Intestinal Perforation, Necrotizing Enterocolitis, Patent Ductus Arteriosus, Surgery
Conditions
Keywords
patent ductus arteriosus, patent ductus arteriosus ligation, necrotizing enterocolitis, spontaneous intestinal perforation
Brief summary
The primary goal of the trial is to compare two different Patent Ductus Arteriosus (PDA) treatment approaches: 1) an early treatment approach or 2) a conservative approach. For the purposes of the study infants will be enrolled if they are delivered before 28 weeks gestation and have a moderate/large PDA present at 5-7 days after birth. The hypothesis is: treatment of a moderate size patent ductus arteriosus (PDA) will decrease the time needed for assisted respiratory support, diuretic therapy, and gavage feeding assistance, in addition to decreasing the incidence of ductus ligations or need for future outpatient cardiology follow-up appointments. The investigators hypothesize that one or more of these benefits will occur without an increase in the time taken to achieve full enteral feedings or in the incidence of necrotizing enterocolitis (NEC) or spontaneous intestinal perforations (SIP).The investigators will be comparing the effectiveness of early pharmacologic treatment with a control group of conservatively managed infants who will only receive treatment if they meet specific criteria for rescue treatment.
Detailed description
Prior studies showed that, if a moderate/large Patent Ductus Arteriosus (PDA) is still present at 5 days after birth (among infants delivered at 23 and 0/7 to 25 and 6/7 weeks gestation) or at 7 days after birth (among infants delivered at 26 and 0/7 to 27 and 6/7 weeks gestation), it will persist for at least another 4-12 weeks if it is left untreated.
Interventions
OTHERpharmacologic treatment of the PDA
Following randomization, infants will be treated with medications used to produce PDA closure.
OTHERno pharmacologic treatment of the PDA
Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
DRUGNSAID
Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met
Eligibility
Sex/Gender
ALL
Age
5 Days to 14 Days
Healthy volunteers
No
Inclusion criteria
This will be a prospective randomized, multi-center, controlled trial that will enroll infants delivered between 23 & 0/7 - 27 & 6/7 weeks gestation: 1. infants must be between 5-14 days old (if delivered between 23 and 0/7 - 25 and 6/7 weeks) or 7-14 days old (if delivered between 26 & 0/7 - 27 & 6/7 weeks) and 2. have a moderate size PDA (defined as a PDA on echocardiogram that has at least one of the following criteria: internal ductus diameter ≥1.5 mm/kg (or PDA:LPA ratio ≥0.5), ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus \<8 mm, LA/Ao ratio ≥1.5, left pulmonary artery diastolic (or mean) flow velocity \>0.2 (or \>0.42) m/sec, respectively, and/or reversed diastolic flow in the descending aorta)(13, 68, 69) and 3. are receiving respiratory support consisting of either mechanical ventilation, nasal CPAP, SiPAP, or nasal cannula flow ≥2 L/min. \-
Exclusion criteria
prior treatment with indomethacin, ibuprofen, or acetaminophen, contraindications for the use of indomethacin, ibuprofen, or acetaminophen (these include: hydrocortisone administration within 24 hrs, urine output \< 1 ml/kg/h during the preceding 8 h, serum creatinine level \>1.6 mg/dl, platelet count \<50, 000/mm3, abnormal coagulation studies, or total bilirubin concentration (in mg/dL) \> 8 x weight (in kg)), chromosomal anomalies, congenital or acquired gastrointestinal anomalies, prior episode of necrotizing enterocolitis or intestinal perforation. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits) | through hospital discharge (approximately 6 months unless death occurs first) | Number of infants who undergo in hospital PDA ligations or who have an open ductus at the time of discharge (that need future outpatient cardiology follow-up visits) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Bronchopulmonary Dysplasia or Death | determined between 36-37 weeks corrected age | incidence of bronchopulmonary dysplasia or death |
| the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment | 10 days after enrollment | the incidence of persistent moderate-to-large PDA shunt 10 days after enrollment The echocardiographic studies included two dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described. A moderate-to-large PDA was defined by a ductus internal diameter ≥ 1.5mm (or PDA:left pulmonary artery diameter ratio ≥0.5) and one or more of the following echocardiographic criteria: a) left atrium-to-aortic root (LA/Ao) ratio ≥1.6, b) ductus flow velocity ≤2.5m/sec or mean pressure gradient across the ductus ≤8mm, c) left pulmonary artery diastolic flow velocity \> 0.2 m/sec, and/or d) reversed diastolic flow in the descending aorta. Ductus that failed to meet these criteria were considered to be constricted (small or closed) and not eligible for enrollment or treatment. |
