Oral Sucrose Versus Glucose for Procedural Pain in Premature Neonates

Premature neonates 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) that cause pain. Through our NIH funded research, we made the novel observation that exposure to a single TDP can significantly increase ATP utilization and oxidative stress, as evidenced by increased plasma levels of hypoxanthine, uric acid and malondialdehyde in neonates exposed to TDPs as compared to controls (no TDP). Because neonates are exposed to numerous TDPs, it is relevant to explore the energy costs of repeated exposures to painful procedures, an important information that is currently not known, as the effect of this cumulative metabolic dysfunction could result in potentially treatable or preventable cell injury.

Oral sucrose analgesia is frequently given to relieve procedural pain in neonates on the basis of its effect on behavioral and physiological pain scores. However, we found, through our prospective, randomized, double blind study funded by NIH, that although oral sucrose significantly reduced pain scores, its administration before a single TDP (heel lance) significantly increased ATP utilization. This is evidenced by higher plasma concentrations of hypoxanthine and uric acid in neonates given sucrose compared to control neonates (no TDP, no sucrose) or neonates just given a pacifier. These novel findings raise concern because preterm neonates have limited ATP stores and are susceptible to cell injury due to ATP depletion. In addition, it raises the relevant concern: If a single dose of oral sucrose can alter ATP metabolism, what are the effects of exposure to multiple doses of oral sucrose? More importantly, what is the effect of multiple TDPs and/or multiple oral sucrose dosages on ATP utilization, oxidative stress and cell injury? This application will also explore the effect of 30% oral glucose, another sweet solution currently used to relieve pain, on ATP metabolism.

In this study, we will test the general hypothesis that exposure to multiple TDPs and/or multiple doses of oral sucrose analgesia compared to oral glucose or standard care, alter biochemical markers of ATP utilization, oxidative stress and cell injury. We will use a prospective randomized clinical research design to test this hypothesis during days of life 3-7 of human premature neonates. Increased ATP utilization will be quantified by concentrations of hypoxanthine, xanthine and uric acid measured using HPLC. Oxidative stress will be quantified by concentrations of allantoin using gas chromatography/mass spectroscopy, and cell injury will be quantified through urinary concentration of intestinal fatty acid binding protein, an early marker of enterocyte injury. Data from this application will provide insight into the cellular and biochemical effects of repetitive and accumulated TDPs and/or multiple doses of oral sucrose. With this knowledge, we will propose and test innovative strategies that will not only decrease pain but also will prevent cell injury or cell death.

Study Overview

• Status: Completed
• Conditions: Neonatal Procedural Pain
• Intervention / Treatment: Other: 24% oral sucrose; Other: 30% oral glucose

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Potential subjects are premature infants ≤ 34 weeks gestation and ≤ 7 days of age postnatally

Exclusion Criteria:

1. requirement for surgery
2. intraventricular hemorrhage (IVH) ≥ grade 3
3. neonates on medications such as morphine, fentanyl, versed, muscle relaxants, phenobarbital, or dilantin,
4. renal injury (plasma creatinine > 1 mg/dl,
5. severe cyanotic heart disease or severe respiratory distress,
6. known abdominal wall or intestinal anomaly or injury (NEC),
7. chromosomal anomaly and (8) facial anomaly

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Neonates randomized to this arm will receive the standard of practice at Loma Linda University NICU.
Experimental: 24% oral sucrose with pacifier; Neonates randomized to this arm will receive 24% sucrose before every painful procedure on days of life 3-7 in the NICU.	Other: 24% oral sucrose
Experimental: 30% oral glucose with pacifier; Neonates randomized to this arm will receive 30% oral glucose before every painful procedure on days of life 3-7.	Other: 30% oral glucose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
We will determine the relationship between oral sucrose or glucose on urinary markers of ATP utilization, oxidative stress and cell injury compared to multiple doses of oral glucose (30%) or to control group	To quantify ATP utilization, we will measure urinary concentrations of Hx, Xa, UA. To quantify oxidative stress, we will measure urinary concentrations of allantoin. To quantify cell injury, we will measure urinary concentrations of intestinal fatty acid binding protein.	Day of life 3-7

Collaborators and Investigators

• Sponsor: Loma Linda University
• Investigators: Principal Investigator: Danilyn Angeles, PhD, Loma Linda University

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): July 31, 2020
• Study Completion (Actual): July 31, 2020

Study Registration Dates

• First Submitted: July 1, 2013
• First Submitted That Met QC Criteria: July 3, 2013
• First Posted (Estimate): July 10, 2013

Study Record Updates

• Last Update Posted (Actual): September 2, 2020
• Last Update Submitted That Met QC Criteria: August 31, 2020
• Last Verified: August 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: 5130117