Non-pharmacological Interventions for Procedural Pain in Premature Neonates

A. Specific Aims Premature infants admitted to the neonatal intensive care unit (NICU) require up to several hundred procedures during their hospitalization. Many of these are tissue-damaging procedures (TDPs) known to cause pain [1]. Through funding from NINR, the investigators found that TDPs not only caused pain but also increased markers of ATP degradation and oxidative stress[2[. The TDP was tape removal, a commonly performed procedure in the NICU2.

Based on this finding, the investigators sought to determine if interventions that relieve pain also reduce biochemical markers of ATP degradation and oxidative stress. The investigators first examined the effect of oral sucrose, a commonly used intervention, when given before a heel lance. The investigators chose heel lance because it is the most predominant painful procedure in the NICU, as shown in 29 different clinical trials[3]. The investigators hypothesized that since oral sucrose is documented to significantly reduce pain scores, then administration of this analgesic will also decrease markers of ATP degradation and oxidative stress. However,the investigators observed the opposite effect. Although a single dose of oral sucrose reduced behavioral markers of pain, it significantly increased biochemical markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress (allantoin) over time[4]. More importantly, the effect of oral sucrose on breakdown markers of ATP were enhanced and were significantly higher in neonates that were intubated or were receiving more than 30% FiO25. These findings lead to the question: If oral sucrose does not effectively reduce the biochemical effects of procedural pain, what intervention or groups of intervention will decrease both behavioral markers of procedural pain and reduce ATP utilization and oxidative stress in premature neonates? For this RO1 renewal, the investigators propose to test the individual and additive effects of two commonly used interventions for procedural pain. These interventions are (a) administration of 30% oral glucose and non-nutritive sucking (NNS) (b) facilitated tucking and NNS c) administration of 30% oral glucose, facilitated tucking and NNS. Administration of 30% oral glucose was documented to decreased procedural pain scores[6-9] without the potential adverse effects of fructose, a key ingredient of sucrose[10-11]. Facilitated tucking is the gentle positioning of preterm infants with arms and legs in a flexed, midline position close to the body, while either in a side-lying or prone position[12]. Because tachycardia often accompanies pain, a documented benefit of facilitated tucking is stabilization of heart rate and reduction of motor activity (flailing)[12-13]. Non-nutritive sucking refers to the provision of a weight-appropriate pacifier[14]. The painful procedure will be a clinically required heel lance, which refers to the puncture of a newborn's heel for blood glucose using a specially designed lancet. Our general hypothesis is that commonly used clinical interventions known to reduce procedural pain alter biochemical markers of ATP degradation, oxidative stress and cell injury.

Specific Aim 1 will determine whether (a) 30% oral glucose and NNS or (b) facilitated tucking and NNS or (c) 30% oral glucose with facilitated tucking and NNS will decrease procedural pain.

• Pain will be quantified using a validated pain scoring tool, the Premature Infant Pain Profile (PIPP). Individual and additive effect of interventions will be determined.

Specific Aim 2 will determine whether (a) 30% oral glucose and NNS or (b) facilitated tucking and NNS or (c) 30% oral glucose with facilitated tucking and NNS will decrease biochemical markers of ATP degradation, oxidative stress and oxidative cell injury.

• Products of ATP breakdown in plasma-hypoxanthine (Hx), xanthine (Xa), and uric acid (UA)-will be measured using high performance liquid chromatography.
• Oxidative stress will be quantified by measuring plasma levels of allantoin using mass spectrometry.
• Cell injury will be quantified by measuring plasma levels of F2 isoprostane using liquid-chromatography/mass spectrometry.

Study Overview

• Status: Completed
• Conditions: Prevention of Procedural Pain; Reduction of Procedural Pain; Biochemical Effects of Oral Dextrose
• Intervention / Treatment: Other: Oral glucose and NNS; Other: Oral glucose, facilitated tucking, NNS; Other: Facilitated tucking and NNS

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Children's 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:

• Potential subjects are premature infants between 28-36 weeks gestation, have an arterial or central catheter in place and have a clinically required heel lance.

Exclusion Criteria:

• Requirement for surgery
• Intraventricular hemorrhage (IVH) ≥ grade 3
• Neonates on medications such as morphine, fentanyl, versed, muscle relaxants, phenobarbital, or dilantin
• Renal injury (plasma creatinine > 1 mg/dl)
• Severe cyanotic heart disease or severe respiratory distress
• Chromosomal anomaly
• Facial anomaly

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Oral glucose and NNS	Other: Oral glucose and NNS
ACTIVE_COMPARATOR: Oral glucose and facilitated tucking and NNS; Oral glucose, facilitated tucking and NNS	Other: Oral glucose, facilitated tucking, NNS
ACTIVE_COMPARATOR: Facilitated Tucking and NNS; Facilitated tucking and NNS	Other: Facilitated tucking and NNS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decreased pain score using the Premature Infant Pain Profile pain scoring tool	A decrease in pain score will be quantified using the validated tool Premature Infant Pain Profile, which will be scored by a neonatologist blinded to group assignment.	at time of heelstick

Collaborators and Investigators

• Sponsor: Loma Linda University

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2014
• Primary Completion (ACTUAL): December 1, 2019
• Study Completion (ACTUAL): December 1, 2019

Study Registration Dates

• First Submitted: August 7, 2014
• First Submitted That Met QC Criteria: August 8, 2014
• First Posted (ESTIMATE): August 12, 2014

Study Record Updates

• Last Update Posted (ACTUAL): March 13, 2020
• Last Update Submitted That Met QC Criteria: March 12, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Pain, Procedural
• Other Study ID Numbers: IRB5140027