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.