Analgesic Efficacy of Different Doses of Sucrose During Blood Sampling in Preterm Infants

Study Overview
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Brief Summary
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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
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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: Premature Infant Pain Profile (PIPP) at 30 and 60 seconds after the skin puncture Face, Legs, Activity, Cry, Consolability (FLACC) scale at 30 seconds 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

Official Title
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Analgesic Efficacy of Different Doses of Sucrose During Blood Sampling in Preterm Infants: Prospective, Randomized, Controlled, Double Blind, Clinical Trial

Conditions
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Pain

Intervention / Treatment
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* Dietary Supplement: sucrose 24%


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 28 Days

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: sucrose24% 2 minutes before<br>sucrose 24% 0,3 mL if < 1000 g or 0,5 mL if > 1000 g two minutes BEFORE the skin breaking procedure | Dietary Supplement: sucrose 24%<br>* 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.<br>|
| Experimental: sucrose24% 2minutes before and during<br>sucrose 24% 0,3 mL if < 1000 g or 0,5 mL if > 1000 g two minutes BEFORE and DURING the skin breaking procedure | Dietary Supplement: sucrose 24%<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of analgesic efficacy Premature Infant Pain Profile (PIPP) | The primary outcome of this study will be to evaluate the analgesic efficacy of sucrose 24% administration (single versus multiple doses) during blood sampling using Premature Infant Pain Profile (PIPP). | 2 minutes before, at the moment of the skin puncture, and at 30, 60 and 120 seconds after the skin puncture | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of analgesic efficacy Face, Legs, Activity, Cry, Consolability (FLACC) | The analgesic efficacy of sucrose 24% administration (single Vs multiple doses) during blood sampling using Face, Legs, Activity, Cry, Consolability (FLACC) | at 30 and 120 seconds after the skin puncture | 
| Change of analgesic efficacy Visual Analogue Scale (VAS) | The analgesic efficacy of sucrose 24% administration (single Vs multiple doses) during blood sampling using indirect Visual Analogue Scale (VAS). | at 30 and 120 seconds after the skin puncture | 
| Change of analgesic efficacy Pain Monitor (skin electrical conductance) | The analgesic efficacy of sucrose 24% administration (single Vs multiple doses) during blood sampling using Pain Monitor (skin electrical conductance) | 2 minutes before, at the moment of the skin puncture, and at 30, 60 and 120 seconds after the skin puncture | 
| Pain evaluation during heel prick Vs vascular puncture PIPP | Pain evaluation during heel prick Vs vascular puncture will be performed using PIPP scale | Through study completion, an average of 1 year | 
| Pain evaluation during heel prick Vs vascular puncture FLACC | Pain evaluation during heel prick Vs vascular puncture will be performed using FLACC scale | Through study completion, an average of 1 year | 
| Pain evaluation during heel prick Vs vascular puncture VAS | Pain evaluation during heel prick Vs vascular puncture will be performed using VAS scale | Through study completion, an average of 1 year | 
| Pain evaluation during heel prick Vs vascular puncture Pain Monitor (skin electrical conductance) | Pain evaluation during heel prick Vs vascular puncture will be performed using Pain Monitor (skin electrical conductance) | Through study completion, an average of 1 year | 
| Intra--hospital outcome Mechanical Ventilation (MV) duration | Intra--hospital outcome MV duration | Through study completion, an average of 1 year | 
| Intra--hospital outcome non-Invasive MV (nIMV) duration | Intra--hospital outcome nIMV duration | Through study completion, an average of 1 year | 
| Intra--hospital outcome oxygen dependence duration | Intra--hospital outcome oxygen dependence | Through study completion, an average of 1 year | 
| Intra--hospital outcome rate of Bronchopulmonary Dysplasia (BPD) | Intra--hospital outcome rate of BPD | Through study completion, an average of 1 year | 
| Intra--hospital outcome rate of Pneumothorax (PNX) | Intra--hospital outcome rate of PNX | Through study completion, an average of 1 year | 
| Intra--hospital outcome rate of Patent ductus arteriosus (PDA) | Intra--hospital outcome rate of PDA | Through study completion, an average of 1 year | 
| Intra--hospital outcome incidence Intraventricular hemorrhage (IVH)/ Periventricular leukomalacia (PVL) | Intra--hospital outcome incidence of IVH/PVL | Through study completion, an average of 1 year | 
| Intra--hospital outcome incidence death within 28 days of life | Intra--hospital outcome incidence of death within 28 days of life | within 28 days of life | 
| Intra--hospital outcome incidence hydrocephalus | Intra--hospital outcome incidence of hydrocephalus | Through study completion, an average of 1 year | 
| Intra--hospital outcome time to Full Enteral Feeding (FEF) | Intra--hospital outcome time to FEF | Through study completion, an average of 1 year | 
| Intra--hospital outcome rate of Necrotizing Enterocolitis (NEC) | Intra--hospital outcome rate of NEC (all stages according to the modified Bell's criteria) | Through study completion, an average of 1 year | 
| Intra--hospital outcome rate of proved sepsis | Intra--hospital outcome rate of proved sepsis | Through study completion, an average of 1 year | 
| Intra--hospital outcome rate of suspected sepsis | Intra--hospital outcome rate of suspected sepsis | Through study completion, an average of 1 year | 
| Intra--hospital outcome rate of Retinopathy of Prematurity (ROP) | Intra--hospital outcome rate of ROP | Through study completion, an average of 1 year | 
| Intra--hospital outcome time to regain birth weight | Intra--hospital outcome time to regain birth weight | Through study completion, an average of 1 year | 
| Intra--hospital outcome hospitalization length | Intra--hospital outcome hospitalization length | Through study completion, an average of 1 year | 
| Intra--hospital outcome incidence hospital discharge without major morbidities | Intra--hospital outcome incidence of hospital discharge without major morbidities | Through study completion, an average of 1 year | 
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Safety [achieved by monitoring and registering adverse events (AEs), serious adverse events (SAEs) even those unexpected (SUSARs), and measuring vital signs] | Through study completion till patient discharge, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm infants, Pain, Sucrose