Objectives: This study examined a more effective pain management method, without sucrose, on heel lance in preterm infants using the Premature Infant Pain Profile (PIPP). Design: In a nonblinded, randomized controlled, two-period, two-sequence crossover trial, 25 infants were randomly allocated to intervention (a Brahms lullaby with non-nutritive sucking, facilitated tucking and holding) or standard care (facilitated tucking and holding). Setting: Local Perinatal Medical Centre's NICU in Japan, July 2014 until June 2015. Outcome measures: The primary outcome variable was PIPP, and secondary outcomes were heart rate (HR), oxygen saturation, and abnormal HR (> baseline mean plus 2 SDs, or <120 minus 2 SDs). Results: The infants were 33.8 weeks gestational age at birth, 1,983.7 g birth weight, and 32 to 35 weeks postconceptual age. At all 10 measurement points, constructed of every 30 seconds postheel lance, mean PIPP of infants during the intervention (3.6 to 2.4) was significantly lower than during the standard care (8.0 to 4.6) (range, P=0.0039 to P<0.0001). All PIPP reduction rates from the 30 seconds point were similar between the two groups. The HR of preterm infants at the 120 seconds points were significantly lower (P=0.0151), and the HRs of 6 points were considerably lower during the intervention than during the standard care (range, P≤0.0879 to P≥0.049). The abnormal HR total number was significantly lower during the intervention (2) than the standard care (23) (frequency ratio=0.087, P<0.0001). Conclusion: This method demonstrated stronger analgesia, early pain relief, and maintenance of homeostasis on heel lance in preterm infants.

The abnormal HR total number was significantly lower in the intervention group (2) than in the standard care group (23) (frequency ratio=0.087, P<0.0001). 3) Figure 2 was incorrect and has since been corrected in the article. The correct Figure 2 is shown below.

study involving preterm infants, frequent pain was associated with lower body weight and head circumference at 32 weeks [10] and a reduction of the white matter and subcortical gray matter at the termequivalent age [11] even though other medical confounding factors were adjusted.Repeated pain in the neonatal period has a long-term negative influence. In preterm infants, poorer cognition and motor function in infancy [12], a reduction of Full Scale IQ (FSIQ) at school age [13], and a reduction of the cognitive score in late adolescence [14] have been reported even though other medical confounding factors were adjusted for (after comprehensively adjusting for multiple clinical factors). Moreover, internalizing behaviors, such as depression and anxiety, were clearly noted in infancy in preterm infants compared with full-term infants even though other medical confounding factors were adjusted for [15], and it continues to school age, late adolescence, and young adulthood [16][17][18][19][20].Painful procedures in the NICU include heel lance, blood sampling, arterial puncture, lumbar puncture, and placement and intramuscular injection, and heel lance is one of the most frequently performed painful procedures [21]. Of the painful procedures performed 3,605 times in total in 55 neonates who stayed in the NICU for 28 days or longer, heel lance accounted for 71% [22]. However, the pain of the most frequently performed heel lance in the NICU is not sufficiently managed. In Italy, 30% of 140 medical workers of 5 NICUs (89 nurses and 51 physicians) answered that no intervention is performed for heel lance [23].

To clarify the possibility of event-related potential (ERP) evoked by heel lance in neonates as an index of pain assessment, knowledge acquired by and problems of the methods used in studies on ERP evoked by heel lance in neonates were systematically reviewed, including knowledge about Aδ and C fibers responding to noxious stimuli and Aβ fibers responding to non-noxious stimuli. Of the 863 reports searched, 19 were selected for the final analysis. The following points were identified as problems for ERP evoked by heel lance in neonates to serve as a pain assessment index: (1) It is possible that the ERP evoked by heel lance reflected the activation of Aβ fibers responding to non-noxious stimuli and not the activation of Aδ or C fibers responding to noxious stimulation; (2) Sample size calculation was presented in few studies, and the number of stimulation trials to obtain an averaged ERP was small. Accordingly, to establish ERP evoked by heel lance as a pain assessment in neonates, it is necessary to perform a study to clarify ERP evoked by Aδ- and C-fiber stimulations accompanied by heel lance in neonates.