Preterm neonates hospitalized in the neonatal intensive care unit (NICU) undergo frequent painful procedures daily (range 7-17), most commonly heel lance or venipuncture, with less than half receiving any form of pain relief.7 Untreated early pain has been associated with both immediate physiologic instability and pain sensitivity and long-lasting deleterious effects16 including cognitive delays and behavioral problems,32 altered brain development,8,23 and long-lasting alteration in later pain sensitivity.31 Although pharmacological interventions may appear as a logical solution to minimize pain, they can be unavailable, impractical, or inappropriate for repeated procedures such as heel lance or intramuscular injection.9,20 Strong evidence from systematic reviews suggests that maternal-infant skin-to-skin contact, the upright holding of a diaper clad infant on the mother's bare chest15 (kangaroo care [KC], 25 studies, n = 2001), often referred to as KC, sucrose28 (74 studies, n = 7049), and nonsucrose sweet-tasting solutions13 (168 studies, n = 1175) are effective strategies to reduce procedural pain during a single exposure. Although considered to be the current most effective strategies to reduce procedural pain in neonates, the effect of these interventions to reduce pain would be considered moderate. Most notably, in the most recent Cochrane review, of the 17 studies (n = 810) that compared KC with a no-treatment control, 5 studies, (n = 267), able to be meta-analyzed, reported composite pain scores, measured using the Premature Infant Pain Profile (PIPP).15 Findings favoured KC at 30 seconds (mean difference [MD] −3.21, 95% confidence interval [CI] −3.94 to −2.47), 60 seconds (3 studies; n = 156) (MD −1.64, 95% CI −2.86 to −0.43), and 90 seconds (n = 156) (MD −1.28, 95% CI −2.53 to −0.04), but at 120 seconds, there was no difference (n = 156) (MD 0.07, 95% CI −1.11 to 1.25).
Regarding sustained efficacy over repeated procedures, 8 randomized controlled trials (n = 782) have reported on efficacy of sucrose over repeated procedures and generally report sustained pain-reducing effects.11 Only 1 small study, which randomly assigned preterm infants to receive maternal KC (n = 38) or standard no-treatment control (incubator care) (n = 37) over 4 repeated heel lances, has supported sustained pain-relieving efficacy of KC.12 Given the association of adverse outcome in neonates after exposure to repeated untreated procedures, it is imperative that nonpharmacological interventions used for frequent procedures over extended admission are fully evaluated to ensure that they remain efficacious over time while being safe. Moreover, little is known regarding whether the combination of KC with sucrose may augment the effectiveness of pain relief or whether these interventions provided during pain may impact early neurodevelopmental outcomes. Therefore, we conducted a single-blind randomized controlled trial to determine the sustained comparative pain-reducing efficacy of KC, alone or combined with 24% oral sucrose, compared with the standard care of 24% oral sucrose alone, as well as the potential intervention effects on preterm infant development.
2.1. Study setting and population
A detailed description of the study protocol has been previously published.4 In brief, this randomised controlled clinical trial (RCT), registered at ClinicalTrials.gov (NCT01561547), was conducted in an NICU in Eastern Canada after institutional ethical approval. Infants were considered eligible for enrollment if they were born less than or equal to 36 6/7 weeks of gestational age (GA) according to early ultrasound and able to be enrolled within 7 days of birth, considered clinically stable enough to be held in maternal KC (determined by the neonatal attending team), and whose mothers provided written consent and were able to be available for KC for the duration of their infant's hospital stay. Infants diagnosed with major congenital anomalies, requiring surgery, or receiving additional analgesics or sedatives within 24 hours of the procedures recorded for primary outcome analyses were excluded.
2.2. Study outcomes
The primary outcome was biobehavioural pain response measured using the PIPP, a reliable and valid pain assessment tool for preterm infants. The measure consists of 7 indicators: 3 behavioral (facial actions: brow bulge, eye squeeze, and nasolabial furrow), 2 physiological (heart rate and oxygen saturation), and 2 contextual factors (GA and behavioral state) summed to calculate a composite pain score between 0 and 21. Scores ranging 0 to 6 indicate no to mild pain, 7 to 12 indicating moderate pain, and greater than 12 indicating severe pain.27 Secondary outcomes included the Neurobehavioral Assessment of the Preterm Infant (NAPI).19 Assessments conducted during standardized testing periods at 32 and 36 weeks of corrected GA and term equivalence, considered to be 38 weeks, were performed on all eligible infants. Gestational age at birth and study enrollment dictated total completed assessments based on the standardized scoring windows of the NAPI, as described above.19 Assessment periods included a range of ± 10 days for each specific period, eg, an infant enrolled at 33 weeks and 1 day would still fall within the 32-week standardized testing period. Severity of medical risk at birth was assessed by the SNAP-II (Simplified Newborn Illness Severity and Mortality Risk Score).24 A daily number of tissue-damaging and non–tissue-damaging painful procedures were recorded from the hospital chart, and the number of hours spent in KC was calculated from a maternal self-report diary, confirmed with daily research personnel follow-up.
