Background Worldwide, oral sucrose is standard of care in many neonatal intensive care units to relieve procedural pain in neonates. This study aims to determine if time interval between sucrose administration and heelstick correlates with pain scores. Methods Neonates were prospectively studied with variable time intervals and assessed with the Premature Infant Pain Profile-Revised (PIPP-R). Results 150 neonates were included with a median gestational age of 30+6 (IQR 27+6-33+2) weeks and a median time interval of 72 (IQR 39-115) seconds between sucrose administration and heelstick. In multiple regression analysis, this time interval was not significantly related to the PIPP-R (B=0.004, 95% CI -0.005 to 0.013, p=0.37). Providing non-nutritive sucking combined with sucrose was significantly related to lower PIPP-R scores (B=-3.50, 95% CI -4.7 to -2.3, p<0.001). Conclusions Our study suggests that there is no need to wait 2 min after sucrose administration before a painful procedure. Sucrose-induced non-nutritive sucking shows a fast pain-relieving effect in neonates

Anker, J.N. (John) van den

Dijk, M. (Monique) van

Meesters, N.J. (Naomi)

Reiss, I.K.M. (Irwin)

Rosmalen, J.M. (Joost) van

Simons, S.H.P. (Sinno)

PubMed

Erasmus University Digital Repository

Waiting 2 minutes after sucrose administration—unnecessary?Naomi Meesters,1 Sinno Simons,1 Joost van Rosmalen,2 Irwin Reiss,1John van den Anker,3,4,5 Monique van Dijk1,41Division of Neonatology,Department of Pediatrics,Erasmus MC–Sophia Children’sHospital, Rotterdam, TheNetherlands2Department of Biostatistics,Erasmus MC, Rotterdam, TheNetherlands3Division of Pediatric ClinicalPharmacology, Children’sNational Health System,Washington, USA4Intensive Care andDepartment of PediatricSurgery, Erasmus MC –SophiaChildren’s Hospital, Rotterdam,The Netherlands5Division of PaediatricPharmacology andPharmacometrics, UniversityChildren’s Hospital Basel,Basel, SwitzerlandCorrespondence toNaomi Meesters, Division ofNeonatology Department ofPediatrics, Erasmus MC–SophiaChildren’s Hospital,Wytemaweg 80, Rotterdam3015 CN, The Netherlands;n.meesters@erasmusmc.nlReceived 7 March 2016Revised 7 August 2016Accepted 8 August 2016To cite: Meesters N,Simons S, van Rosmalen J,et al. Arch Dis Child FetalNeonatal Ed PublishedOnline First: [please includeDay Month Year]doi:10.1136/archdischild-2016-310841ABSTRACTBackground Worldwide, oral sucrose is standard ofcare in many neonatal intensive care units to relieveprocedural pain in neonates. This study aims todetermine if time interval between sucrose administrationand heelstick correlates with pain scores.Methods Neonates were prospectively studied withvariable time intervals and assessed with the PrematureInfant Pain Proﬁle-Revised (PIPP-R).Results 150 neonates were included with a mediangestational age of 30+6 (IQR 27+6–33+2) weeks and amedian time interval of 72 (IQR 39–115) secondsbetween sucrose administration and heelstick. In multipleregression analysis, this time interval was notsigniﬁcantly related to the PIPP-R (B=0.004, 95% CI−0.005 to 0.013, p=0.37). Providing non-nutritivesucking combined with sucrose was signiﬁcantly relatedto lower PIPP-R scores (B=−3.50, 95% CI −4.7 to−2.3, p<0.001).Conclusions Our study suggests that there is no needto wait 2 min after sucrose administration before apainful procedure. Sucrose-induced non-nutritive suckingshows a fast pain-relieving effect in neonates.INTRODUCTIONOral administration of sucrose signiﬁcantly reducesprocedural pain in newborns.1 It is most effectivewhen combined with non-nutritive sucking(NNS).1 This intervention is therefore recom-mended in international neonatal pain guidelines.2In most studies, sucrose is administered 2 minprior to the painful procedure.1 To our knowledge,only one study evaluated the effect of this timeinterval and found it optimal.3 Because this studyincluded healthy newborns only, we aimed to testwhether this conclusion also holds true for prema-ture or critically ill neonates.We hypothesised that pain scores for prematureor critically ill term neonates will be lowest when atime interval of approximately 2 min is used. Theaim of the study was to determine if the time inter-val between sucrose administration and heelstick iscorrelated with pain scores.METHODSThis prospective study was conducted fromSeptember 2014 to February 2015 at a