Acute Asthma, Asthma, Reactive Airway Exacerbation
Conditions
Keywords
Asthma, Acute, Treatment, Children, Pediatric, Inhaled corticosteroid, Budesonide, Budesonide inhalation suspension, Asthma score, Emergency, Emergency Department, Asthma flare, Clinical trial, Randomized clinical trial, Randomized trial, Pulmonary index score, Hospitalization, Moderate asthma, Severe asthma, Mixing budesonide, Budesonide admixture, Albuterol, Continuous albuterol, Ipratropium bromide
Brief summary
The purpose of this study is to determine whether the addition of budesonide inhalation suspension (BIS) to the standard therapy of albuterol, ipratropium bromide, and systemic corticosteroids (SCS) for moderate to severe asthma flares in children reduces asthma severity more rapidly than standard therapy alone.
Detailed description
Context: Acute asthma is a leading cause of emergency department (ED) visits and hospitalizations. Although standard therapy for acute asthma includes systemic corticosteroids (SCS), these drugs take many hours to have an effect. Recent studies demonstrate that inhaled corticosteroids (ICS) may improve patients' asthma severity more rapidly than SCS and may decrease hospitalizations. Only a few small studies have evaluated ICS added to standard therapy for acute asthma in children. Objective: To determine if adding the nebulized steroid budesonide to standard therapy including SCS improves patients' asthma severity faster than standard therapy alone and leads to fewer hospitalizations. Study Design/Setting/Participants: A double-blind, randomized, controlled trial of budesonide inhalation suspension (BIS) versus placebo for children 2 to 18 years of age who present to a tertiary care, urban pediatric ED with a moderate to severe asthma flare. Intervention: Participants will receive standard therapy including SCS, albuterol, and ipratropium bromide and will be randomly assigned to also receive either nebulized BIS or saline. Study Measures: Differences in asthma scores, vital signs, and the need for hospitalization will be compared between treatment groups.
Interventions
DRUGBudesonide inhalation suspension (0.5 mg/2mL) 2mg, albuterol (5mg/mL) 7.5 or 10mg
Patients randomized to budesonide inhalation suspension (BIS) receive 2 nebulized albuterol sulfate (5mg/mL) doses (2mL =10mg for patients over 20kg, 1.5mL =7.5mg for patients 10-20kg) mixed with 8mL (2mg) of BIS(0.5mg/2mL). The albuterol sulfate and BIS mixture is delivered by a medium volume, high flow nebulizer (AirLife Mister FinityTM)with an oxygen flow rate of 8L/min via a tight-fitting face mask.
DRUGPrednisolone, prednisone, or methylprednisolone
All patients are given 2mg/kg of systemic corticosteroids (max 60mg). Patients who can tolerate pills are given oral prednisone, those who cannot are given oral prednisolone, and those who cannot tolerate oral medications are given IV methylprednisolone.
DRUGAlbuterol, ipratropium bromide
While guardians are approached for possible participation, patients are given a single nebulized dose of albuterol sulfate (5mg/mL) mixed with ipratropium bromide (500mcg/2.5mL). Patients who weigh 10-20kg receive 3.75mg of albuterol. Patients over 20kg receive 5mg of albuterol. All patients receive 500mcg of ipratropium bromide. Albuterol sulfate and ipratropium bromide are delivered by a medium volume, high flow nebulizer (AirLife Mister FinityTM)with an oxygen flow rate of 8L/min via a tight-fitting face mask.
DRUGIpratropium bromide
500 mcg/2.5mL. All patients receive a final dose of ipratropium bromide after the intervention or placebo. The ipratropium bromide is delivered by a medium volume, high flow nebulizer (AirLife Mister FinityTM) with an oxygen flow rate of 8L/minute via a tight-fitting face mask.