Given previous reports that maternal stress measured by cortisol levels has been correlated with infant pain response, we asked mothers to provide cortisol samples at 3 points throughout the study.30 Mothers were asked to provide salivary cortisol samples upon awakening on the study days on which the infants underwent a medically required painful procedure.
2.3. Study design and interventions
After parental consent obtained by the research nurse, eligible infants stratified by GA at birth (< and ≥32 weeks) were randomized to 1 of 3 possible groups, using randomly permuted block of 4 and 8 using a computerized off-site password protected web site accessed only by the study research nurse. All members of the research and clinical teams, with the exception of the research nurse, were kept blind to group assignment. Although it was impossible to blind whether the infant received KC, it was unknown whether sucrose or placebo (sterile water) was given.
2.4. Kangaroo care alone
After collection of a 1-minute baseline measurement while in an incubator (BL1), infants wearing only a diaper were placed upright at an angle of approximately 60° on their mothers' bare chest, providing maximal skin contact between mother and baby for at least 15 minutes before the painful procedure. A second baseline (BL2) measurement was collected for 1 minute. Two minutes before the heel lance procedure, the infant received 1/4 of the recommended (based on NICU protocol range at the time of the study of 0.4 to 1.0 mL depending on infant weight) volume of sterile water onto the tongue. The remainder of the total recommended dose was given in small increments throughout the procedure.
2.5. Sucrose alone
Half an hour before the heel lance procedure, the research nurse placed the infant in the supine position in an incubator or infant cot and set up the monitoring equipment. All monitoring took place while the infant was in the incubator or cot. Baseline measurements were collected at similar time points as described above. Two minutes before the procedure, the baby was administered 24% oral sucrose solution by syringe onto the tip of the tongue using the same dosing criteria and timing described above, consistent with the NICU's clinical protocol.
2.6. Kangaroo care and sucrose combined
For KC and sucrose combined group, the infant was placed in KC as in the KC alone group but also received 24% oral sucrose solution instead of sterile water in the manner described previously.
2.7. Rescue sucrose
For ethical reasons, nursing staff were permitted to deviate from the protocol and give off-study doses of rescue sucrose, regardless of group assignment, when performing any of the predefined routine neonatal painful procedures (ie, heel lance, venipuncture, intravenous line insertion, intramuscular injection, and nasogastric tube insertion) throughout the infant's entire hospitalization or during the collection of the primary outcome during heel lance, if they assessed the infant as having a PIPP score >6 (considered to indicate moderate to severe pain). Nurses in the NICU were trained as part of the standardized unit training policy to use the PIPP in clinical practice and routinely monitored and recorded pain scores and sucrose administration for all procedures.
2.8. Intervention fidelity
Although only 3 heel lance procedures were recorded to calculate the primary outcome, it was expected that staff would maintain the assigned intervention protocol for all routine preassigned painful procedures conducted throughout the infant's entire NICU stay. Staff adherence was monitored daily by the research nurse, and staff reminders and feedback were provided. For infants assigned to 1 of the 2 KC groups, all attempts were made to alter timing of procedures to correlate with the mother's schedule. If the mother was unavailable to provide KC during a routine painful procedure, or in the case of a significant clinical deterioration of the infant's condition requiring emergent care, the infant was swaddled, provided a pacifier, and given the randomized study solution. All off-study use of rescue sucrose, mother's unavailability, and/or deviations from the study protocol due to clinical condition were recorded.