level 3 neo-natal intensive care unit. Eligible for inclusion wereall preterm and critically ill term neonates with anindication for blood sampling by heelstick. Patientswere selected by convenience sampling and couldbe included only once. This study consisted of twoconsecutive parts, A and B. In part A, 100 heelstickprocedures were performed without any guidanceon time interval. In part B, the medical team wasinstructed to adhere to a 2 min time interval3during 50 heelstick procedures. This way, weexpected a large variation of time intervals and asufﬁcient population to perform a regression ana-lysis. The institutional ethical review board waivedthe need for approval (MEC-2014-357).Data collectionThe procedure, starting with the commencement ofsucrose administration (T=0), was timed with astopwatch. The paciﬁer was gently applied into themouth and sucrose was administered inside thecheek. Without pressure, the nurse held the paciﬁerin place until the infant started to suck.Primary outcome was the pain score obtainedwith the validated Premature Infant PainProﬁle-Revised (PIPP-R),4 applied during the ﬁrst30 s after the heelstick. A score <7 suggests no orlittle pain, 7–12 slight-to-moderate pain and scores>12 are thought to reﬂect moderate-to-severe pain.All assessments were performed by a research nurse(NM) trained to score the PIPP-R (linearlyweighted kappa compared with a trained neonat-ologist=0.85). If one of the PIPP-R items could notbe assessed, a proportional score was calculated bymultiplying the total score by 7/6.What is already known on this topic?▸ Administration of sucrose to neonates prior toa heelstick procedure signiﬁcantly reduces pain.▸ Sucrose is most effective in combination withnon-nutritive sucking.▸ Most studies and guidelines recommendadministering sucrose at least 2 min before apainful procedure.What this study adds?▸ No correlation was found between painintensity and time interval betweenadministration of sucrose and the heelstickprocedure, suggesting that 2 min waiting isunnecessary.▸ Sucrose-induced non-nutritive sucking was theonly variable signiﬁcantly correlated with areduction in pain scores.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F3. doi:10.1136/archdischild-2016-310841 F1Short report ADC-FNN Online First, published on October 18, 2016 as 10.1136/archdischild-2016-310841Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence. group.bmj.com on November 1, 2016 - Published by http://fn.bmj.com/Downloaded from Other variables recorded were: gestational age, postnatal age,NNS at time of the prick, number of doses, total volume ofsucrose administered, size of the lance (BD MicrotainerQuickheel Lancet Preemie or Infant), number of heel squeezesand number of pricks needed. All heelsticks were performed bytrained lab personnel, while a nurse or healthcare assistant pro-vided facilitated tucking.Our clinical treatment protocol prescribed the use of sucrose24% with a maximum volume of 0.5 or 2.0 cc in patients withbodyweight <1000 or >1000 g, respectively.Data analysisThe association between PIPP-R and the time interval was esti-mated with Spearman’s rank correlation coefﬁcient. Multiplelinear regression analysis with PIPP-R total score as outcomevariable and the time interval in seconds as predictor variablewas applied. The relevant covariates postnatal age in days, NNS,total volume of sucrose in millilitres and gender were alsoentered into the regression model. Gestational age was notincluded because it is included in the PIPP-R score. A sensitivityanalysis was performed by replacing time interval in secondswith study phase (part A or part B) in the regression model.RESULTSOne hundred and ﬁfty patients were included with a gestationage between 24+1 and 42+1 weeks. One patient in part Breceived a second dose of sucrose during the time interval andwas excluded from the analysis. Table 1 shows backgroundcharacteristics and main study parameters.The correlation between PIPP-R and time interval was 0.11(95% CI −0.05 to 0.27, p=0.17). Large variations in both timeinterval and PIPP-R scores were found (ﬁgure 1).Multivariate analysisIn multiple regression analysis, too, the time interval was notsigniﬁcantly associated with PIPP-R scores, with an estimatedassociation of 0.004 (95% CI −0.005 to 0.013, p=0.37) pointson the PIPP-R per second. NNS was correlated with an