Bronchopulmonary Dysplasia, Very Low Birth Weight
Conditions
Keywords
Bronchopulmonary dysplasia, very low birth weight, albuterol, pulmonary function test
Brief summary
The purpose of this study is to help determine the best dose of inhaled albuterol sulfate in premature babies at risk of developing bronchopulmonary dysplasia (BPD). BPD is the chronic lung disease of prematurity and is associated with increased morbidity and mortality, longer hospital stays, and increased healthcare utilization. Albuterol is an inhaled medication frequently used in premature infants with chronic lung disease and in people with asthma. It is believed to be safe, but the optimal dose for infants is not clear. The investigators hypothesize that albuterol may help a subset of premature infants with lung disease, but they need to determine the best dose prior to doing research about how effective it is for chronic lung disease/BPD. Response to each of three doses of albuterol will be measure using pulmonary function tests.
Detailed description
1. Recruitment: Subjects at risk for developing bronchopulmonary dysplasia will be recruited from the Doernbecher Neonatal Care Center (DNCC).The subjects' mother will be approached by the investigators and consent obtained if she agrees to participate. 2. Medical Record and Interview: Information about the pregnancy, delivery, and neonatal course will be obtained from the medical record. This will include maternal body mass index (BMI) at first prenatal visit, maternal age and parity, birthweight, gestational age at birth, history of maternal betamethasone for fetal lung maturation, indication for preterm delivery (e.g. pre-eclampsia, preterm labor), surfactant administration, history of intubations and duration of mechanical ventilation in the infant, current level of respiratory support, use of diuretics, bronchodilators, and corticosteroids in the neonate. A brief interview will also be obtained from the subject's mother. The questions asked will involve tobacco exposure during the pregnancy and family history of asthma. The purpose of the data collected on the infant's mother is to help identify factors that may predict which premature infants will respond to albuterol. 3. Procedures: Pulmonary function tests (PFTs) are the procedures involved in this study. PFTs are non-invasive, require no sedation, and are commonly used to provide standard medical care to preterm infants in the DNCC. PFTs involve placing a mask over the nose and mouth during quiet sleep. We will record flow-volume loops with passive respiration and measure respiratory compliance and passive respiratory resistance (Rr) using the single breath occlusion technique. A dose of albuterol will be given after baseline measurements are obtained; the PFTs will be repeated 15 minutes after administration. The testing will be the same for each of the three sessions, except the dose of albuterol will be altered each session (see below). There will be only one session per day, and all three sessions will occur within a 7 day period. Vital signs (respiratory rate, heart rate, oxygen saturation) will be continuously monitored during the testing. 4. Study Drug: Albuterol is a bronchodilator frequently prescribed in neonatal ICUs to help treat the symptoms of BPD. About 50% of preterm infants in the DNCC with evolving BPD have shown an improvement in their PFT after 2 puffs (180 micrograms) of albuterol (unpublished data). The typical dosing is 2-4 puffs every 4-6 hours but the optimal dose in premature infants is not known. In this study, 2 puffs (180 micrograms) will be given on the first day of PFTs, 3 puffs (270 micrograms) the second day, and 4 puffs (260 micrograms) on the third day.
Interventions
DRUGVaried albuterol dose response
Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 28w0d to 33w6d. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a sinlge dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique.
Sponsors
Oregon Health and Science University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Days to No maximum
Healthy volunteers
No
Inclusion criteria
* very low birthweight infant (\<1500g) * gestational age at birth \<32 weeks * age 14 or more days and corrected to 28w0d to 33w6d gestational age * continuing to require respiratory support and/or supplemental oxygen
Exclusion criteria
* chromosomal abnormalities * major congenital anomalies * congenital heart disease, except atrial septal defect and patent ductus arteriosus * clinical providers determine subject too unstable to undergo pulmonary function testing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Respiratory Resistance | Within one week of performing pulmonary function tests | The primary outcome is the percentage of subjects who show a positive response to each dose of albuterol. A positive response is defined as a greater than or equal to 10% decrease in respiratory resistance (Rrs). The change in RRs was measured at baseline and again after each dose of albuterol. All measurements were taken within a 7 day time frame for each subject such that each subject would have up to 3 results measured during a 7 day period, if he/she were able to complete three sets of PFTs according to study protocol. The change in Rrs was calculated by subtracting the baseline Rrs from the post-albuterol Rrs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Etiology of Preterm Delivery | within one week of entering study | Reason for each subject's preterm delivery was classified as either preterm labor or delivery for maternal indications (eg pre-eclampsia). |
| Number of Participants With Positive Response at Different Albuterol Doses | Data collected 15 minutes after dose in each session. Study includes 3 sessions within a 7 day period. | Compare number of subjects who have a positive response (greater than or equal to 10% decrease in respiratory resistance) to each dose of albuterol |
