Clinical trial NCT02859376: Analgesic Efficacy of Different Doses of Sucrose During Blood Sampling in Preterm Infants
Official title: Analgesic Efficacy of Different Doses of Sucrose During Blood Sampling in Preterm Infants: Prospective, Randomized, Controlled, Double Blind, Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Pain
Keywords: Preterm infants
Pain
Sucrose
Lead sponsor: University Hospital Padova
Sponsor class: OTHER
First posted: 2016-08-09
Enrollment: 144
Sex: ALL
Minimum age (years): 1
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The objective of this trial is to compare the analgesic effect of a single dose of oral sucrose 24% administered two minutes before a blood sampling (either heel prick or vascular puncture) versus multiple doses of oral sucrose 24% administered two minutes before and during the procedure in a population of preterm newborns of Gestational Age ≤ 36+6 weeks hospitalized in Neonatal Intensive Care Unit, using neonatal pain scales (Premature Infant Pain Profile (PIPP), Face, Legs, Activity, Cry, Consolability (FLACC) and indirect Visual Analogue Scale (VAS)) and Skin Conductance (SC) measurement (Pain Monitor).

Detailed description: This is a controlled, randomized, double blind, (double--dummy) study to evaluate the analgesic efficacy of sucrose. The study staff will evaluate all inborn newborns admitted to the Neonatal Intensive Care Unit (NICU) with a Gestational Age (GA) ≤36+6 weeks; the newborns will be immediately screened for eligibility based upon the pre--defined study inclusion/exclusion criteria.

Then, the parents will be informed about the study and the written informed consent form will be signed. Those eligible will be randomized into the study through computer generated randomization list.

The population of the study consists of premature infants undergoing blood sampling. It is estimated that approximately 144 premature neonates (72 per group either heel prick or venepuncture) will be included in the randomized study.

All eligible neonates whose parents have agreed to participate in the study by signing the informed consent form will be randomized as soon as they are admitted to the NICU.

This study will be conducted in 3 phases:

* Pre--randomization The following items will be obtained: Maternal history including the mother's medical and pregnancy history, prenatal care status; Antenatal analgesics and sedative drugs given to the mother; Estimated GA, birth weight and length. All the data have to be noted on the Case Report Form (CRF);
* Study phase: Premature neonates undergoing blood samples through skin breaking procedures, meeting inclusion criteria, will be randomized as soon as the doctor decision to drown the blood is made, to either sucrose 24% 0,3 mL if ≤ 1000 g or 0,5 mL if \> 1000 g two minutes before the skin breaking procedure or sucrose 24% 0,3 mL if ≤ 1000 g or 0,5 mL if \> 1000 g two minutes before and during the skin breaking procedure, according to a computer generated randomization list. A trained operator (a nurse or a doctor) will perform heel pricks using an automatic lance (Tenderfoot® micro--preemie for infants \< 1000 g and Tenderfoot preemie for infants \> 1000 grams) and venipuncture using a butterfly needle 23--25 gauge. Any skin breaking procedure, either heel prick or venipuncture, for each patient will be noted down;; patients will be video--recorded during blood sampling to allow at least two operators to evaluate the analgesic efficacy of the intervention by algometric measurements. In a subgroup of patients skin conductance will also be measured.

Algometric measurements: The pain evaluation will be done visualizing the video of the procedure. Two different evaluators independently will assign the pain score with:

1. Premature Infant Pain Profile (PIPP) at 30 and 60 seconds after the skin puncture
2. Face, Legs, Activity, Cry, Consolability (FLACC) scale at 30 seconds
3. Indirect Visual Analogue Scale (VAS) at 30 seconds for inter--rater agreement. One week later the same evaluators will assign again the pain scores for the intra--rater agreement.

Instrumental PAIN examinations: Pain Monitor is an instrument that measures SC. It detects hand or foot skin conductance gradient, which is directly related to the painful stimuli. The sympathetic nervous system releases acetylcholine that acts on muscarine receptors inducing a sweating and SC increase in response to painful stimuli. Pain monitor is simple to use: tree electrodes positioned on neonate foot sole are connected to the central system. Pain monitor immediately and continuously reacts to stimuli without being influenced neither by hemodynamic variability nor by neuromuscular blocks. The measurement its represented on a compatible computer monitor through a graphic function with SC values expressed in microsiemens on the ordinate axis and time on the abscissa axis. Stressful and painful stimuli related SC variability is represented by peaks and the under peaks area defines pain intensity at detection moment. During monitoring you can note down directly on the graphic every intervention on the patient (medication, blood sample, ect.). Detection can be extrapolated with Excel for statistical analysis.

- Follow--up phase: it will begin from the end of the blood samples. Assessments will continue until hospital discharge.

