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The minimally effective dose of sucrose for procedural pain relief in neonates: a randomized controlled… Stevens, Bonnie; Yamada, Janet; Campbell-Yeo, Marsha; Gibbins, Sharyn; Harrison, Denise; Dionne, Kimberley; Taddio, Anna; McNair, Carol; Willan, Andrew; Ballantyne, Marilyn; Widger, Kimberley; Sidani, Souraya; Estabrooks, Carole; Synnes, Anne; Squires, Janet; Victor, Charles; Riahi, Shirine Feb 23, 2018

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RESEARCH ARTICLE Open AccessThe minimally effective dose of sucrosefor procedural pain relief in neonates:a randomized controlled trialBonnie Stevens1*, Janet Yamada2, Marsha Campbell-Yeo3, Sharyn Gibbins4, Denise Harrison5, Kimberley Dionne6,Anna Taddio7, Carol McNair8, Andrew Willan9, Marilyn Ballantyne10, Kimberley Widger11, Souraya Sidani12,Carole Estabrooks13, Anne Synnes14, Janet Squires15, Charles Victor16 and Shirine Riahi17AbstractBackground: Orally administered sucrose is effective and safe in reducing pain intensity during single, tissue-damaging procedures in neonates, and is commonly recommended in neonatal pain guidelines. However, there iswide variability in sucrose doses examined in research, and more than a 20-fold variation across neonatal caresettings. The aim of this study was to determine the minimally effective dose of 24% sucrose for reducing pain inhospitalized neonates undergoing a single skin-breaking heel lance procedure.Methods: A total of 245 neonates from 4 Canadian tertiary neonatal intensive care units (NICUs), born between 24 and42 weeks gestational age (GA), were prospectively randomized to receive one of three doses of 24% sucrose, plus non-nutritive sucking/pacifier, 2 min before a routine heel lance: 0.1 ml (Group 1; n = 81), 0.5 ml (Group 2; n = 81), or 1.0 ml(Group 3; n = 83). The primary outcome was pain intensity measured at 30 and 60 s following the heel lance, using thePremature Infant Pain Profile-Revised (PIPP-R). The secondary outcome was the incidence of adverse events. Analysis ofcovariance models, adjusting for GA and study site examined between group differences in pain intensity acrossintervention groups.Results: There was no difference in mean pain intensity PIPP-R scores between treatment groups at 30 s (P = .97) and60 s (P = .93); however, pain was not fully eliminated during the heel lance procedure. There were 5 reported adverseevents among 5/245 (2.0%) neonates, with no significant differences in the proportion of events by sucrose dose(P = .62). All events resolved spontaneously without medical intervention.Conclusions: The minimally effective dose of 24% sucrose required to treat pain associated with a single heel lance inneonates was 0.1 ml. Further evaluation regarding the sustained effectiveness of this dose in reducing pain intensity inneonates for repeated painful procedures is warranted.Trial registration: ClinicalTrials.gov: NCT02134873. Date: May 5, 2014 (retrospectively registered).Keywords: Adverse event, Analgesia, Heel lance, Neonates, NICU, Pain, PIPP-R, Preterm infants, Sucrose* Correspondence: bonnie.stevens@sickkids.ca1The Hospital for Sick Children, Lawrence S. Bloomberg Faculty of Nursing,University of Toronto, 686 Bay Street, Toronto, Ontario M5G 0A4, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Stevens et al. BMC Pediatrics  (2018) 18:85 https://doi.org/10.1186/s12887-018-1026-xBackgroundMultiple trials and recent systematic reviews with meta-analyses have shown that sweet solutions, includingorally administered sucrose, are effective and safe inreducing pain intensity (using clinical observational orcomposite measures) during single, tissue-damaging pro-cedures in neonates [1, 2]. These solutions are com-monly recommended in neonatal pain guidelines [3].However, there is wide variability in sucrose doses exam-ined in research, and more than a 20-fold variationacross neonatal care settings [4]. Despite the large num-ber of randomized controlled trials in the 2016Cochrane review [2], an optimal dose of sucrose couldnot be determined due to the wide range of volumesand