averagedecrease in mean PIPP-R score of 3.5 points (95% CI −4.7 to−2.3, p<0.001). Replacing time interval with study phase in theregression model, the PIPP-R score was on average 0.99 pointshigher in part B (95% CI −0.29 to 2.26, p=0.13). Postnatalage, gender and volume of sucrose were not signiﬁcantly corre-lated to PIPP-R scores.DISCUSSIONWe found that in the studied hospitalised newborns, theheelstick-related pain intensity was not correlated with thelength of the time interval between the administration ofsucrose and the heelstick. This is in contradiction with the onlyother comparable study, which led to the worldwide clinicalimplementation of a 2 min time interval.3 In that study,Table 1 Patients’ background characteristics and main study parameters (N=149)Variables Part A (N=100) Part B (N=49) p ValueBoy/girl; N (%) 61 (61)/39 (39) 24 (49)/25 (51) 0.16Gestational age in weeks+days 30+6 (28+5–33+2) 30+6 (26+6–33+2) 0.26Birth weight in grams 1483 (1158–2015) 1280 (888–1950) 0.18Postnatal age in days 4 (2–8) 5 (2–10) 0.11Time interval in seconds 48 (31–79) 127 (107–153) <0.001Non-nutritive sucking; N (%) 48 (48) 23 (47) 0.90Patients with one dose; N (%)* 98 (98%) 44 (90%) 0.27Total volume of sucrose in mL 0.5 (0.5–0.75) 0.5 (0.5–0.75) 0.78Size of the lance: preemie; N (%)/infant; N (%) 12 (12)/88 (88) 7 (14)/42 (86) 0.69Unable to score nasolabial furrow; N (%) 44 (44) 30 (61) 0.05Duration of procedure in seconds 112 (59–191) 154 (97–257) 0.014Number of squeezes 17 (8–28) 22 (13–36) 0.04Analgesics/sedatives; N (%)† 5 (5) 5 (10) 0.23PIPP-R 6 (0–9) 7 (2–9) 0.22Data are presented as median (IQR) for all continuous variables. Part A and part B data were compared using the χ2 test for categorical variables and the Mann-Whitney U test forcontinuous variables.*Patients who received one dose during the total procedure (from sucrose administration until the end of the blood collection).†Patients who received continuous or intermittent morphine/fentanyl and/or midazolam during or <3 hours before the heelstick procedure.PIPP-R, Premature Infant Pain Profile-Revised.Figure 1 Correlation between time interval after sucroseadministration and Premature Infant Pain Proﬁle-Revised (PIPP-R) score(N=149). Reference lines are at the time interval of 120 s and thecut-off score for PIPP-R of 7 or higher. Markers differentiate betweenyes/no non-nutritive sucking.F2 Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F3. doi:10.1136/archdischild-2016-310841Short reportgroup.bmj.com on November 1, 2016 - Published by http://fn.bmj.com/Downloaded from however, the primary outcome was ‘crying’ and only healthynewborns were included. We used the validated PIPP-R,4 whichwas not yet available at the time of the previous study andincluded premature and critically ill term neonates.Our ﬁnding does not correspond with the supposition that acertain length of time must elapse to mediate opioid responsesand inhibit nociceptive impulses.5 The absence of a time intervalversus effect relationship in our study suggests that sucroseinduces a change in the patient’s behavioural state rather than apharmacological effect. Thus, our ﬁnding underlines the uncer-tainties concerning the working mechanisms of sucrose.2The PIPP-R was applied during the ﬁrst 30 s following theheelstick, according to the instructions of the instrument, whileblood sampling lasted for a median of 2 min. This way, wefocused on pain related to the insertion of the lance. Accordingto the previous research, the effect of sucrose can persist 5–10 min after a painful stimulus.5 Since time interval aftersucrose administration did not affect relief of the acute painupon insertion of the lance, we expect that likewise it does notaffect relief of the pain related to the preceding squeezingeither. If faster onset of action is received, fewer sucrose dosesmay be needed, which would reduce the possible negative effectof sucrose on neurodevelopment.2Strictly adhering to a 2 min time interval1 was difﬁcult, forexample, when an unstable infant needed time to recover beforethe heelstick procedure could start.The study design led to several limitations with uncontrollableconfounders that could possibly have inﬂuenced time intervaland pain intensity. Potential confounders were, for example, theintensity and number of times the heel was squeezed. Also, wedid not take into account the