Sponsors
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Chief complaint of respiratory distress, asthma, trouble breathing, or reactive airway disease * Males or females age 2 to 18 years * Weight greater than or equal to 10 kilograms * Two or more prior Emergency Department or primary care visits for asthma or reactive airway disease * Identified in triage as either acute or critical * Asthma score of 8 or greater * Systemic corticosteroid prescribed in the Emergency Department * English-speaking parent/guardian present * Parental/guardian permission (informed consent) and if appropriate, child assent
Exclusion criteria
* Systemic corticosteroid use in the last 30 days * Chronic lung diseases including cystic fibrosis * Sickle cell anemia * Immunodeficiency * Cardiac disease requiring surgery or medications * Adverse drug reaction or allergy to budesonide, albuterol, ipratropium bromide, prednisone, prednisolone, or methylprednisolone * Known renal or hepatic dysfunction * Exposure to varicella in the last 21 days * Impending respiratory failure requiring positive pressure ventilation * Altered level of consciousness * Suspected foreign body aspiration or croup * Prior enrollment in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Change in Asthma Score 2 Hours After Intervention | Initial asthma score minus score 2 hours after budesonide/albuterol intervention or saline placebo/albuterol comparator | The scale used is the Asthma Score published by Qureshi et al. The Asthma Score ranges from a low of 5 to maximum of 15 points. One to 3 points are given for each of 5 categories: age-based respiratory rate, oxygen saturation, wheeze, retractions, and dyspnea. For category detalails, please see the Qureshi reference. Scores of 5-7 are considered mild, 8-11 moderate, and 12-15 severe. Asthma Scores are recorded prior to any intervention and at 2 hours after budesonide inhalation suspension/albuterol intervention or saline placebo/albuterol comparator. |
| Mean Change in Asthma Score at 2 Hours | Initial asthma score minus score 2 hours after budesonide/albuterol intervention or saline placebo/albuterol comparator | The scale used is the Asthma Score published by Qureshi et al. The Asthma Score ranges from a low of 5 to maximum of 15 points. One to 3 points are given for each of 5 categories: age-based respiratory rate, oxygen saturation, wheeze, retractions, and dyspnea. For category detalails, please see the Qureshi reference. Scores of 5-7 are considered mild, 8-11 moderate, and 12-15 severe. Asthma Scores are recorded prior to any intervention and at 2 hours after budesonide inhalation suspension/albuterol intervention or saline placebo/albuterol comparator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Heart Rate | From the initial heart rate to heart rate 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator | Mean of heart rate in beats per minute before treatment minus mean of heart rate 2 hours after treatment with either budesonide/albuterol or saline/albuterol |
| Mean Change in Respiratory Rate. | Initial rate, minus rate taken 2 hours after budesonide/albuterol intervention or saline/albuterol comparator | Mean respiratory rate in breaths per minute before treatment minus respiratory rate 2 hours after treatment with either budesonide/albuterol or saline/albuterol comparator. |
| Oxygen Saturation. | 2 hours after treatment with either budesonide/albuterol or saline/albuterol comparator | Mean oxygen saturation (non-invasive pulse-oximetry, % hemoglobin saturation) 2 hours after treatment with either budesonide/albuterol or saline/albuterol comparator minus mean oxygen saturation before treatment. |
| Number of Subjects Remaining in the Severe Asthma Category | From the initial score to 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator | Of the patients who presented in the severe asthma category (Asthma Severity score of 12-15), those who remained in this category 2 hours after the budesonide/albuterol intervention or saline/albuterol comparator. |
| Number of Participants With Adverse Events (Non-serious). | within 30 days of the ED visit | — |