concentrations (0.05 ml of 24% to 2.0 ml of 50% so-lution) studied, and due to variation in study methods(e.g., administration techniques, types of painful proce-dures, outcome measures, and co-interventions). Thereare no definitive conclusions about the minimally effect-ive dose of sucrose associated with a clinically significantreduction in pain intensity scores in neonates.To our knowledge, there have been no direct compari-sons of different volumes of sucrose at the same concen-tration. In this study, we evaluated the three smallestdoses of sucrose most commonly reported to be effectivein previous research (i.e., 0.1 ml, 0.5 ml, and 1.0 ml of24% sucrose) [2] to determine the minimally effectivedose for neonates undergoing a skin-breaking heel lanceprocedure while in the neonatal intensive care unit(NICU). Doses smaller than 0.1 ml were not included inthe study due to challenges posed by accurate measure-ment and delivery. All neonates received sucrose forprocedural pain (i.e., there was no placebo or no-treatment group), which was consistent with neonatalpain guidelines and in keeping with the ethical conductof clinical trials in newborns [5–7]. We hypothesized that(a) there was no difference in pain intensity between thesucrose doses, measured at 30 and 60 s following the heellance using the Premature Infant Pain Profile-Revised(PIPP-R), and (b) adverse events would be minimal.MethodsA prospective multi-centered single-blind randomizedcontrolled trial was conducted from July 2013–April2015 at 4 Canadian tertiary NICUs following researchethics approval. The inclusion criteria were neonates 24to 42 weeks gestational age (GA) at birth and less than30 days of life/or less than 44 weeks GA at the time ofthe intervention, scheduled to receive a heel lance, andwho had not received opioids within 24 h prior to theheel lance. The exclusion criteria were neonates with acontraindication for sucrose administration (e.g., weretoo ill or unstable as per neonatologist’s assessment, un-able to swallow, pharmacologically muscle relaxed) and/or inability to assess behavioral responses to pain accur-ately (e.g., the neonate’s face was blocked with taping). Wedid not use the diagnosis of neurological impairment as anexclusion criterion because the timing of diagnosis and de-termining the severity of impairment can be very difficultin this population. However, inability to swallow had theeffect of excluding neonates with severe neurologic impair-ment from hypoxic-ischemic encephalopathy. Observationof the procedure was timed to ensure that no additionalsucrose doses were provided within the previous 4 h. Allparents or legal guardians provided informed consent.Randomization was performed using a web-based priv-acy protected randomization service [8]. Randomizationwas block stratified by GA at birth (< 29 weeks or 29–42 weeks) to enhance balanced intervention groups. Aresearch nurse, aware of group allocation, drew up theassigned sucrose dose into an amber colored syringe.The dose was double-checked by a second nurse, not in-volved with the study, and documented on the medica-tion administration record as per unit protocol. Theresearch nurse followed a standard dose administrationtime to blind the bedside nurse performing the heellance to the sucrose volume. The syringes used to ad-minister sucrose were also shielded from view by the re-search nurse from the bedside nurse and videorecording. No other study personnel had access to thetreatment allocation.The treatment intervention was videotaped and in-cluded 4 phases. (a) Baseline observation of the neonatefor 2 min prior to the heel lance. (b) Administering thetotal volume of 24% sucrose [0.1 ml(Group 1), 0.5 ml(Group 2), or 1.0 ml (Group 3)] drop-by-drop via syringeover the anterior surface of the tongue, allowing for indi-vidual neonate swallowing rates over a period of 1–2 min (for the largest dose). A pacifier was offered to allneonates immediately following sucrose administrationto facilitate non-nutritive sucking, which has beenshown to enhance sucrose efficacy in a synergistic way[9]. (c) Conducting the heel lance procedure with