropolitan area population of 2 million), which serves a population covered primarily by public insurance programs. Inpatient pediatric care is provided by a group of academic pediatric hospitalists employed by the University of Texas Health Science Center at San Antonio, with ∼15% of medical service inpatients being cared for by physicians in private practice. Yearly admissions with the primary diagnosis of bronchiolitis in this institution ranged between 350–500 patients per year over the past 5 years.
Inclusion criteria were age of <2 years, primary diagnosis of acute viral bronchiolitis (International Classification of Diseases, Ninth Revision, code 466.11 or 466.19), and hospitalization on 1 of the 2 medical service floors at Christus Santa Rosa Children's Hospital. The time period was chosen because of the availability of an extensive database being maintained for an ongoing quality improvement project. The 2 medical service floors were chosen for the database because they hospitalized the vast majority of patients with bronchiolitis in the hospital, had a fixed capacity from year to year, had clear admission criteria (ie, no cardiac monitoring), and had stable nurse/patient ratios and therefore would provide a stable denominator with little variation in severity of disease for the quality improvement project.
Exclusion criteria were the presence of complicating underlying illnesses (bronchopulmonary dysplasia or chronic lung disease, neuromuscular impairment, immunodeficiency, or congenital heart disease).
Information was obtained through review of an existing database documenting all bronchiolitis hospitalizations on the regular medical service floors. The database was established as part of a quality improvement project centered on the use of a bronchiolitis respiratory distress score. The score was adapted from a score reported by the Children's Hospital and Medical Center of Cincinnati (Fig 1).20 Our modification consisted of dropping 1 of the original 5 assessment sections for the score, namely, estimation of an inspiration/expiration ratio. The protocol specified external nasal suctioning before scoring and finding a score of ≥3 before proceeding to any type of nebulized therapy. Use of the scoring system and/or protocol order set was on a voluntary basis.
The primary outcomes for this study were the rate of adverse reactions to 3% saline solution and the methods of delivery of the therapy (ie, concomitantly with bronchodilators, within 4 hours after bronchodilator administration, or alone). We use the phrase “without adjunctive bronchodilators” to indicate doses of 3% saline solution that were administered without preceding bronchodilator administration within 4 hours and that did not result in bronchodilator administration in the 4 hours immediately after the dose. For study purposes, adverse reactions were defined quite broadly to include any documented symptom that was alleged to result from administration of the nebulized therapy. This strategy was undertaken deliberately, to provide the most-liberal assessment of potential adverse effects of nebulized 3% saline solution, because the goals of the study were to provide documentation to support the safety of a novel therapy. There was no standardized method of reporting adverse events in response to nebulized therapies in our center. We created a new process for respiratory therapy documentation in the chart in association with the scoring system used for the protocol, with addition of a comment section for each score. Although respiratory therapists documented findings routinely in our electronic medical records, the requirement to document a score was new, as was the immediate prompt for comments on the score. We met with the respiratory therapists regularly during the project, to promote the scoring system and to encourage increased documentation. In general, adverse events are underreported in health care settings; therefore, we considered it necessary to take special steps to increase reporting during the study period. We did not provide a definition of an adverse event to the respiratory therapists, although we encouraged them to document any symptoms they thought were related to the administration of any nebulized therapy.
One hundred fifty-eight patients met the inclusion criteria for the study cohort. Four patients were excluded, 1 because of chronic lung disease of prematurity and static encephalopathy, 2 because of diagnoses of bronchopulmonary dysplasia, and 1 because of trisomy 21 with neuromuscular impairment, which left 154 patients constituting the study cohort. The study cohort is described in Table 1, with reference to any receipt of 3% saline solution.
Sixty-eight (44%) of 154 patients received any 3% saline solution. All doses of 3% saline solution in the study cohort were 4 mL in volume and nebulized with a 6-L flow of oxygen from a wall source, with the hospital's standardized configuration. A total of 444 doses of 3% saline solution were documented, with a mean of 6.5 doses per patient (median: 4 doses per patient [interquartile range: 2–10 doses per patient]). Sixty-seven doses (15%) were administered concomitant with or within 4 hours of administration of any β-adrenergic receptor agonist, with 377 doses (85%) being administered without adjunctive bronchodilators.
Four adverse events, all defined as respiratory in nature, occurred among 377 doses administered without adjunctive bronchodilators, for a 1.0% adverse event rate (95% confidence interval [CI]: 0.3%–2.8%). One additional adverse event was documented for a dose of 3% saline solution administered concomitantly with albuterol, for an overall rate of 1.1% (95% CI: 0.4%–2.7%) for all doses. All events were respiratory in nature, generally were described as coughing, and are fully characterized in Table 2. With inclusion of only events considered significant enough to result in discontinuation of the therapy for the remainder of the hospitalization (2 of 377 doses), the adverse event rate was 0.5% (95% CI: 0.02%–2%). Finally, with consideration of only events documented as bronchospasm (the potential adverse effect generating the most concern), the adverse event rate was 0.3% (95% CI: <0.01%–1.6%). All rates are presented in Table 3.