| Number of Subjects Moving From the Severe Asthma to Mild Asthma Category | From the initial score to 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator | Of the patients who presented in the severe asthma category (Asthma Severity score of 12-15), those who moved to the mild category (Asthma Severity score 5-7) 2 hours after the budesonide/albuterol intervention or saline/albuterol comparator. |
| Relapse / Readmission Numbers. | within 5 days of ED visit | Participants admitted to the hospital within 5 days of the ED visit |
| Serious Adverse Events | 0-5 days | Serious Adverse Events |
| Number of Subjects Moving From the Severe Asthma to Moderate Asthma Category | From the initial score to 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator | Of the patients who presented in the severe asthma category (Asthma Severity score of 12-15), those who moved to the moderate category (Asthma Severity score 8-11) 2 hours after the budesonide/albuterol intervention or saline/albuterol comparator. |
| Number of Patients Hospitalized | within 4 hours after the budesonide/albuterol intervention or saline/albuterol placebo | The number of patients requiring hospital admission 4 hours after budesonide/albuterol intervention or saline/albuterol comparator. All hospitalization decisions are made at the discretion of the attending physician. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Budesonide Inhalation Suspension (BIS) standardized treatment with nebulized Budesonide Inhalation Suspension (BIS) | 91 |
| Placebo (Saline) standardized treatment with nebulized saline | 88 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 2 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo (Saline) | Budesonide Inhalation Suspension (BIS) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 88 Participants | 91 Participants | 179 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 6.3 years STANDARD_DEVIATION 4 | 6.2 years STANDARD_DEVIATION 3.9 | 6.2 years STANDARD_DEVIATION 4 |
| Region of Enrollment United States | 88 participants | 91 participants | 179 participants |
| Sex: Female, Male Female | 34 Participants | 27 Participants | 61 Participants |
| Sex: Female, Male Male | 54 Participants | 64 Participants | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 91 | 27 / 91 |
| serious Total, serious adverse events | 3 / 91 | 2 / 88 |
Outcome results
Primary
Mean Change in Asthma Score at 2 Hours
The scale used is the Asthma Score published by Qureshi et al. The Asthma Score ranges from a low of 5 to maximum of 15 points. One to 3 points are given for each of 5 categories: age-based respiratory rate, oxygen saturation, wheeze, retractions, and dyspnea. For category detalails, please see the Qureshi reference. Scores of 5-7 are considered mild, 8-11 moderate, and 12-15 severe. Asthma Scores are recorded prior to any intervention and at 2 hours after budesonide inhalation suspension/albuterol intervention or saline placebo/albuterol comparator.
Time frame: Initial asthma score minus score 2 hours after budesonide/albuterol intervention or saline placebo/albuterol comparator
Population: 88 of the 91 patients randomized to budesonide were evaluable for the primary outcome (1 was discharged home, 1 had no 2 hour score, and 1 did not have a valid initial score). 81 of the 89 patients randomized to placebo were evaluable (1 inadvertently received standard therapy, 2 withdrew, and 5 were admitted before a 2 hour score evaluation).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Mean Change in Asthma Score at 2 Hours | -2.9 Units on a scale |
| Placebo (Normal Saline) | Mean Change in Asthma Score at 2 Hours | -3.0 Units on a scale |
p-value: 0.7895% CI: [-0.6, 0.8]t-test, 2 sided
Primary
Median Change in Asthma Score 2 Hours After Intervention
The scale used is the Asthma Score published by Qureshi et al. The Asthma Score ranges from a low of 5 to maximum of 15 points. One to 3 points are given for each of 5 categories: age-based respiratory rate, oxygen saturation, wheeze, retractions, and dyspnea. For category detalails, please see the Qureshi reference. Scores of 5-7 are considered mild, 8-11 moderate, and 12-15 severe. Asthma Scores are recorded prior to any intervention and at 2 hours after budesonide inhalation suspension/albuterol intervention or saline placebo/albuterol comparator.