an au-tomated lancet approximately 2 min after the sucroseadministration, to allow for peak effects [10]. (d) Obser-vation of return-to-baseline pain indicator values over30 s to several minutes. The bedside nurse conductedthe heel lance according to the specific unit policy, whilethe research nurse experienced in NICU care ensuredcomplete data collection.We did not limit participating neonates from receivingother pain-relieving parent-initiated interventions (e.g.,skin-to-skin/kangaroo care and breastfeeding) [11] asper unit protocols. These were documented by the re-search nurse, so any group differences could be con-trolled for in the analysis. Pharmacological interventionsshown to be ineffective in reducing heel lance pain (e.g.,acetaminophen) [12] were not administered.Stevens et al. BMC Pediatrics  (2018) 18:85 Page 2 of 8Outcome measuresThe primary outcome was pain intensity measured withthe PIPP-R [13, 14], which has demonstrated constructvalidity in neonates of varying GA [13–15]. The PIPP-Rincludes 2 physiological (heart rate, oxygen saturation), 3behavioral (brow bulge, eye squeeze, nasolabial furrow)and 2 contextual (GA, behavioral state) variables knownto modify pain responses. Throughout the treatmentintervention, physiological and behavioral/facial indica-tors of pain intensity were collected using an infantmonitoring system developed and used extensively bythe research team over the past decade. The researchnurse placed pulse oximetry probes on the neonate torecord heart rate and oxygen saturation continuously,and positioned a digital video recorder to capture facialmovements. Electronic event markers synchronized allphysiological and behavioral data, and demarcated the 4phases of the treatment intervention.Two trained coders, blinded to group allocation andstudy purpose, viewed the physiological and behavioraldata captured by the infant monitoring system, andcoded neonates’ pain intensity using the PIPP-R. Aninter-rater reliability > 0.9 was achieved on a randomsample of 5 neonates, early in the study and with each25% of data collected.The secondary outcome was frequency of a priori spe-cified adverse event/tolerance criteria (heart rate > 240beats/min or heart rate < 80 beats/min for > 20 s; oxygensaturation < 80% for > 20 s; no spontaneous respirationsfor > 20 s; and choking/gagging). Adverse event datawere collected by the research nurse during the inter-vention. The research nurse kept a record of ‘rescuedoses’ administered (i.e., additional doses of sucrosegiven on direction of the nurse caring for the neonate, ifthe neonate became overly distressed during theprocedure).Statistical analysesWe estimated a sample size of 71 neonates per group(total sample size of 213). The sample size calculationaccounts for multiple testing due to 3 interventiongroups, and is based on a type I error probability of5%, a power of 80%, and a smallest minimally clinic-ally significant difference of 1 on the PIPP-R with astandard deviation (SD) of 2. Consistent with previousresearch, this minimally clinically significant differencewas justifiable given the lack of a treatment controlin this study versus preceding studies [16]. Toaccount for potential missing data (e.g., equipmentfailure), we increased the sample size by 15% to 245.Analysis of covariance models adjusting for GA andstudy site examined between group differences inPIPP-R scores.ResultsRandomization and demographic characteristicsThe trial profile is presented in Fig. 1. Of the 4172 neo-nates screened for eligibility, 248 were enrolled and ran-domly allocated to Group 1, 2 or 3. Three neonates wereexcluded following randomization, as they did notundergo a heel lance, leaving 245 for the outcomes ana-lyses. Demographic characteristics in all 3 groups wereadequately matched (Table 1). These included GA atbirth, days since birth, birth weight, sex, severity ofillness assessed using the Score for Neonatal AcutePhysiology Perinatal Extension-II (SNAPPE-II) [17, 18],number of prior painful procedures, number of previousdoses of sucrose, and concurrent use of non-pharmacologic pain strategies. As standard care