AE that are ongoing during the study phase as well as clinical outcomes (that are major clinical diagnoses) will be assessed until hospital discharge. Clinical data will be recorded on CRF. In addition the following information will be collected at hospital discharge:

* Number of previous skin breaking procedures
* Number of previous sucrose doses
* Clinical status of the infant
* Duration of hospitalization
* Number of Ventilated Days
* Need for oxygen/monitor at discharge
* Need for supplemental oxygen at 36 weeks post--menstrual age

Eligibility criteria: Inclusion Criteria:

* preterm neonates with gestational age ranging from 23+ 0 to 36+ 6 weeks
* undergoing blood sampling (either heel prick or vascular puncture)
* age ≤ 40 week GA + 28 days at the time of blood sampling
* 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 5 at 5 minutes of age and/or umbilical arterial pH \< 7.0
* Known genetic or chromosomal disorders
* Myopathies and neuropathies interfering with pain assessment by pain scales
* Sedation
* Presence of central catheter allowing blood sampling without skin breaking
* Other painful procedure less than 2 hours before blood sampling
* Physiological instability (more than 6 episodes of bradycardia and/or apnea per day)
* Maternal drug abuse

Primary outcomes:
measure: Change of analgesic efficacy Premature Infant Pain Profile (PIPP)
timeFrame: 2 minutes before, at the moment of the skin puncture, and at 30, 60 and 120 seconds after the skin puncture
Secondary outcomes:
measure: Change of analgesic efficacy Face, Legs, Activity, Cry, Consolability (FLACC)
timeFrame: at 30 and 120 seconds after the skin puncture
measure: Change of analgesic efficacy Visual Analogue Scale (VAS)
timeFrame: at 30 and 120 seconds after the skin puncture
measure: Change of analgesic efficacy Pain Monitor (skin electrical conductance)
timeFrame: 2 minutes before, at the moment of the skin puncture, and at 30, 60 and 120 seconds after the skin puncture
measure: Pain evaluation during heel prick Vs vascular puncture PIPP
timeFrame: Through study completion, an average of 1 year
measure: Pain evaluation during heel prick Vs vascular puncture FLACC
timeFrame: Through study completion, an average of 1 year
measure: Pain evaluation during heel prick Vs vascular puncture VAS
timeFrame: Through study completion, an average of 1 year
measure: Pain evaluation during heel prick Vs vascular puncture Pain Monitor (skin electrical conductance)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome Mechanical Ventilation (MV) duration
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome non-Invasive MV (nIMV) duration
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome oxygen dependence duration
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome rate of Bronchopulmonary Dysplasia (BPD)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome rate of Pneumothorax (PNX)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome rate of Patent ductus arteriosus (PDA)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome incidence Intraventricular hemorrhage (IVH)/ Periventricular leukomalacia (PVL)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome incidence death within 28 days of life
timeFrame: within 28 days of life
measure: Intra--hospital outcome incidence hydrocephalus
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome time to Full Enteral Feeding (FEF)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome rate of Necrotizing Enterocolitis (NEC)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome rate of proved sepsis
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome rate of suspected sepsis
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome rate of Retinopathy of Prematurity (ROP)
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome time to regain birth weight
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome hospitalization length
timeFrame: Through study completion, an average of 1 year
measure: Intra--hospital outcome incidence hospital discharge without major morbidities
timeFrame: Through study completion, an average of 1 year
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
timeFrame: Through study completion till patient discharge, an average of 1 year
Other outcomes:
Locations:
city: Padova
country: Italy
facility: University Hospital of Padova
Study officials:
name: Paola Lago, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cignacco EL, Sellam G, Stoffel L, Gerull R, Nelle M, Anand KJ, Engberg S. Oral sucrose and "facilitated tucking" for repeated pain relief in preterms: a randomized controlled trial. Pediatrics. 2012 Feb;129(2):299-308. doi: 10.1542/peds.2011-1879. Epub 2012 Jan 9.
citation: Shah PS, Herbozo C, Aliwalas LL, Shah VS. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database Syst Rev. 2012 Dec 12;12(12):CD004950. doi: 10.1002/14651858.CD004950.pub3.
citation: Simonse E, Mulder PG, van Beek RH. Analgesic effect of breast milk versus sucrose for analgesia during heel lance in late preterm infants. Pediatrics. 2012 Apr;129(4):657-63. doi: 10.1542/peds.2011-2173. Epub 2012 Mar 5.
citation: Yin T, Yang L, Lee TY, Li CC, Hua YM, Liaw JJ. Development of atraumatic heel-stick procedures by combined treatment with non-nutritive sucking, oral sucrose, and facilitated tucking: a randomised, controlled trial. Int J Nurs Stud. 2015 Aug;52(8):1288-99. doi: 10.1016/j.ijnurstu.2015.04.012. Epub 2015 Apr 23.
citation: Shah VS, Ohlsson A. Venepuncture versus heel lance for blood sampling in term neonates. Cochrane Database Syst Rev. 2011 Oct 5;2011(10):CD001452. doi: 10.1002/14651858.CD001452.pub4.
citation: Stevens B, Yamada J, Lee GY, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD001069. doi: 10.1002/14651858.CD001069.pub4.