| the Incidence of Rescue Treatment Eligibility Criteria Met | through hospital discharge (approximately 6 months unless death occurs first) | Infants were eligible for rescue PDA drug treatment if they met one or more of the following prespecified Rescue criteria: 1) Inotrope-dependent hypotension for at least 3 days. 2) Oliguria that persisted for at least 2 days with no obvious cause, other than the moderate PDA, to explain the condition. 3) Requirement for gavage feedings beyond 35 weeks corrected age due to increased work of breathing. 4) Respiratory support needed after the following postnatal ages that surpassed specific minimal ventilation and FiO2 requirements: \>15 days (if still required intubation and FiO2 \>0.30), \>20 days (if still required intubation and FiO2 ≤0.30; or still required Nasal CPAP or Nasal ventilation and FiO2 \>0.30), \>30 days (if still required Nasal CPAP or Nasal ventilation and FiO2 0.25-0.30), and \>45 days (if still required Nasal CPAP or Nasal ventilation and FiO2 \<0.25). |
| Number of Infants Receiving ≥ 14 Days of Diuretic Treatment | through hospital discharge (approximately 6 months unless death occurs first) | number of infants receiving ≥ 14 days of diuretic treatment |
| Duration of Gavage Feeding Assistance | up to 20 weeks of age | duration of gavage feeding assistance |
| Incidence of Necrotizing Enterocolitis or Spontaneous Perforation | through hospital discharge (approximately 6 months unless death occurs first) | incidence of necrotizing enterocolitis or spontaneous perforation |
| the Average Daily Weight Gain | up to 20 weeks of age | the average daily weight gain |
| Incidence of Death | through hospital discharge (approximately 6 months unless death occurs first) | incidence of death |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Pulmonary Hemorrhage | through hospital discharge (approximately 6 months unless death occurs first) | incidence of pulmonary hemorrhage |
| Incidence of Bacteremia | through hospital discharge (approximately 6 months unless death occurs first) | incidence of bacteremia |
| Number of Infants Who Received Dopamine for ≥3 Days | through hospital discharge (approximately 6 months unless death occurs first) | number of infants who received dopamine for ≥3 days |
Countries
Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Early Treatment Infants randomized to the early treatment group will receive pharmacologic treatment of the PDA to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency.
Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up.
pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure. | 104 |
| Conservative Treatment Infants randomized to the Conservative Treatment approach will receive no pharmacologic treatment of the PDA but will be followed to determine if they meet criteria for later PDA rescue treatment (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.)
Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up.
no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time). | 98 |
| Total | 202 |
Baseline characteristics
| Characteristic | Conservative Treatment | Early Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 98 Participants | 104 Participants | 202 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 | 8.3 days after birth STANDARD_DEVIATION 2.3 | 8.1 days after birth STANDARD_DEVIATION 2.1 | 8.2 days after birth STANDARD_DEVIATION 2.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 25 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 79 Participants | 79 Participants | 158 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gestation | 25.9 weeks of gestation STANDARD_DEVIATION 1.1 | 25.7 weeks of gestation STANDARD_DEVIATION 1.2 | 25.8 weeks of gestation STANDARD_DEVIATION 1.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 12 Participants | 26 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 14 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 73 Participants | 76 Participants | 149 Participants |
| Region of Enrollment Sweden | 7 participants | 7 participants | 14 participants |
| Region of Enrollment Turkey | 15 participants | 14 participants | 29 participants |
| Region of Enrollment United Kingdom | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 72 participants | 80 participants | 152 participants |
| Sex: Female, Male Female | 55 Participants | 56 Participants | 111 Participants |
| Sex: Female, Male Male | 43 Participants | 48 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 20 / 104 | 10 / 98 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 17 / 104 | 19 / 98 |
Outcome results
Primary
Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits)
Number of infants who undergo in hospital PDA ligations or who have an open ductus at the time of discharge (that need future outpatient cardiology follow-up visits)
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits) | 33 Participants |
| Conservative Treatment | Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits) | 38 Participants |
Secondary
Duration of Gavage Feeding Assistance
duration of gavage feeding assistance