administration of analgesics andsedatives. In addition, the research nurse observed the total pro-cedure and thus was not blinded to the time interval. Still, thisis the ﬁrst study that questioned if the worldwide implementa-tion of the 2 min time interval based on one study was indeedjustiﬁed. In future studies, blinded coders should score thePIPP-R from video recordings. A blinded randomised controlledtrial comparing different time intervals is underway.CONCLUSIONOur study does not justify the need to wait at least 2 min aftersucrose administration, but needs re-evaluation in a randomisedcontrolled trial. Shorter time intervals importantly improve efﬁ-ciency in busy intensive care units. It is best to give sucrose with apaciﬁer to stimulate sucrose-induced NNS to reduce pain responses.Acknowledgements Ko Hagoort is thanked for editorial assistance.Contributors NM conceptualized and designed the study and data collectioninstruments, carried out data collection and initial analyses, drafted the initialmanuscript and approved the ﬁnal manuscript as submitted. SS conceptualized anddesigned the study, critically reviewed and revised the manuscript and approved theﬁnal manuscript as submitted. JvR supervised initial analyses, critically reviewed andrevised the manuscript and approved the ﬁnal manuscript as submitted. IR criticallyreviewed and revised the manuscript and approved the ﬁnal manuscript assubmitted. JvdA critically reviewed and revised the manuscript and approved theﬁnal manuscript as submitted. MvD conceptualized and designed the study,supervised data collection and initial analyses, critically reviewed and revised themanuscript and approved the ﬁnal manuscript as submitted.Competing interests None declared.Ethics approval METC Erasmus MC.Provenance and peer review Not commissioned; externally peer reviewed.Data sharing statement All data are available upon request.Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/REFERENCES1 Stevens B, Yamada J, Lee GY, et al. Sucrose for analgesia in newborn infantsundergoing painful procedures. Cochrane Database Syst Rev 2013;1:CD001069.2 Committee on Fetus and Newborn and Section on Anesthesiology and PainMedicine. Prevention and management of procedural pain in the neonate: an update.Pediatrics 2016;137:e20154271.3 Blass EM, Shah A. Pain-reducing properties of sucrose in human newborns. ChemSenses 1995;20:29–35.4 Gibbins S, Stevens BJ, Yamada J, et al. Validation of the Premature Infant PainProﬁle-Revised (PIPP-R). Early Hum Dev 2014;90:189–93.5 Gibbins S, Stevens B. Mechanisms of sucrose and non-nutritive sucking in proceduralpain management in infants. Pain Res Manag 2001;6:21–8.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F3. doi:10.1136/archdischild-2016-310841 F3Short reportgroup.bmj.com on November 1, 2016 - Published by http://fn.bmj.com/Downloaded from unnecessary?−−administration minutes after sucrose Waiting 2van den Anker and Monique van DijkNaomi Meesters, Sinno Simons, Joost van Rosmalen, Irwin Reiss, John published online October 18, 2016Arch Dis Child Fetal Neonatal Ed  http://fn.bmj.com/content/early/2016/10/18/archdischild-2016-310841Updated information and services can be found at: These include:References #BIBLhttp://fn.bmj.com/content/early/2016/10/18/archdischild-2016-310841This article cites 5 articles, 2 of which you can access for free at: Open Accesshttp://creativecommons.org/licenses/by-nc/4.0/non-commercial. See: provided the original work is properly cited and the use isnon-commercially, and license their derivative works on different terms, permits others to distribute, remix, adapt, build upon this workCommons Attribution Non Commercial (CC BY-NC 4.0) license, which This is an Open Access article distributed in accordance with the CreativeserviceEmail alertingbox at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in theCollectionsTopic Articles on similar topics can be found in the following collections  (857)Infant health (927)Neonatal health (339)Neonatal and paediatric intensive care (1513)Child health (179)Pain (neurology) (53)Open accessNoteshttp://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:http://journals.bmj.com/cgi/reprintformTo order reprints go to:http://group.bmj.com/subscribe/To subscribe to BMJ go to:group.bmj.com on November 1, 2016 - Published by http://fn.bmj.com/Downloaded from 