Time frame: Initial asthma score minus score 2 hours after budesonide/albuterol intervention or saline placebo/albuterol comparator
Population: 88 of the 91 patients randomized to budesonide were evaluable for the primary outcome (1 was discharged home, 1 had no 2 hour score, and 1 did not have a valid initial score). 81 of the 89 patients randomized to placebo were evaluable (1 inadvertently received standard therapy, 2 withdrew, and 5 were admitted before a 2 hour score evaluation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Median Change in Asthma Score 2 Hours After Intervention | -3 Units on a scale |
| Placebo (Normal Saline) | Median Change in Asthma Score 2 Hours After Intervention | -3 Units on a scale |
p-value: 0.44Wilcoxon (Mann-Whitney)
Secondary
Change in Mean Heart Rate
Mean of heart rate in beats per minute before treatment minus mean of heart rate 2 hours after treatment with either budesonide/albuterol or saline/albuterol
Time frame: From the initial heart rate to heart rate 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Change in Mean Heart Rate | 12 Beats per minute |
| Placebo (Normal Saline) | Change in Mean Heart Rate | 13 Beats per minute |
95% CI: [-7, 6]t-test, 2 sided
Secondary
Mean Change in Respiratory Rate.
Mean respiratory rate in breaths per minute before treatment minus respiratory rate 2 hours after treatment with either budesonide/albuterol or saline/albuterol comparator.
Time frame: Initial rate, minus rate taken 2 hours after budesonide/albuterol intervention or saline/albuterol comparator
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Mean Change in Respiratory Rate. | -6 Breaths per minute |
| Placebo (Normal Saline) | Mean Change in Respiratory Rate. | -6 Breaths per minute |
95% CI: [-3, 3]t-test, 2 sided
Secondary
Number of Participants With Adverse Events (Non-serious).
Time frame: within 30 days of the ED visit
Population: Of the 180 patients randomized, 91 were to BIS, 89 were to placebo. Two patients were lost to follow-up in the BIS group and 4 in the placebo group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Number of Participants With Adverse Events (Non-serious). | Rhinorrhea | 6 Participants |
| Budesonide Inhalation Suspension (BIS) | Number of Participants With Adverse Events (Non-serious). | Headache | 5 Participants |
| Budesonide Inhalation Suspension (BIS) | Number of Participants With Adverse Events (Non-serious). | Diarrhea | 3 Participants |
| Budesonide Inhalation Suspension (BIS) | Number of Participants With Adverse Events (Non-serious). | Sore throat | 4 Participants |
| Budesonide Inhalation Suspension (BIS) | Number of Participants With Adverse Events (Non-serious). | Cough | 2 Participants |
| Budesonide Inhalation Suspension (BIS) | Number of Participants With Adverse Events (Non-serious). | Hyperglycemia | 2 Participants |
| Placebo (Normal Saline) | Number of Participants With Adverse Events (Non-serious). | Cough | 3 Participants |
| Placebo (Normal Saline) | Number of Participants With Adverse Events (Non-serious). | Rhinorrhea | 11 Participants |
| Placebo (Normal Saline) | Number of Participants With Adverse Events (Non-serious). | Sore throat | 3 Participants |
| Placebo (Normal Saline) | Number of Participants With Adverse Events (Non-serious). | Headache | 9 Participants |
| Placebo (Normal Saline) | Number of Participants With Adverse Events (Non-serious). | Hyperglycemia | 0 Participants |
| Placebo (Normal Saline) | Number of Participants With Adverse Events (Non-serious). | Diarrhea | 7 Participants |
Secondary
Number of Patients Hospitalized
The number of patients requiring hospital admission 4 hours after budesonide/albuterol intervention or saline/albuterol comparator. All hospitalization decisions are made at the discretion of the attending physician.
Time frame: within 4 hours after the budesonide/albuterol intervention or saline/albuterol placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Number of Patients Hospitalized | 56 Participants |
| Placebo (Normal Saline) | Number of Patients Hospitalized | 55 Participants |
p-value: 0.9795% CI: [-0.14, 0.14]Chi-squared
Secondary
Number of Subjects Moving From the Severe Asthma to Mild Asthma Category
Of the patients who presented in the severe asthma category (Asthma Severity score of 12-15), those who moved to the mild category (Asthma Severity score 5-7) 2 hours after the budesonide/albuterol intervention or saline/albuterol comparator.