| Birth Weight of Albuterol Responders vs Non Responders | within one week of entering study | birth weight in grams of each subject was recorded at time of enrollment |
| Gestational Age at Birth | within one week of entering study | Average gestational age (GA) in weeks at birth for subjects who responded to albuterol versus subjects without a positive response |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maternal BMI at Time of Pregnancy and Likelihood of Positive Response to Albuterol | Maternal information collected at enrollment; albuterol response assessed within one week | Maternal BMI will be obtained from her medial record, and she will be asked about weight gain during pregnancy at time of enrollment. Results will be compared for infants born to women with a normal BMI vs. those with obese BMI (\>30). |
| Association of Smoke Exposure During Pregnancy and Neonatal Response to Albuterol | Smoking and second hand smoke exposure history will be obtained at enrollment. Albuterol response will be obtained within one week. | Mothers who smoked cigarettes during pregnancy and the rate of albuterol response of their infants |
| Family History of Asthma and Likelihood to Respond to Albuterol | History collected at enrollment, albuterol response assessed within one week | Family history was obtained from verbal history by subject's mother at time of enrollment in study. A positive family history was noted if a first degree relative of the subject (infant) had a diagnosis of asthma. |
Countries
United States
Participant flow
Pre-assignment details
1 subject was consented into the study, but then became too clinically unstable to participate in the study and remained unstable throughout the eligibility period.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm: Varied Albuterol Dose Response Subjects will be evaluated in three sessions within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique.
Varied albuterol dose response: Subjects will be evaluated in three sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 2 | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Second Dose (270 mcg Albuterol) | elevated HR with first dose | 1 |
| Third Dose (360 mcg Albuterol) | Clinically unstable, unable to do PFT | 1 |
| Third Dose (360 mcg Albuterol) | Elevated HR with 2nd dose | 4 |
Baseline characteristics
| Characteristic | Single Arm: Varied Albuterol Dose Response |
|---|---|
| Age, Continuous | 36 days |
| birthweight | 895 grams |
| ever received albuterol prior to study entry | 0 Participants |
| family history of asthma | 2 Participants |
| gestational age at birth | 26.9 weeks |
| history of any mechanical ventilation | 8 Participants |
| maternal age, years (mean) | 26.4 years |
| maternal BMI (mean, range) | 25.5 kg/ m^2 |
| maternal diabetes mellitus (pregestational or gestational) | 4 Participants |
| maternal smoking during pregnancy | 4 Participants |
| reason for preterm delivery: preterm labor | 6 Participants |
| received antenatal corticosteroids | 13 Participants |
| received diuretics prior to study entry | 3 Participants |
| received surfactant | 7 Participants |
| respiratory support at study entry, CPAP | 12 Participants |
| respiratory support at study entry, mechanical ventilation | 2 Participants |
| second hand smoke exposure during pregnancy | 6 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 1 / 14 |
| serious Total, serious adverse events | 0 / 14 |
Outcome results
Primary
Change in Respiratory Resistance
The primary outcome is the percentage of subjects who show a positive response to each dose of albuterol. A positive response is defined as a greater than or equal to 10% decrease in respiratory resistance (Rrs). The change in RRs was measured at baseline and again after each dose of albuterol. All measurements were taken within a 7 day time frame for each subject such that each subject would have up to 3 results measured during a 7 day period, if he/she were able to complete three sets of PFTs according to study protocol. The change in Rrs was calculated by subtracting the baseline Rrs from the post-albuterol Rrs.
Time frame: Within one week of performing pulmonary function tests
Population: Some subjects did not receive all 3 doses (based on how they tolerated initial dose(s))
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Change in Respiratory Resistance | dose 1 | 0.011 cm h2o/mL/sec | Standard Deviation 0.016 |
| Single Arm: Varied Albuterol Dose Response | Change in Respiratory Resistance | dose 2 | 0.006 cm h2o/mL/sec | Standard Deviation 0.008 |
| Single Arm: Varied Albuterol Dose Response | Change in Respiratory Resistance | dose 3 | 0.014 cm h2o/mL/sec | Standard Deviation 0.014 |
Secondary
Birth Weight of Albuterol Responders vs Non Responders
birth weight in grams of each subject was recorded at time of enrollment
Time frame: within one week of entering study
Population: This data included 10 subjects who responded to albuterol at at least one dose, and 3 subjects who did not show a positive response to albuterol at any dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Birth Weight of Albuterol Responders vs Non Responders | albuterol responders | 847.2 grams | Standard Deviation 296 |
| Single Arm: Varied Albuterol Dose Response | Birth Weight of Albuterol Responders vs Non Responders | albuterol non responders | 1147.7 grams | Standard Deviation 216 |
Comparison: comparison of mean birth weights between responders and non-respondersp-value: 0.14Chi-squared
Secondary
Etiology of Preterm Delivery
Reason for each subject's preterm delivery was classified as either preterm labor or delivery for maternal indications (eg pre-eclampsia).
