Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus

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

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.

Study Overview

• Status: Completed
• Conditions: Patent Ductus Arteriosus
• Intervention / Treatment: Drug: Ibuprofen EchoG; Drug: Standard ibuprofen treatment

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28046
    • Department of Neonatology, La Paz University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EchoG; 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; 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.; Other Names: Echocardiographically guided ibuprofen treatment
Other: ST (standard treatment); 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; Infants received 3 doses of ibuprofen at 24-hour intervals, independently of ductal size, as long as additional doses were not contraindicated.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
• Investigators: Principal Investigator: María Carmen Bravo, PhD MD, Department of Neonatology, La Paz University Hospital; Study Chair: Fernando Cabañas, PhDMD, Department of Neonatology, La Paz University Hospital; Study Chair: Joan Riera, Bio-Engineer, Department of Neonatology, La Paz University Hospital; Study Chair: Elia Pérez-Fernández, Division of Statistics, La Paz University Hospital. Madrid, Spain.; Study Chair: José Quero, PhDMD, Department of Neonatology, La Paz University Hospital. Madrid, Spain.; Study Chair: Jesús Pérez-Rodríguez, PhDMD, Department of Neonatology, La Paz University Hospital. Madrid, Spain.; Study Director: Adelina Pellicer, PhDMD, Department of Neonatology, La Paz University Hospital. Madrid, Spain.

Publications and helpful links

General Publications

• Carmo KB, Evans N, Paradisis M. Duration of indomethacin treatment of the preterm patent ductus arteriosus as directed by echocardiography. J Pediatr. 2009 Dec;155(6):819-822.e1. doi: 10.1016/j.jpeds.2009.06.013. Epub 2009 Jul 29.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: May 3, 2012
• First Submitted That Met QC Criteria: May 4, 2012
• First Posted (Estimate): May 8, 2012

Study Record Updates

• Last Update Posted (Estimate): May 8, 2012
• Last Update Submitted That Met QC Criteria: May 4, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Functional echocardiography; Patent ductus arteriosus; power Doppler cranial ultrasonography; N-terminal probrain natriuretic peptide
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Ductus Arteriosus, Patent; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ibuprofen
• Other Study ID Numbers: IbuEchoG