Continuous Infusion of Fentanyl in Preterm on MV

Study Overview
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Brief Summary
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The objective of this randomized, double-blind trial is to compare the efficacy and safety of 2 therapeutic regimens of fentanyl administration in a population of preterm newborns of GA <= 32 weeks in MV: Group A) continuous infusion of Fentanyl + open label boluses of Fentanyl; Group B) continuous infusion of placebo + open label boluses of Fentanyl.

Detailed Description
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The primary objective of the study is to evaluate the analgesic superiority of Fentanyl given as 'continuous infusion + boluses' versus 'boluses alone' by comparing pain scores obtained by the application of validated algometric scales for chronic pain (EDIN - Echelle Douleur Inconfort Nouveau-Nè) and acute pain (PIPP- Premature Infant Pain Profile). The secondary objective of the study is to evaluate the safety equivalence of the above 2 therapeutic regimens by recording: Rate of mechanically ventilated newborns at one week of age Age at which neonates will reach total enteral feeding Age (hours) of first meconium passage Incidence of intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL) or death within 28 days of life Incidence of bladder globe during the first week of life Incidence of hypotension during the first week of life 5.2.1 Pain measurement: during the study phase acute pain will be measured once a day during a heel prick by a validated algometric scale for acute pain (PIPP); chronic pain will be measured 3 times a day by a validated algometric scale for chronic pain (EDIN). Inter-rater reliability has been shown acceptable for both scales (26,27). Moreover, in October 2006 the Coordinating Center organized a theoretical and practical course on the correct application of the PIPP and EDIN scales (26,27) for all the participating centers in order to reduce the inter-Center variability in pain measurement. The EDIN scores will be recorded in a specific CRF (CRF N°1, p. 15). The PIPP scores will be reported in a specific CRF (CRF N° 1, pp. 8-14). 5.2.2 Painful procedures: the following painful procedures, as well as the action taken to reduce pain, will be recorded in the same CRF (CRF N° 1, pp. 8-14): heel pricks endotracheal aspirations venous blood samplings pneumothorax drainage peripherally inserted central catheter positioning others (specify) 5.2.3 Fentanyl open label boluses administration: all the boluses of open label fentanyl administered according to the criteria reported in paragraph 6.1.1 have to be recorded in a special CRF (CRF N° 1, p. 7). 5.2.4 Instrumental examinations: a heart ultrasound has to be obtained in all newborns in the first week of life in order to diagnose patent ductus arteriosus. Brain ultrasound has to be repeated at 4, 7 days of age and then twice a month or when clinically indicated.

Official Title
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Efficacy and Safety of Continuous Infusion of Fentanyl for Pain Control in Preterm Newborn on Mechanical Ventilation

Conditions
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Pain, Infant, Premature, Diseases, Respiration; Insufficient or Poor, Newborn

Intervention / Treatment
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* Drug: Fentanyl
* Drug: 5% glucose solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: inborn neonates preterm neonates ≤ 32+ 6 days weeks gestation < 72 hours of life newborns on MV within 24 hours from the beginning of MV administered through an endotracheal tube parental written informed consent for participation in the study must be obtained Exclusion Criteria: Evidence of severe birth asphyxia, that is an APGAR score below 4 at 5 minutes of age and/or umbilical arterial pH < 7.0 Known genetic or chromosomal disorders Severe IVH (> grade II according to Volpe classification (30)) Need for post-operative analgesic therapy in the first week of life Participation in another clinical trial of any placebo, drug, biological, or device conducted under the provisions of a protocol

Ages Eligible for Study
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Maximum Age: 32 Weeks

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: fentanyl<br>Patients assigned to this arm will receive continuous infusion of fentanyl + open label boluses of Fentanyl if necessary. | Drug: Fentanyl<br>* The experimental drug will be diluted according to each NICU scheme and administered as an attach dose of 1 mcg/kg in 30' followed by continuous i.v. infusion of 1 mcg/kg/h. Infusion of the experimental drug has to begin within 24 hrs from the beginning of MV and has to be continued until the end of MV and not after 7 days of life. If the newborn is still on MV after the 7th day of life he/she will be treated for pain according to local protocols. Open label boluses of Fentanyl during the study phase will be administered, in both groups when the EDIN pain score is > 6 and before performing the following invasive procedures:Peripherally inserted central venous catheter positioning;Re-intubation;Lumbar puncture;Pneumothorax or hydrothorax drainage.<br>|
| Placebo Comparator: placebo<br>Patients assigned to this arm will receive continuous infusion of placebo+ open label boluses of Fentanyl if necessary. | Drug: 5% glucose solution<br>* ev continuous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary efficacy variable for this study will be the pain scores obtained during the study period. Procedural pain will be measured once a day by the PIPP scale. Chronic pain will be evaluated through the application of the EDIN scale 3 times a day. |  | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of MVd newborns at one week of age;Age at which neonates will reach total enteral feeding;Age of first meconium passage;Incidence of IVH, PVL or death within 28 days of life;Incidence of bladder globe and hypotension during the first week of life |  | until discharge from hospital | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioids infusion, mechanical ventilation