in eachunit included parent-initiated non-pharmacologic strat-egies (e.g., swaddling, skin-to-skin/kangaroo care, andbreastfeeding) we could not ethically disallow these in-terventions during the painful procedure. However, therewas no difference in the use of parent-initiated painstrategies across groups (Table 1). All neonates were of-fered a pacifier for non-nutritive sucking following su-crose administration. Overall 204/ 245 (83.2%) suckedon the pacifier, while the remainder refused or did notreceive the pacifier due to medical considerations (e.g.,intubated, or not tolerated well). We noted a discrepancybetween the number of painful procedures documentedand the number of sucrose doses documented sincebirth. Information on non-pharmacologic interventionswas often not available in the neonates’ medical records;therefore, it was difficult to discern if the discrepancywas an administration or documentation issue.Pain intensityThe mean pain intensity [SD] PIPP-R scores at 30 spost heel lance (Group 1 6.8[3.5]; Group 2 6.8[3.2];Group 3 6.7[3.4]) were not statistically different afteradjusting for GA and research site (F[6233] = 0.01, P= .97; Table 2). Similarly, there were no significantdifferences in mean PIPP-R scores between groups at60 s (F [2229] = 0.10, P = .93; Table 2). Mean painintensity PIPP-R scores at 30 and 60 s were inverselyassociated with GA (P < .001) and significantly differ-ent when stratified by site (P < .001; Table 3);therefore both factors were controlled for in theanalysis. Mean PIPP-R scores ranged from 6.03 (3.37) forneonates > 36 weeks GA to 9.07 (4.00) for neonates< 28 weeks GA at 30 s and 5.70 (3.31) for neonates> 36 weeks GA to 9.43 (4.04) for neonates < 28 weeksGA. No associations were found between pain intensityscores and other demographic characteristics [i.e.,SNAPPE-II/ severity of illness on admission, gender,concurrent use of non-pharmacologic pain strategies(e.g. breastfeeding and skin-to-skin care), and numberStevens et al. BMC Pediatrics  (2018) 18:85 Page 3 of 8Table 1 Demographic characteristics of the sucrose intervention groupsIntervention0.1 ml n = 81 0.5 ml n = 81 1.0 ml n = 83Sex, n (%)-Female 44 (54.3) 32 (39.5) 41 (49.4)-Male 37 (45.7) 49 (60.5) 42 (50.6)Gestational age in weeks, mean (SD) 32.6 (4.2) 32.5 (4.1) 32.7 (4.1)Weight in grams, mean (SD) 2002.3 (859.5) 1933.0 (927.0) 2055.5 (886.0)Day of life, median (interquartile range) 6 (4 to 9) 7 (4 to 10) 6 (4 to 9)Birthplace, n (%) (55 missing)-Inborn 31 (52.5) 33 (51.6) 40 (59.7)-Outborn 28 (47.5) 31 (48.4) 27 (40.2)SNAPPE-II score on admission, median (interquartile range) 5.0 (0 to 19) 5.0 (0 to 18) 8.0 (0 to 18)Number of painful procedures since birth, median (interquartile range) 22 (14 to 34) 23 (15 to 37) 23 (13 to 40)Number of sucrose doses since birth, median (interquartile range) 5 (2 to 8) 5 (3 to 9) 6 (3 to 9)Use of concurrent non-pharmacologic pain strategies, n (%) 27 (33.3) 31 (35.2) 30 (34.1)SNAPPE-II scores range from 0 to 158. Higher scores indicate greater severity of illnessFig. 1 Consort flow diagram of all neonates in participating NICUs screened for eligibility and randomized to sucrose intervention groups.Reasons for exclusion included not meeting inclusion criteria, refusals to participate, and other reasons [e.g., exclusion criteria, medical refusal(palliative care, social issues, and multiple research studies), isolation precautions, and researcher or parents unavailable for consent discussion]Stevens et al. BMC Pediatrics  (2018) 18:85 Page 4 of 8of painful procedures and sucrose doses since birth;Table 3]. Pain intensity scores across the 3 groupsequated to mild pain for the majority of neonates(scores of < 7 on the PIPP-R; Table 4).Adverse events and rescue dosesThere were 5 reported adverse events among 5/245(2.0%) neonates as defined by the a priori criteria. Theseevents included 3 neonates who gagged/choked, 1 withheart rate < 80 bpm and 1 with oxygen saturation < 80%following sucrose administration. All events resolvedspontaneously without medical intervention. The neo-nate who experienced oxygen saturation < 80%, wasrepositioned and