Continuous Infusion of Fentanyl in Preterm on MV

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.

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