During data collection for the primary outcome, physiologic data on heart rate were collected by using a Compumedics PSG-III (Compumedics USA, Inc, Charlotte, NC) data acquisition system. Transcutaneous oxygen saturation levels were collected using infrared oximeter (Masimo Radical, Irvine, CA) placed on a hand of the infant and connected to the data acquisition system. Close-up video recordings that focused solely on the infant's face were collected using a Sony DCR-SR82 (Toronto, Canada, MFR# DCRSR82) digital camera. Simultaneous physiologic monitoring and facial videotape recordings were obtained before, during, and after the infant underwent a medically indicated heel lance at 3 different time points throughout their NICU stay. All efforts were made to space these collection periods as soon as possible after enrollment, midway through the infant's hospital stay, and as close as possible to discharge from the NICU. Recorded sessions were completed a minimum of 24 hours apart.
Before the painful procedure that was to be recorded, the research nurse notified parents and staff of group assignment and coordinated the timing of the procedure. During the recorded procedures, all phases were marked (BL1 one at beginning of monitoring, BL2 before procedure initiation, heel warming, heel lance, application of bandage, and heart rate return to baseline). The research nurse marked epochs with colored cards held briefly in front of the video camera, which were later matched to the built-in timer of the monitor used to record physiologic data, and ensured that the camera was focused on the infant's face only to keep coders naïve to study purpose or group assignment. Coders were trained to no less than 0.95 interclass correlation coefficient; inter-rater reliability and intra-rater reliability were maintained greater than 0.92 interclass correlation coefficient agreement throughout the study.
Trained personnel, blind to study purpose and group assignment, conducted up to 3 neurodevelopmental assessments, depending on the GA of the infant at enrollment. All personnel conducting the NAPI were nurses. Each assessor was required to achieve reliability on NAPI scoring based on training requirements and determination from an expert trainer.
Mothers were asked to record the amount of time they provided KC regardless of group assignment. Salivary cortisol samples were collected from the mothers shortly after enrollment of the infant, halfway through the stay, and near discharge. To standardize cortisol collection and detect diurnal peak levels, mothers were asked to collect a salivary sample on awakening on the days their infants were scheduled for blood collections. Cortisol levels were measured using a kit from Salimetrics and correlated over time with infant pain response, accounting for group assignment.
Mothers and nursing staff were also asked to complete a brief questionnaire regarding their attitudes of using KC as an intervention to reduce pain, and results are reported elsewhere.1
2.10. Allocation concealment mechanism
The pharmacy at the study site supplied the syringes containing the study solutions of sterile water and 24% sucrose. The study solution was labeled with a code known only by pharmacy and the one unblinded research nurse overseeing the study. The primary investigator remained blinded to group assignment until analysis was complete. Solutions were prepared and packaged in an identical matter. Upon knowing infant assignment, the research nurse labeled each syringe with the infant's study number and placed them at the infant's bedside. Compliance was recorded by the research nurse from daily syringe counts.
2.11. Sample size
Based on previous data (Campbell-Yeo et al.5), a sample of 258 (86 per group) was required to provide a power of 0.9 to detect a difference of 1.5 points (considered to be a clinically meaningful difference when comparing treatments) with an alpha level of 0.05 and an SD of 3 on the PIPP.
2.12. Statistical analysis
All analyses used an intention-to-treat approach. Categorical data were analyzed using χ2. For all outcomes, means ± SD or medians (interquartile range) were reported according to whether the data were normally distributed or skewed. Mean or median differences with 95% CIs and P-values were calculated. Primary and secondary outcomes were analyzed by comparing the mean among the 3 groups. The mean difference in PIPP scores was contrasted between groups using a 1-way analysis of variance. Hierarchical linear modeling (growth curve analysis) was used to determine efficacy over time using SAS STAT (Version 9.3, Proc Genmod, SAS Institute, Inc, Cary, NC). The inter-rater reliability and intra-rater reliability of PIPP scoring were assessed using intraclass correlation from a random-effects model with 95% CIs.
3.1. Study groups
Of the 1276 infants who were screened during the study period, July 2012 and March 2016, 562 infants were eligible and 449 were approached to participate. Following parental consent, 242 infants with a mean GA of 32 weeks (range 27 1/7 and 36 5/7 weeks at birth) were enrolled and randomly assigned to receive KC/placebo (n = 81), KC/sucrose (n = 80), and sucrose (n = 81), respectively. Short length of NICU stay was the most common reason for ineligibility. The refusal rate was 46%. Primary reasons for refusal were that mothers felt too overwhelmed or that the parents were not interested in participating in any research (Fig. 1). No statistically significant differences in baseline maternal or infant characteristics were found among groups (Table 1). Nor were there any statistically significant group differences in maternal salivary cortisol levels over time. As such, no adjustment of the analyses was undertaken.