recovered quickly. There were no sig-nificant differences in the proportion of adverse eventsby sucrose group (P = .62); however, a higher proportionof younger neonates experienced an adverse event (6.7%< 29 weeks versus 1.0% 29–42 weeks; P = .044).In 13/245 (5.3%) neonates, the bedside nurse perceivedthat the intervention was not effective in minimizingpain during the procedure, and the research nurse (atthe discretion of the bedside nurse) administered a “res-cue” dose of sucrose (amount determined by the unitstandard/policy). There was no significant difference inthe number of rescue doses by sucrose group (P = .33),site (P = .070), or GA (P = .47).DiscussionOral administration of a very small dose of sucrose(0.1 ml) appears to be equally effective at reducing painin neonates during a single painful procedure as largerdoses. Sucrose administration in the clinical setting wasassociated with very few adverse events. This trial wasTable 2 Mean pain intensity scores at 30s and 60s post heel lanceIntervention P0.1 ml 0.5 ml 1.0 mlPIPP-R 30s n = 79 n = 81 n = 80Mean (SD): 6.8 (3.5) Mean (SD): 6.8 (3.2) Mean (SD): 6.7 (3.4) 0.97Min: 0 Min: 1.0 Min: 0Max: 17.5 Max: 16.3 Max: 18.7PIPP-R 60s n = 76 n = 80 n = 80Mean (SD): 7.0 (3.3) Mean (SD): 6.9 (3.6) Mean (SD): 6.7 (3.4) 0.93Min: 0 Min: 0 Min: 0Max: 17.0 Max: 18.0 Max: 18.7PIPP-R scores range from 0 to 21. Higher scores indicate greater pain intensityTable 3 Association of mean pain intensity scores with site and demographic characteristicsPIPP-R 30 seconds PIPP-R 60 secondsMean (SD) P Mean (SD) PSite < 0.001 < 0.0011 5.68 (3.31) 5.66 (3.26)2 7.55 (3.58) 8.09 (4.16)3 6.13 (2.31) 6.05 (2.54)4 8.21 (3.87) 8.23 (3.55)SNAPPE-II score on admission 0.087 0.058-Median or below (0 to 5) 6.35 (3.06) 6.38 (3.22)-Above Median (6+) 7.03 (3.53) 7.17 (3.70)Gender 0.31 (3.32) 0.44 −0.05 (3.49) 0.90Concurrent use of non-pharmacologicpain strategies during heel lance0.38 (3.31) 0.33 0.10 (3.49) 0.82Spearman’s correlation (rs) P Spearman’s correlation (rs) PGestational age −0.26 < 0.001 − 0.30 < 0.001Number of painful procedures 0.07 0.24 0.03 0.61Number of sucrose doses since birth 0.004 0.95 −0.02 0.74PIPP-R scores range from 0 to 21. Higher scores indicate greater pain intensity. SNAPPE-II scores range from 0 to 158. Higher scores indicate greater severity of illnessStevens et al. BMC Pediatrics  (2018) 18:85 Page 5 of 8more closely aligned with a pragmatic design on thecontinuum between pragmatic and exploratory trials[19]. Unlike explanatory trials that test interventionsunder optimal conditions, pragmatic trials are moregeneralizable; however, they are also more prone to co-intervention.Although site was controlled for in the primary out-come analyses, there was a difference in PIPP-R scoresacross sites (Table 3) that may be partially explained byorganizational contextual factors that were not con-trolled for or assessed in the analyses. For example, al-though we enrolled neonates in the first 30 of days oflife and collected information on exposure to painfulprocedures and sucrose received since birth, it is pos-sible that sucrose administration and documentationpractices differed due to clinical practice guidelines ororganizational contextual factors (e.g., workload/staffratios, unit culture, and the research or clinical experi-ence of the bedside nurses) [20]. We also found higherpain scores were associated with more preterm neonates(P < .001; Table 3) and they experienced a slightly greaterproportion of adverse events (3 versus 2 in neonates> 29 weeks GA), although total numbers were verysmall. Despite higher pain scores with lower GA,there was no difference in the number of rescuedoses across GA, which might be explained by sitedifferences in sucrose administration practices.We could think of two possible explanations for whyPIPP-R scores were significantly higher in the least ma-ture group of neonates: (a) the PIPP-R measure inher-ently scores younger GA higher, or b) sucrose is lesseffective in these babies (e.g., they are less able tomount an endogenous opioid response that is theunderlying mechanism of action of sweet taste [21]).Differences seen in mean pain intensity were notthought to be due to additional weighting in the PIPP-R measure by GA [< 28 weeks (+ 3), 28–31 weeks and6 days (+ 2), 32 weeks to 35 weeks and 6 days (+ 1), and≥ 36 weeks (0)], as there were no corresponding incre-mental differences seen by GA group. In terms of thelatter explanation (b), this needs to be furtherresearched with an adequate sample size of extremelypremature neonates (< 28 weeks GA).Our findings are consistent with past research (primar-ily in animals) that demonstrated that the analgesic ef-fects of sucrose were primarily mediated by exposureand not dose [10, 22]. Although there was no differencein pain intensity at 30 and 60 s, pain was not fullyeliminated during the heel lance procedure. Mean painintensity scores equated to mild pain (Table 2), or ap-proximately 3/10 if converted to the more common 10-point scale metric. As pain intensity was measured on acontinuum, and treatment failure was not defined, theincidence of treatment failure was not determined. How-ever, severe pain could definitely be considered a treat-ment failure and this occurred in 7.5 to 11.3% ofneonates (Table 4) across sucrose doses. These resultsare similar to systematic reviews of other behavioralinterventions, including breastfeeding [23] and skin-to-skin care [24]. Given that the majority of previous stud-ies have used a single procedure, it is uncertain if thewide variably in neonatal pain response is attributed tothe intervention or other factors which remain unknown[25]. Future work in the repeated use of interventions iswarranted. In the meantime, we would recommend thatif the initial dose of sucrose does not appear to beameliorating the pain that additional rescue doses beprovided during the procedure up to a specified amount.We would also recommend that multiple non-pharmacologic strategies be implemented simultaneouslyincluding swaddling, facilitated tucking, skin-to-skin/kangaroo care, breastfeeding, and/ or pacifiers.Knowledge is lacking on the long-term effects of su-crose with repeated administration. Of the studies thathave evaluated repeated doses of sucrose [26–30], nonehave evaluated long-term outcomes of using sucrose forall painful procedures performed throughout the neo-nate’s stay in the NICU. Johnston [26, 31] reported that107 preterm infants < 31 weeks GA who were exposedto > 10 doses of sucrose per day in the first 7 days of life,after which time no pain relief was used, were morelikely to exhibit poorer attention and motor develop-ment on the Neurobehavioral Assessment of PretermInfants (NAPI) scale in the early months of life.Conversely, Banga [32] reported that of 93 neonates ran-domized to either repeated doses of sucrose or water forpainful procedures for 7 consecutive days, there were nosignificant differences in NAPI scores or adverse events.Stevens [27] found no statistically significant differencesbetween sucrose plus pacifier, water plus pacifier, or theTable 4 Frequency of pain intensity scores by severity at 30sand 60s post heel lanceIntervention P0.1 ml 0.5 ml 1.0 mlPIPP-R at 30s, n (%) n = 79 n = 81 n = 80 0.74-None (0) 2 (2.5) 0 (0.0) 2 (2.5)-Mild (1 to 6.9) 40 (50.6) 46 (56.8) 39 (48.8)-Moderate (7 to 11.9) 30 (38.0) 27 (33.3) 33 (41.3)-Severe (12+) 7 (8.9) 8 (9.9) 6 (7.5)PIPP-R at 60s, n (%) n = 76 n = 80 n = 80 0.97-None (0) 1 (1.3) 1 (1.3) 2 (2.5)-Mild (1 to 6.9) 38 (50.0) 44 (55.0) 41 (51.3)-Moderate (7 to 11.9) 29 (38.2) 26 (32.5) 30 (37.5)-Severe (12+) 8 (10.5) 9 (11.3) 7 (8.8)PIPP-R scores range from 0 to 21. Higher scores indicate greater pain intensityStevens et al. BMC Pediatrics  (2018) 18:85 Page 6 of 8standard care group on neurobiological risk statusoutcomes. Future research needs to address therepeated use of minimally effective doses of sucroseon the neurodevelopment of neonates and effective-ness over time.Approximately 2% of neonates suffered adverseevents. These all resolved spontaneously without med-ical intervention or with minimal caregiver interven-tion (e.g. positioning). Most adverse events occurredat one site, where the highest proportion of the sick-est