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.