Non-pharmacological pain relief interventions and contextual factors influencing pain response in preterm infants : are we measuring what we intend to measure?
Preterm birth is one of the most significant worldwide problems in perinatology. The limited viability of preterm infants have been advanced thanks to the ongoing development of neonatal intensive medicine, although the rates of mortality and morbidity vary according to gestational age. Beside mortality the challenges of preterm birth are associated with short-term morbidity during the neonatal period and moderate to severe long-term morbidity, such as childhood disabilities 1,2 and high financial burdens for the society 1. Preterm infants are spending the first period of their life in a neonatal intensive care unit (NICU), which is critical for their survival. However, this period is characterized by repeated pain exposure, which is occurring during the critical window of central nervous system development 3,4. Recurrent pain exposure during this critical time is associated with permanent changes in peripheral, spinal and supraspinal pain processing, neuroendocrine function and neurologic development 5,6. Furthermore, these changes can be manifested by alterations in pain thresholds, stress responses, cognitive function, behavioral disorders, and long-term disabilities in learning and dampened behavioral pain response 4,7-19. This information brought the pain expert community to recognition that efficient pain management in this population is critical for their future development.
The average number of painful procedures preterm infants are exposed to in a NICU stands on +14 procedures per day 20-22, while most of these procedures being associated with minor to moderate pain. While pharmacological pain relief agents are appropriate for severe pain management, they are not adequate to manage minor and routine painful procedures such as heel-stick 20. Furthermore, most of pain medications used for preterm infants in NICUs are off-label or unlicensed for use in this population 23. Therefore, non-pharmacological pain relief interventions are proposed to overcome these challenges. These interventions include methods that involve reducing the sensitivity of the neonates during and after minor painful procedures (e.g. sucrose, non-nutritive sucking, kangaroo care, and facilitated tucking) 24,25. A number of studies have reported the efficacy of non-pharmacological pain relief interventions. Most of these studies, however, examined single painful events. Information is lacking regarding the comparative effectiveness of these interventions and their efficacy over time. In order to provide a basis for efficient pain management, comprehensive pain assessment is required.
Pain assessment has gone through major development in the past decades 26, with more than two-dozen pain assessment instruments developed and evaluated. The recommendation is for comprehensive multidimensional assessment method, which include both behavioral (cry, facial expression) and physiological (heart rate, oxygen saturation) measures 27. Despite the major advances in pain assessment in neonates, challenges in understanding the behavior of pain in preterm infants remain. Pain response in preterm infants is variable within and between infants 22,28, and weak correlations are repeatedly reported between behavioral and physiological responses 28-30, which makes clinical interpretation of pain scores difficult. These phenomenon reinforce the belief that pain response in these vulnerable infants seems to involve more than the invasive procedure itself but is further influenced by demographic and medical contextual factors 20,22-24,45. In the past years the scientific pain expert community has widely recognized the issue of contextual factors associated with pain response. The results in the existing literature indicate that the contextual factors consistently associated most with pain responses of preterm infants are age related factors 31-40, previous pain exposure 15,31,34-36,39,41,42, and severity of illness 15,30,34-36,41-43. However, findings even in relation to these contextual factors are not consistent across studies. One explanation for this inconsistency is the varying methodological approaches used in these studies. Therefore, further research is needed to determine which contextual factors are most strongly associated with pain response and to progress one step further with more comprehensive pain assessment instruments.
The overall purpose of this project was to compare the effectiveness of two non-pharmacological pain relief interventions over time, and to explore the association between medical and demographic contextual factors and pain response of preterm infants under the impact of non-pharmacological pain relief interventions during repeated routine heel-stick procedures.
This thesis includes 7 chapters:
Chapter I presents a comprehensive introduction into the relevance of pain in neonates, particularly in preterm infants. The chapter gives an overview of the problem of premature neonatal pain within the context of neurologic development in preterm infants. This leads to the issue of the serious short and long-term consequences of high pain exposure during the neonatal period. The challenges in pain assessment are described within the complexity of the neonatal pain experience in the NICU, leading to the importance of pain management with non-pharmacological pain relief interventions. The last part of the introduction presents the theoretical framework this study was based on. Chapter II describes the specific aims of the dissertation.