neonates is cared for, although this is not repre-sented in the study sample. This adverse event rate isconsistent with the 2016 Cochrane sucrose review [2].Although researchers are becoming more vigilant inobserving and reporting adverse events, it remainsunclear how adverse events are reported (i.e., chartreview is considerably different from careful directobservation of every newborn infant who is receivingthe intervention).A few study limitations need mention. Pain intensitydid not differ significantly between the 30 and 60-stime points. Although these time intervals have beenused in multiple research studies of acute proceduralpain, they are arbitrary and designed based on meanbehavioral response time; observing neonates forlonger periods of time may demonstrate additionalresponses of less typical responders or other types ofresponses (e.g. physiologic, cortical). Although therehas been significant validation and updating of thePIPP-R measure, there remains no gold standard formeasuring pain in infants that may influence the de-termination of the effectiveness (or lack thereof ) ofpain relieving interventions. The future, which in-cludes novel strategies for better understanding of thedeveloping cortical pain circuitry, will pave the wayfor better prevention and treatment of pain in thisvulnerable population.Finally, we were limited by the documentation inthe medical records, which may not have included allpain relieving strategies such as sucrose and non-pharmacologic interventions. Although we believeinfants should receive some form of intervention forall painful procedures, it is difficult to speculate onwhether the discrepancy between number of docu-mented painful procedures and pain-relieving inter-ventions is an administration or documentation issue.As the number of painful procedures included sincebirth was extensive (e.g., tape removals, bloodwork,injections, vascular access attempts/insertions, NG/OG tube insertions and suctioning, chest tube at-tempts/insertions, lumbar punctures, eye exams, andurinary catheterizations), it is possible oral sucrose isnot routinely administered for each of these types ofprocedures, depending on unit standards/practices.ConclusionsNo difference in pain intensity was shown among 3doses of sucrose during an acute tissue-damaging pro-cedure in hospitalized neonates. The 0.1 ml of 24% su-crose dose was the minimally effective dose that can berecommended for use out of the 3 doses most com-monly reported to be effective in previous research. Sub-sequent study is required to determine the sustainedeffectiveness of this dose in reducing pain intensity dur-ing painful procedures neonates experience in the NICUover time and across GA, and the long-term effects ofcumulative sucrose use.AbbreviationsGA: Gestational age; NAPI: Neurobehavioral assessment of preterm infants;NICU: Neonatal intensive care unit; PIPP-R: Premature infant pain profile-revised; SD: Standard deviation; SNAPPE-II: Score for neonatal acutephysiology perinatal extension- IIAcknowledgementsThank you to the research nurses who collected data at each site: KC, BG,MP, JR and JW; the research database manager: VK; and the neonatalintensive care units that agreed to participate.FundingSupported by the Canadian Institutes of Health Research (MOP-126167). Allstudy sucrose and supplies were purchased through grant funds. The funderhad no role in the design and conduct of the study; collection, management,analysis, and interpretation of the data; preparation, review, or approval of themanuscript; and decision to submit the manuscript for publication.Availability of data and materialsThe datasets used and/or analysed during the current study are availablefrom the corresponding author on reasonable request.Authors’ contributionsThe authors have read and given final approval for this version to be published,and take full responsibility for the work. Each meets the criteria set out byICMJE for authorship. BS and CV had full access to all of the data in the studyand take responsibility for the integrity of the data and the accuracy of the dataanalysis. Study design and