Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus

Study Overview
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Brief Summary
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Patent ductus arteriosus (PDA) is a very common condition in immature newborn babies and it has been associated to morbidity and mortality. Ibuprofen is the drug of choice for PDA treatment according to the last version of the Cochrane review. Nowadays the best dose regimen for ibuprofen remains uncertain. The investigators aim to perform a randomized controlled clinical trial to assess whether echocardiographically guided PDA ibuprofen treatment versus standard treatment could reduce the number of doses of ibuprofen without increasing the reopening rate and reducing the side effects associated to this medication.

Detailed Description
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Patent ductus arteriosus (PDA) is presented in 55 to 70% of the preterm infants with a gestational age lower than 30 weeks or a birth weight lower than 1000 grams. PDA has being associated to mortality or morbidity such as ischemic or hemorrhagic cerebral events, necrotising enterocolitis, renal disfunction or poor pulmonary outcome; however, it is not clear whether these are a consequence of the PDA presence, the treatment implemented for closing it, or the immaturity of these population. PDA standard treatment (ST) consists on three doses of indomethacin or ibuprofen (10-5-5mg/kg) given 24 hours apart, being the surgical closure a second line therapeutic option. In spite of ibuprofen has been pointed as the drug of choice for PDA treatment by the last version of the Cochrane review, side effects have been associated to both medication. Standard ibuprofen treatment is based on a clinical trial where the three-dose protocol seemed to be more effective than one-dose scheme for PDA closure; however, the sample size was not powered to find differences statistically significant, so nowadays the best dose regimen for ibuprofen remains uncertain. Functional echocardiographic assessment is spreading to all over the world. In this scenario, it has been proposed its implementation to guide PDA treatment in order to individualize the number of doses of indomethacin administered as a function of patient's response, limiting the doses and side effects in those where PDA presented an early constriction. The investigators hypothesized whether echocardiographically guided PDA ibuprofen treatment could reduce the number of doses of ibuprofen without increasing the reopening rate and reducing the side effects associated to this medication.

Official Title
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Randomised Controlled Clinical Trial of Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus: a Pilot Study

Conditions
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Patent Ductus Arteriosus

Intervention / Treatment
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* Drug: Ibuprofen EchoG
* Drug: Standard ibuprofen treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants with a gestational age lower than 37 weeks of gestational age PDA ≥ 1.5 mm No contraindication to receive ibuprofen Informed consent signed. Exclusion Criteria: Life-threatening congenital defects Congenital heart disease Contraindication for ibuprofen administration such as oligoanuria < 1cc/kg/h or recent severe intraventricular bleeding (IVH grade III) or creatinine serum level > 1.5 mg/dl or potential intestinal ischemia. Informed consent refused

Ages Eligible for Study
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Maximum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EchoG<br>Infants in the experimental group (echoG treatment) received additional doses of ibuprofen only if PDA was still ≥ 1.5 mm at the time of the corresponding ibuprofen dose. | Drug: Ibuprofen EchoG<br>* Infants in the experimental group (echoG treatment) received additional doses of ibuprofen only if PDA was still ≥ 1.5 mm at the time of the corresponding ibuprofen dose.<br>* Other names: Echocardiographically guided ibuprofen treatment;|
| Other: ST (standard treatment)<br>Infants received 3 doses of ibuprofen at 24-hour intervals, independently of ductal size, as long as additional doses were not contraindicated. | Drug: Standard ibuprofen treatment<br>* Infants received 3 doses of ibuprofen at 24-hour intervals, independently of ductal size, as long as additional doses were not contraindicated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PDA re-opening rate | PDA re-opening after echocardiographically documented closure, which the attending physician deemed amenable to additional treatment. Infants with ventilator weaning difficulty, protracted metabolic acidosis or persistent hemodynamic instability were included in this category. | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment failure | PDA ≥ 1.5 mm 24 hours after a complete ibuprofen course | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| need for surgical ligation | need for surgical ligation | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| need for additional ibuprofen doses | need for additional ibuprofen doses after treatment was completed | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| urine output | urine output | before the first ibuprofen dose was administered (between 12-72 hours of life) until 24 hours after the last dose of ibuprofen was administered (between 36-168 h of life) | 
| serum creatinine | serum creatinine | before the first ibuprofen dose was administered (between 12-72 hours of life) until 24 hours after the last dose of ibuprofen was administered (between 36-168 h of life) | 
| mortality | mortality | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| bronchopulmonary dysplasia | bronchopulmonary dysplasia (O2 need at 36 postmenstrual weeks) | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| necrotising enterocolitis | necrotising enterocolitis | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| intraventricular hemorrhage | intraventricular hemorrhage | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| White matter damage | White matter damage | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| Laser therapy for retinopathy | Laser therapy for retinopathy | Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks | 
| peak systolic velocity | peak systolic velocity measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries | before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered | 
| end-diastolic velocity | end-diastolic velocity measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries | before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered | 
| resistance index | resistance index measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries | before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered | 
| pulsatility index | pulsatility index measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries | before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional echocardiography, power Doppler cranial ultrasonography, N-terminal probrain natriuretic peptide, Patent ductus arteriosus