The bronchiolitis protocol, which allowed us to track respiratory scores, was used for 98 patients. The institutional bronchiolitis protocol emphasized supportive care only, and patients were required to achieve a respiratory score at or above an intervention threshold of 3 to receive anything other than nasopharyngeal suctioning and oxygen administration. Forty-two patients (43%) treated according to the protocol received any 3% saline solution. Fifty-6 patients (57%) did not receive any nebulized therapies during hospitalization, which indicates that their respiratory scores remained <3. Of the total of 444 doses of 3% saline solution, 211 were administered to patients being treated according to the scoring protocol, with a mean of 2 doses per patient (median: 0 doses per patient [interquartile range: 0–2 doses per patient]). Of the 211 doses administered according to the protocol, only 24 (9%) were administered concomitant with or within 4 hours of a bronchodilator. Respiratory scores after 3% saline solution administration improved for 188 (89%) of 211 doses administered; however, we do not necessarily interpret this improvement as resulting from the 3% saline solution, because additional nasal or nasopharyngeal suctioning and increases in oxygen delivery also might have occurred and we did not attempt to assess systematically the efficacy of the therapy in this project. Respiratory scores worsened after 3% saline solution administration for 2 (1%) of 211 doses administered. Both of these events, including the scores, are described in Table 2.
Respiratory scores, where available, were different between the patients who received any 3% saline solution and those who did not, both on average and at presentation (Table 1). This is to be expected, because patients were required to reach a cutoff respiratory score before proceeding to any nebulized therapy and patients who received any nebulized therapy necessarily would have higher scores. We also noted a small age difference between the groups, with the patients in the 3% saline solution group being slightly younger. Rates of use of other therapies, such as antibiotics or steroids, were similar between the 2 groups. Rates of readmission and transfer to a higher level of care were equivalent for patients who received 3% saline solution and those who did not (Table 1).
Our study is the first to address directly the adverse effect profile of 3% saline solution, used without adjunctive bronchodilators, in bronchiolitis. It is notable that 377 doses of 3% saline solution were administered without adjunctive bronchodilators for 68 patients, with a 1.0% adverse event rate. Most of our adverse events were mild and were described as coughing. Two adverse events (0.5% of all doses administered) resulted in discontinuation of the therapy, and 1 adverse event was classified as bronchospasm and resulted in a physician being called to evaluate the patient. The physician who responded to the event documented stabilization of the patient's condition after a single dose of racemic epinephrine. The patient in question progressed to respiratory failure over the next 24 hours; however, the documented reason for intubation was apnea.
One adverse event (3.8% of doses administered) associated with a dose of racemic epinephrine administered <10 minutes after a dose of 3% saline solution was documented; this involved a 4-month-old patient for whom a physician was called because of a heart rate of 189 beats per minute. No interventions were performed, and the patient experienced an uncomplicated hospitalization, without administration of any additional nebulized therapies. This adverse event was not considered to be related to 3% saline solution for the purposes of this study, because no tachycardia or concern regarding tachycardia was documented before the dose of epinephrine. One adverse event in response to albuterol administered with 3% saline solution was documented, as detailed in Table 2. No adverse reactions to albuterol alone were found in the available documentation in our study; however, literature findings suggest that a decrease in oxygen saturation after administration of albuterol occurs in bronchiolitis.21 Unfortunately, attempts to quantify oxygen saturation levels in our database were abandoned because too many values were found to be missing.
The possibility of overreporting of adverse events by respiratory therapists in our study is likely. As stated previously, we actively encouraged reporting during the study period, through several methods, and the fact that all of our adverse events were reported by respiratory therapists supports the contention that respiratory therapists were predisposed to report on the basis of their involvement in the protocol. Also, given the fact that the intervention was unblinded, overreporting because of personal bias regarding the use of a novel therapy might be more likely. In addition, the fact that excessive coughing was the most-common adverse reaction may be questionable, because cough is encountered frequently with nebulized therapies and we were unable to provide a standardized definition of excessive coughing.
The possibility of underreporting also must be considered. If the comments section was left blank, then this was interpreted as the absence of an adverse event. Furthermore, patients who received 3% saline solution and were not being treated according to the protocol (n = 26) did not have the added oversight of receiving a score before each dose, which might have served as a prompt to document adverse events. However, each of those charts was carefully reviewed for any respiratory therapist documentation in standard locations, and 1 of the adverse events was identified in this manner.
Our study clearly is limited by its retrospective nature, and we might have missed some doses of hypertonic saline solution because of incompleteness of the database, which was generated retrospectively through chart review and review of pharmacy, respiratory therapy, and nursing electronic records. We were able to report only adverse events that were documented in the physician, respiratory therapist, or nursing notes, which leaves the possibility that the adverse event rate would be higher if documentation was incomplete. Finally, because of our study design, our data cannot be applied to questions regarding the efficacy of 3% saline solution.
The use of 3% saline solution without adjunctive bronchodilators for young children hospitalized with bronchiolitis had a low rate of adverse events in our center. Additional clinical trials of 3% saline solution in bronchiolitis should evaluate the effectiveness of 3% saline solution in the absence of adjunctive bronchodilators, because these medications are not routinely indicated in bronchiolitis, on the basis of current evidence.
- Accepted May 28, 2010.
- Address correspondence to Shawn Ralston, MD, University of Texas Health Science Center at San Antonio, Department of Pediatrics, 7703 Floyd Curl Dr, MSC 7829, San Antonio, TX 78229. E-mail:
Dr Martinez's current affiliation is QTC Medical Services, San Antonio, TX.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
- CI =
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- Copyright © 2010 by the American Academy of Pediatrics