Time frame: up to 20 weeks of age
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Treatment | Duration of Gavage Feeding Assistance | 76 days |
| Conservative Treatment | Duration of Gavage Feeding Assistance | 80 days |
Secondary
Incidence of Bronchopulmonary Dysplasia or Death
incidence of bronchopulmonary dysplasia or death
Time frame: determined between 36-37 weeks corrected age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Incidence of Bronchopulmonary Dysplasia or Death | 60 Participants |
| Conservative Treatment | Incidence of Bronchopulmonary Dysplasia or Death | 56 Participants |
Secondary
Incidence of Death
incidence of death
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Incidence of Death | 20 Participants |
| Conservative Treatment | Incidence of Death | 10 Participants |
Secondary
Incidence of Necrotizing Enterocolitis or Spontaneous Perforation
incidence of necrotizing enterocolitis or spontaneous perforation
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Incidence of Necrotizing Enterocolitis or Spontaneous Perforation | 17 Participants |
| Conservative Treatment | Incidence of Necrotizing Enterocolitis or Spontaneous Perforation | 19 Participants |
Secondary
Number of Infants Receiving ≥ 14 Days of Diuretic Treatment
number of infants receiving ≥ 14 days of diuretic treatment
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Number of Infants Receiving ≥ 14 Days of Diuretic Treatment | 36 Participants |
| Conservative Treatment | Number of Infants Receiving ≥ 14 Days of Diuretic Treatment | 45 Participants |
Secondary
the Average Daily Weight Gain
the average daily weight gain
Time frame: up to 20 weeks of age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Treatment | the Average Daily Weight Gain | 22.5 gm/kg/day | Standard Deviation 4.8 |
| Conservative Treatment | the Average Daily Weight Gain | 22.8 gm/kg/day | Standard Deviation 4.6 |
Secondary
the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment
the incidence of persistent moderate-to-large PDA shunt 10 days after enrollment The echocardiographic studies included two dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described. A moderate-to-large PDA was defined by a ductus internal diameter ≥ 1.5mm (or PDA:left pulmonary artery diameter ratio ≥0.5) and one or more of the following echocardiographic criteria: a) left atrium-to-aortic root (LA/Ao) ratio ≥1.6, b) ductus flow velocity ≤2.5m/sec or mean pressure gradient across the ductus ≤8mm, c) left pulmonary artery diastolic flow velocity \> 0.2 m/sec, and/or d) reversed diastolic flow in the descending aorta. Ductus that failed to meet these criteria were considered to be constricted (small or closed) and not eligible for enrollment or treatment.
Time frame: 10 days after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment | 43 Participants |
| Conservative Treatment | the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment | 78 Participants |
Secondary
the Incidence of Rescue Treatment Eligibility Criteria Met
Infants were eligible for rescue PDA drug treatment if they met one or more of the following prespecified Rescue criteria: 1) Inotrope-dependent hypotension for at least 3 days. 2) Oliguria that persisted for at least 2 days with no obvious cause, other than the moderate PDA, to explain the condition. 3) Requirement for gavage feedings beyond 35 weeks corrected age due to increased work of breathing. 4) Respiratory support needed after the following postnatal ages that surpassed specific minimal ventilation and FiO2 requirements: \>15 days (if still required intubation and FiO2 \>0.30), \>20 days (if still required intubation and FiO2 ≤0.30; or still required Nasal CPAP or Nasal ventilation and FiO2 \>0.30), \>30 days (if still required Nasal CPAP or Nasal ventilation and FiO2 0.25-0.30), and \>45 days (if still required Nasal CPAP or Nasal ventilation and FiO2 \<0.25).
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | the Incidence of Rescue Treatment Eligibility Criteria Met | 32 Participants |
| Conservative Treatment | the Incidence of Rescue Treatment Eligibility Criteria Met | 61 Participants |
Other Pre-specified
Incidence of Bacteremia
incidence of bacteremia
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Incidence of Bacteremia | 31 Participants |
| Conservative Treatment | Incidence of Bacteremia | 21 Participants |
Other Pre-specified
Incidence of Pulmonary Hemorrhage
incidence of pulmonary hemorrhage
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Incidence of Pulmonary Hemorrhage | 2 Participants |
| Conservative Treatment | Incidence of Pulmonary Hemorrhage | 2 Participants |
Other Pre-specified
Number of Infants Who Received Dopamine for ≥3 Days
number of infants who received dopamine for ≥3 days
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Treatment | Number of Infants Who Received Dopamine for ≥3 Days | 14 Participants |
| Conservative Treatment | Number of Infants Who Received Dopamine for ≥3 Days | 25 Participants |