concept: BS, MB, MCY, KD, CE, SG, DH, CM, SS, JS, AS,AT, CV, KW, AW, and JY. Management, analysis, and interpretation of data: BS,MCY, SG, DH, CM, SR, AT, CV, KW, and JY. Preparation, review, or approval of thefinal manuscript: BS, MB, MCY, KD, CE, SG, DH, CM, SR, SS, JS, AS, AT, CV, KW, AW,and JY. Statistical analysis: CV. Obtained funding: BS, MB, MCY, KD, CE, SG, DH,CM, SS, JS, AS, AT, CV, KW, AW, and JY. Administrative, technical, or materialsupport: BS and CV. Study supervision: BS, MCY, KD, SG, DH, and JY. All authorsread and approved the final manuscript.Ethics approval and consent to participateThis study was approved by the Research Ethics Boards at The Hospital forSick Children (1000038052), Sunnybrook Health Sciences Centre (354–2013),IWK Health Centre (1013855), The Ottawa Hospital (20130327-01H), andChildren’s Hospital of Eastern Ontario (13/12E). Informed written consent wasobtained from a parent prior to study enrollment.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Stevens et al. BMC Pediatrics  (2018) 18:85 Page 7 of 8Author details1The Hospital for Sick Children, Lawrence S. Bloomberg Faculty of Nursing,University of Toronto, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada.2Daphne Cockwell School of Nursing, Ryerson University, 350 Victoria Street,Toronto, Ontario M5B 2K3, Canada. 3School of Nursing and Departments ofPediatrics, Psychology, and Neuroscience, Dalhousie University, IWK HealthCentre, Forrest Building, P.O. Box 15000, Halifax, Nova Scotia B3H 4R2,Canada. 4Trillium Health Partners, 100 Queensway West, Mississauga, OntarioL5B 1B8, Canada. 5Faculty of Health Sciences, School of Nursing, University ofOttawa, Children’s Hospital of Eastern Ontario, Research Institute, 451 SmythRoad, Ottawa, Ontario K1H 8M5, Canada. 6The Hospital for Sick Children, 686Bay Street, Toronto, Ontario M5G 0A4, Canada. 7The Hospital for SickChildren, Leslie Dan Faculty of Pharmacy, University of Toronto, 686 BayStreet, Toronto, Ontario M5G 0A4, Canada. 8The Hospital for Sick Children,686 Bay Street, Toronto, Ontario M5G 0A4, Canada. 9The Hospital for SickChildren, Dalla Lana School of Public Health, University of Toronto, 686 BayStreet, Toronto, Ontario M5G 0A4, Canada. 10Holland Bloorview KidsRehabilitation Hospital, Lawrence S. Bloomberg Faculty of Nursing, Universityof Toronto, 150 Kilgour Road, Toronto, Ontario M4G 1R8, Canada. 11TheHospital for Sick Children, Lawrence S. Bloomberg Faculty of Nursing,University of Toronto, 155 College Street, Suite 130, Toronto, Ontario M5T1P8, Canada. 12Daphne Cockwell School of Nursing, Ryerson University, 350Victoria Street, Toronto, Ontario M5B 2K3, Canada. 13Faculty of Nursing,University of Alberta, 3-141 Edmonton Clinic Health Academy, 11405 87Avenue, Edmonton, Alberta T6G 1C9, Canada. 14Division of Neonatology,Department of Pediatrics, University of British Columbia, 2D19-4480 OakStreet, Vancouver, British Columbia V6H 4V4, Canada. 15Faculty of HealthSciences, School of Nursing, University of Ottawa, Ottawa Hospital ResearchInstitute, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada. 16Institute forClinical Evaluative Sciences (ICES), The Institute of Health Policy,Management and Evaluation, University of Toronto, Veterans Hill Trail, 2075Bayview Avenue G1 06, Toronto, Ontario M4N 3M5, Canada. 17The Hospitalfor Sick Children, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada.Received: 13 April 2017 Accepted: 29 January 2018References1. 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Repeated doses ofsucrose in infants continue to reduce procedural pain during prolongedhospitalizations. Nurs Res. 2009;58(6):427–34.31. Johnston CC, Filion F, Snider L, Limperopoulos C, Majnemer A, Pelausa E, etal. How much sucrose is too much sucrose? Pediatrics. 2007;119(1):226.32. Banga S, Datta V, Rehan HS, Bhakhri BK. Effect of sucrose analgesia, for repeatedpainful procedures, on short-term neurobehavioral outcome of pretermneonates: a randomized controlled trial. J Trop Pediat. 2016;62(2):101–6.Stevens et al. BMC Pediatrics  (2018) 18:85 Page 8 of 8

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