Chapter III presents a publication of the results of the parent study PAMINA (PAin Management In NeonAtes). PAMINA is multicenter randomized control trial (RCT) that aimed to compare the effectiveness of non-pharmacological pain relief interventions; oral sucrose and facilitated tucking, across 5 heel-stick procedures in preterm infants aged between 24 and 32 weeks of gestation. Seventy-one infants were randomly allocated to one of three interventions: sucrose, facilitated tucking, or the combination of both interventions. Four experienced nurses, blinded to the phase of the heel-stick (baseline, heel-stick, and recovery) assessed pain with the Bernese Pain Scale for Neonates (BPSN). The results show that sucrose with and without facilitated tucking had pain-relieving effects even in preterm infants younger than 32 weeks of gestation and remained effective across time.
Chapter IV presents the publication of a commentary article about the intervention of facilitated tucking. In this manuscript we raise the question of the clinical feasibility of facilitated tucking, which requires additional manpower. In light of economic restraints of the health care system, and the lower effectiveness of facilitated tucking compared to sucrose, this commentary encourages re-evaluating the recommendations regarding methods such as facilitated tucking and further recommending for comparative effectiveness studies of non-pharmacological pain relief interventions.
Chapter V presents the results of a systematic review, which examined studies investigating the impact of contextual factors on pain response of heel-stick procedures in preterm infants. A total of 23 studies meeting inclusion criteria were included in the review. The studies varied relative to their design, sample, analysis procedures, and variables examined. Six categories of contextual factors emerged: age, pain exposure, health status, therapeutic interventions, behavioral status, and demographic factors. The review supports the influence of some contextual factors on pain response with the factors most consistently related to pain response being age related factors, previous pain exposure and severity of illness. The examined contextual factors varied in the strength of their association with pain response, and none were consistently related, as evidenced by contradictory findings. In some cases the inconsistencies appeared attributable to the methodological heterogeneity of the studies included in the review. The results of the review also support the low correlation between behavioral and physiological pain responses, and the need for further investigation of contextual factors, to better understand their influence on pain response.
Chapter VI presents the results manuscript of the exploratory sub analysis of the PAMINA study. This study aimed to explore the association of contextual factors with pain response of preterm infants receiving non-pharmacological interventions for repeated heel-stick procedures. In total 10 demographic and medical CFs were extracted from medical charts over the first 14 days of life. In this study we confirmed the low correlation between behavioral and physiologic pain scores in preterm infants. The results of the study emphasize that higher exposure to painful procedures; male infants and having CPAP or mechanical ventilation were the contextual factors associated with physiological responses. The only variables that were significantly associated with the behavioral scores of the Bernese Pain Scale for Neonates, were Apgar scores at 1 and 5 minutes, however these relationships were inconsistent. In this study we examined a variety of contextual factors that previous studies have suggested may influence preterm infants' pain responses. The use of multivariate analysis while controlling for potential confounders allowed us to examine the independent contribution of each examined contextual factor in explaining pain responses. Furthermore, we utilized a pain assessment instrument that allowed us to examine the impact of the contextual factors on both behavioral and physiologic pain responses. Our findings also add to the growing body of research that suggests the need to considering contextual factors when assessing pain in this population. However, given that findings about the impact of CFs are mixed across studies, additional multicenter research including large sample is needed to determine the contextual factors that need to be incorporated into pain assessment instruments.
Finally in Chapter VII the results of all study parts are synthesized and discussed, followed by suggestions for further research and clinical practice development. Pain assessment and management remains a major challenge in preterm infants. The findings of this dissertation support the efficacy of sucrose over time and recommend it over facilitated tucking. While our findings support the importance of considering contextual factors as influencing pain responses in this vulnerable population, the specific contextual factors that need to be incorporated into pain assessment scales remains unclear. Our findings raise important methodological issues that need to be considered as future studies are designed to examine the impact of contextual factors on pain responses of preterm infants