3.2. Premature Infant Pain Profile scores
In all groups, peak mean PIPP scores were highest in the 30 seconds after the heel stick and decreased over time. Mean PIPP scores at 30, 60, or 90 seconds after heel lance at time 1, time 2, and time 3 (Table 2) and the distribution of the percentage of infants reported as having mild, moderate, or severe pain scores were not statistically significantly different among groups (Fig. 2). Few neonates, regardless of group assignment, were reported to have scores suggesting severe pain (0%-12%).
3.3. Neurodevelopmental assessment of the preterm infant score
There were no statistically significant differences in NAPI scores across groups on the subscales of motor development and vigor and alertness and orientation at 32 weeks ± 10 days or 36 weeks ± 10 days of corrected GA (Table 3). Scores were consistent with normative data in this population.18
3.4. Adverse events and 24% sucrose dosing
No statistically significant group differences were found for frequency of additional off-protocol 24% sucrose dosing, the occurrence of adverse effects with respect to apnea, bradycardia (heart rate, <100 beats per minute), oxygen desaturation (<85%), need to complete a second heel lance procedure, or total volume of blood drawn for the videotaped study heel lances, nor in the total number of previous painful procedures.
3.5. Intervention fidelity
No deviation of intervention fidelity regarding group assignment nor need for rescue sucrose occurred during the videotaped study procedures at time 1, 2, or 3 used to determine the primary outcome. Deviation in intervention fidelity and/or need to provide rescue sucrose occurred during 21 procedures across 18 infants undergoing study-specific procedures over the course of all participants' NICU stay. Eighteen infants required a rescue of dose of sucrose for a total of 21 procedures. Of those receiving rescue doses, all but 1 infant received a dose of rescue sucrose while undergoing a procedure when their mother was unavailable. Numerous of these infants were undergoing repeated attempts for difficult intravenous (IV) access or venipuncture attempts for blood collection. One infant in the KC/sucrose group received a rescue dose of sucrose during a repeated IV attempt, and no infant assigned to the sucrose alone received a rescue dose. There were no differences in intervention fidelity between the KC and KC/sucrose group, while the sucrose group had almost perfect fidelity (Table 4).
To the best of our knowledge, this is the first study to examine the sustained effect of KC to reduce biobehavioral pain response measured using a composite pain score alone or in combination with sucrose for preterm infants undergoing repeated tissue-breaking procedures in the NICU. Comparative sustained efficacy was similar across intervention groups in this study, similar to previously reported sustained effects of sucrose.11 Our findings demonstrate that maternal KC, provided 15 minutes before heel lance, seems to remain efficacious as a pain-relieving intervention for preterm infants delivered between 27 and 36 weeks of GA over repeated heel lance procedures throughout their hospitalization and seems to have comparative efficacy to KC plus sucrose or sucrose alone. This finding is consistent with previous work,12 which demonstrated that 30 minutes of maternal KC reduced crying, facial grimacing, and heart rate in preterm infants undergoing repeated heel lances when compared with no treatment.
The study findings demonstrated that not only does KC provide similar pain reducing effects as 24% oral sucrose but also the combination of maternal KC and sucrose does not seem to provide additional pain-reducing benefit. Furthermore, this is the first study demonstrating no evidence of any harm or neurological impact at 32 or 36 weeks' corrected GA of KC alone, sucrose alone, or the combination of interventions during repeated NICU procedures. Given the established benefits of KC in nonpain contexts (Campbell-Yeo et al.3) as well as the positive perspective of parents related to providing KC to their infants during painful procedures10 and an absence of adverse events, KC should be strongly considered as an alternative first-line treatment to the current standard of care (sweet-tasting solutions) for repeated tissue-breaking needle-related procedures for preterm neonates in the NICU.
Findings suggest that the nonpharmacologic interventions of maternal KC, alone or in combination with 24% oral sucrose, and 24% oral sucrose alone provide pain relief for most infants under study, with 88% having pain scores suggesting no, low, or moderate pain. It is important to note that regardless of group assignment, up to 12% of neonates were reported as having severe pain (PIPP score greater than 12). It remains unclear whether these nonresponders are a result of unpredictable within-subject variability in pain responses6 or whether there are stable pain response subgroups.21 Further study is needed to understand individual variance in patterns of pain responding when receiving nonpharmacologic pain-reducing interventions to tailor individually effective intervention to the preterm neonate undergoing needle-related procedures.