Time frame: within one week of entering study
Population: 5 subjects were delivered due to preterm labor, and 8 delivered prematurely due to maternal indications
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Etiology of Preterm Delivery | preterm labor, responsive to albuterol | 4 Participants |
| Single Arm: Varied Albuterol Dose Response | Etiology of Preterm Delivery | maternal indicated delivery, responsive to albuter | 6 Participants |
p-value: 1Fisher Exact
Secondary
Gestational Age at Birth
Average gestational age (GA) in weeks at birth for subjects who responded to albuterol versus subjects without a positive response
Time frame: within one week of entering study
Population: We have data for 10 subjects who responded to albuterol and 3 subjects who did not respond.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Gestational Age at Birth | birth GA albuterol responders, weeks | 26.7 weeks | Standard Deviation 1.9 |
| Single Arm: Varied Albuterol Dose Response | Gestational Age at Birth | birth GA albuterol non responders | 28.5 weeks | Standard Deviation 1.2 |
p-value: 0.16Chi-squared
Secondary
Number of Participants With Positive Response at Different Albuterol Doses
Compare number of subjects who have a positive response (greater than or equal to 10% decrease in respiratory resistance) to each dose of albuterol
Time frame: Data collected 15 minutes after dose in each session. Study includes 3 sessions within a 7 day period.
Population: Measuring Rrs can be technically challenging, particularly in premature infants, and we did not have measurable Rrs for every subject at every time point, therefore the denominator here is not the same as the total number of participants. For example, we have missing/unmeasurable Rrs for 3 subjects at the lowest albuterol dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Number of Participants With Positive Response at Different Albuterol Doses | positive Rrs response at 180 mcg albuterol | 6 participants |
| Single Arm: Varied Albuterol Dose Response | Number of Participants With Positive Response at Different Albuterol Doses | positive Rrs response at 270 mcg albuterol | 4 participants |
| Single Arm: Varied Albuterol Dose Response | Number of Participants With Positive Response at Different Albuterol Doses | positive Rrs response at 360 mcg albuterol | 4 participants |
Other Pre-specified
Association of Smoke Exposure During Pregnancy and Neonatal Response to Albuterol
Mothers who smoked cigarettes during pregnancy and the rate of albuterol response of their infants
Time frame: Smoking and second hand smoke exposure history will be obtained at enrollment. Albuterol response will be obtained within one week.
Population: We have data for 9 subjects whose mothers did not smoke and 4 subjects whose mothers smoked
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Association of Smoke Exposure During Pregnancy and Neonatal Response to Albuterol | albuterol responders of mothers who smoked | 4 participants |
| Single Arm: Varied Albuterol Dose Response | Association of Smoke Exposure During Pregnancy and Neonatal Response to Albuterol | albuterol responders of non-smoker mothers % | 6 participants |
p-value: 0.5Fisher Exact
Other Pre-specified
Family History of Asthma and Likelihood to Respond to Albuterol
Family history was obtained from verbal history by subject's mother at time of enrollment in study. A positive family history was noted if a first degree relative of the subject (infant) had a diagnosis of asthma.
Time frame: History collected at enrollment, albuterol response assessed within one week
Population: only 2 subjects had a history of a first-degree relative (parent or sibling) with asthma
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Family History of Asthma and Likelihood to Respond to Albuterol | family hx of asthma, respond to albuterol | 1 participants |
| Single Arm: Varied Albuterol Dose Response | Family History of Asthma and Likelihood to Respond to Albuterol | no fam hx asthma, respond to albuterol | 9 participants |
Other Pre-specified
Maternal BMI at Time of Pregnancy and Likelihood of Positive Response to Albuterol
Maternal BMI will be obtained from her medial record, and she will be asked about weight gain during pregnancy at time of enrollment. Results will be compared for infants born to women with a normal BMI vs. those with obese BMI (\>30).
Time frame: Maternal information collected at enrollment; albuterol response assessed within one week
Population: We have BMI data on 13 mothers.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Arm: Varied Albuterol Dose Response | Maternal BMI at Time of Pregnancy and Likelihood of Positive Response to Albuterol | mean BMI mothers of albuterol non-responders | 27.3 kg/m^2 | Standard Deviation 3.5 |
| Single Arm: Varied Albuterol Dose Response | Maternal BMI at Time of Pregnancy and Likelihood of Positive Response to Albuterol | mean BMI mothers of albuterol-responders , any dos | 27.4 kg/m^2 | Standard Deviation 8.6 |
p-value: 1Chi-squared