Time frame: From the initial score to 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator
Population: Number of patients who presented in the severe asthma category (Asthma Score 12-15) who moved to the moderate asthma category (Asthma Score 8-11) 2 hours after either the intervention with budesonide/albuterol or saline/albuterol comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Number of Subjects Moving From the Severe Asthma to Mild Asthma Category | 8 Participants |
| Placebo (Normal Saline) | Number of Subjects Moving From the Severe Asthma to Mild Asthma Category | 10 Participants |
p-value: 0.2295% CI: [-0.37, 0.08]Chi-squared
Secondary
Number of Subjects Moving From the Severe Asthma to Moderate Asthma Category
Of the patients who presented in the severe asthma category (Asthma Severity score of 12-15), those who moved to the moderate category (Asthma Severity score 8-11) 2 hours after the budesonide/albuterol intervention or saline/albuterol comparator.
Time frame: From the initial score to 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator
Population: Number of patients who presented in the severe asthma category (Asthma Score 12-15) who moved to the moderate asthma category (Asthma Score 8-11) 2 hours after either the intervention with budesonide/albuterol or saline/albuterol comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Number of Subjects Moving From the Severe Asthma to Moderate Asthma Category | 22 Participants |
| Placebo (Normal Saline) | Number of Subjects Moving From the Severe Asthma to Moderate Asthma Category | 11 Participants |
p-value: 0.0895% CI: [-0.02, 0.47]Chi-squared
Secondary
Number of Subjects Remaining in the Severe Asthma Category
Of the patients who presented in the severe asthma category (Asthma Severity score of 12-15), those who remained in this category 2 hours after the budesonide/albuterol intervention or saline/albuterol comparator.
Time frame: From the initial score to 2 hours after intervention with budesonide/albuterol or saline/albuterol comparator
Population: Number of patients who presented in the severe asthma category (Asthma Score 12-15) who remained in that category 2 hours after either the intervention with budesonide/albuterol or saline/albuterol comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Number of Subjects Remaining in the Severe Asthma Category | 4 Participants |
| Placebo (Normal Saline) | Number of Subjects Remaining in the Severe Asthma Category | 4 Participants |
p-value: 0.6995% CI: [-0.2, 0.14]Chi-squared
Secondary
Oxygen Saturation.
Mean oxygen saturation (non-invasive pulse-oximetry, % hemoglobin saturation) 2 hours after treatment with either budesonide/albuterol or saline/albuterol comparator minus mean oxygen saturation before treatment.
Time frame: 2 hours after treatment with either budesonide/albuterol or saline/albuterol comparator
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Oxygen Saturation. | 1.0 Percent Hemoglobin Saturation |
| Placebo (Normal Saline) | Oxygen Saturation. | 1.0 Percent Hemoglobin Saturation |
95% CI: [-1, 1]t-test, 2 sided
Secondary
Relapse / Readmission Numbers.
Participants admitted to the hospital within 5 days of the ED visit
Time frame: within 5 days of ED visit
Population: 89 of the 91 patients randomized to BIS were available for follow-up. 85 of the 89 patients randomized to placebo were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Relapse / Readmission Numbers. | 2 Participants |
| Placebo (Normal Saline) | Relapse / Readmission Numbers. | 2 Participants |
Secondary
Serious Adverse Events
Serious Adverse Events
Time frame: 0-5 days
Population: 89 of the 91 patients randomized to BIS were available for follow-up. 85 of the 89 patients randomized to placebo were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Budesonide Inhalation Suspension (BIS) | Serious Adverse Events | Return within 5 days with hosptial admission | 2 participants |
| Budesonide Inhalation Suspension (BIS) | Serious Adverse Events | Increased level of care | 1 participants |
| Placebo (Normal Saline) | Serious Adverse Events | Return within 5 days with hosptial admission | 2 participants |
| Placebo (Normal Saline) | Serious Adverse Events | Increased level of care | 0 participants |