No statistically significant group differences were seen in neurobehavioral development measured using the NAPI at 32 and 36 weeks of corrected GA. This is in contrast to findings that preterm infants born at less than 31 weeks' GA who received greater than 10 doses of sucrose per day had lower scores on motor development and vigor and alertness and orientation scales of the NAPI.17 There is theoretical argument that repeated sucrose administration may alter dopaminergic system development and subsequently interfere with attention and motor development of preterm infants.14 Our lack of differences may reflect the slightly older GA in our study population. It may reflect the higher sucrose exposure as it was provided for both tissue-breaking procedures and routine care giving such as diaper changes in previous studies, compared with its use solely for painful procedures in this study (Johnston et al.17).
4.1. Limitations and future directions
Despite the numerous strengths, limitations include the inability to blind care providers and reduced sample size as not all infants required 3 heel lance procedures, and most infants were discharged home before the period associated with the full-term equivalent standardized time period of the NAPI. Given the variability of GA at admission and study enrollment, and wide standardized period ±10 days around each time point, there was a reduction in the number of eligible infants at the 32- and 36-week time points. While an important ethical consideration, the provision of rescue sucrose could be considered a limitation as 17 infants from the KC/placebo arm each received 1 dose of rescue sucrose. While this minimal exposure was unlikely to alter our findings, given concerns raised recently regarding effects of repeated exposure to sweet solutions on brain development in an animal models,22,29 and in very preterm infants,25 further research examining the longer lasting neurobehavioral effects of early exposure to maternal care and pain-reducing interventions is needed. Moreover, with recent advancements in the use of multimodal pain assessment techniques,2 and concerns raised using these measures regarding the analgesic vs sedative effect of nonpharmacological interventions to reduce pain in neonates,26 additional investigation examining the impact of KC on brain-related neonatal pain response would be of interest. Future work examining sustained efficacy of alternative caregiver KC during pain such as fathers may be considered.
Maternal KC seems to remain efficacious over time and repeated procedures, without evidence for harm on very early neurodevelopmental outcome. Kangaroo care seems to have comparative pain-reducing effectiveness to oral sucrose for repeated procedures across NICU hospitalization. Combined use of KC and sucrose does not seem to provide additional benefit. Our findings challenge the existing recommendation of using sucrose as the primary standard of care for the management of repeated tissue-breaking procedures for preterm neonates undergoing procedural pain. Clinicians should consider KC as at least an equivalent alternative.
The authors have no conflicts of interest to declare.
Appendix A. Supplemental digital content
A video abstract associated with this article can be found at http://links.lww.com/PAIN/A843.
The authors are grateful to the infants and parents who participated in this study, in addition to the NICU team and research staff at the IWK Health Centre. The authors acknowledge the paid support of the Research Methods Unit, Halifax, Nova Scotia, most notably, Kara Matheson, for analyses of much of the primary data. The authors also acknowledge the assistance of Dr Theresa Kim for her assistance with post hoc analyses.
This work was supported by the Canadian Institutes of Health Research (CIHR) [244640/2011-7517]; Nova Scotia Health Research Foundation [MED-MAT-2011-7517] and Mayday Fund. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. M. Campbell-Yeo is supported by a Canadian Institutes of Health Research New Investigator Award, Canadian Child Health Clinician Scientist Career Development Award, and Canadian Foundation for Innovation Grant. B. Benoit and T. Disher are supported by the CIHR Vanier Canada Graduate Scholarship Program.
Author contributions: The study was conceived by M. Campbell-Yeo and C. Celeste Johnston, both shared the role of principal investigator. M. Campbell-Yeo led the study. The funding proposals and study design were developed by M. Campbell-Yeo, C. Celeste Johnston, M. Vincer, C.-D. Walker, M. Latimer, D.L. Streiner, and D. Inglis. M. Campbell-Yeo was responsible for the trial management, and K. Caddell had oversight of the day-to-day recruitment and data collection. B. Benoit, T. Disher, and K. Caddell had responsibility for data management. Data analyses were conducted and overseen by M. Campbell-Yeo, B. Benoit, and T. Disher. M. Campbell-Yeo wrote the initial draft of the manuscript. The manuscript was critically reviewed by all authors. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.
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Neonatal; Pain; Kangaroo care; Skin-to-skin contact; RCT
Supplemental Digital Content
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