Waiting 2 minutes after sucrose administration-unnecessary?

Naomi Meesters

Sinno Simons

Joost van Rosmalen

Irwin Reiss

John van den Anker

Monique van Dijk

Crossref

Archives of Disease in Childhood - Fetal and Neonatal Edition

Waiting 2 minutes after sucrose administration—unnecessary?

Meesters, Naomi

Simons, SHP (Sinno)

van Rosmalen, Joost

Reiss, Irwin

van den Anker, John

van Dijk, Monique

NARCIS 

Waiting 2minutes after sucrose administrationunnecessary?

Waiting 2 minutes after sucrose administration—unnecessary?Naomi Meesters,1 Sinno Simons,1 Joost van Rosmalen,2 Irwin Reiss,1John van den Anker,3,4,5 Monique van Dijk1,41Division of Neonatology,Department of Pediatrics,Erasmus MC–Sophia Children’sHospital, Rotterdam, TheNetherlands2Department of Biostatistics,Erasmus MC, Rotterdam, TheNetherlands3Division of Pediatric ClinicalPharmacology, Children’sNational Health System,Washington, USA4Intensive Care andDepartment of PediatricSurgery, Erasmus MC –SophiaChildren’s Hospital, Rotterdam,The Netherlands5Division of PaediatricPharmacology andPharmacometrics, UniversityChildren’s Hospital Basel,Basel, SwitzerlandCorrespondence toNaomi Meesters, Division ofNeonatology Department ofPediatrics, Erasmus MC–SophiaChildren’s Hospital,Wytemaweg 80, Rotterdam3015 CN, The Netherlands;n.meesters@erasmusmc.nlReceived 7 March 2016Revised 7 August 2016Accepted 8 August 2016Published Online First18 October 2016To cite: Meesters N,Simons S, van Rosmalen J,et al. Arch Dis Child FetalNeonatal Ed 2017;102:F167–F169.ABSTRACTBackground Worldwide, oral sucrose is standard ofcare in many neonatal intensive care units to relieveprocedural pain in neonates. This study aims todetermine if time interval between sucrose administrationand heelstick correlates with pain scores.Methods Neonates were prospectively studied withvariable time intervals and assessed with the PrematureInfant Pain Proﬁle-Revised (PIPP-R).Results 150 neonates were included with a mediangestational age of 30+6 (IQR 27+6–33+2) weeks and amedian time interval of 72 (IQR 39–115) secondsbetween sucrose administration and heelstick. In multipleregression analysis, this time interval was notsigniﬁcantly related to the PIPP-R (B=0.004, 95% CI−0.005 to 0.013, p=0.37). Providing non-nutritivesucking combined with sucrose was signiﬁcantly relatedto lower PIPP-R scores (B=−3.50, 95% CI −4.7 to−2.3, p<0.001).Conclusions Our study suggests that there is no needto wait 2 min after sucrose administration before apainful procedure. Sucrose-induced non-nutritive suckingshows a fast pain-relieving effect in neonates.INTRODUCTIONOral administration of sucrose signiﬁcantly reducesprocedural pain in newborns.1 It is most effectivewhen combined with non-nutritive sucking(NNS).1 This intervention is therefore recom-mended in international neonatal pain guidelines.2In most studies, sucrose is administered 2 minprior to the painful procedure.1 To our knowledge,only one study evaluated the effect of this timeinterval and found it optimal.3 Because this studyincluded healthy newborns only, we aimed to testwhether this conclusion also holds true for prema-ture or critically ill neonates.We hypothesised that pain scores for prematureor critically ill term neonates will be lowest when atime interval of approximately 2 min is used. Theaim of the study was to determine if the time inter-val between sucrose administration and heelstick iscorrelated with pain scores.METHODSThis prospective study was conducted fromSeptember 2014 to February 2015 at a level 3 neo-natal intensive care unit. Eligible for inclusion wereall preterm and critically ill term neonates with anindication for blood sampling by heelstick. Patientswere selected by convenience sampling and couldbe included only once. This study consisted of twoconsecutive parts, A and B. In part A, 100 heelstickprocedures were performed without any guidanceon time interval. In part B, the medical team wasinstructed to adhere to a 2 min time interval3during 50 heelstick procedures. This way, weexpected a large variation of time intervals and asufﬁcient population to perform a regression ana-lysis. The institutional ethical review board waivedthe need for approval (MEC-2014-357).Data collectionThe procedure, starting with the commencement ofsucrose administration (T=0), was timed with astopwatch. The paciﬁer was gently applied into themouth and sucrose was administered inside thecheek. Without pressure, the nurse held the paciﬁerin place until the infant started to suck.Primary outcome was the pain score obtainedwith the validated Premature Infant PainProﬁle-Revised (PIPP-R),4 applied during the ﬁrst30 s after the heelstick. A score <7 suggests no orlittle pain, 7–12 slight-to-moderate pain and scores>12 are thought to reﬂect moderate-to-severe pain.All assessments were performed by a research nurse(NM) trained to score the PIPP-R (linearlyweighted kappa compared with a trained neonat-ologist=0.85). If one of the PIPP-R items could notbe assessed, a proportional score was calculated bymultiplying the total score by 7/6.What is already known on this topic?▸ Administration of sucrose to neonates prior toa heelstick procedure signiﬁcantly reduces pain.▸ Sucrose is most effective in combination withnon-nutritive sucking.▸ Most studies and guidelines recommendadministering sucrose at least 2 min before apainful procedure.What this study adds?▸ No correlation was found between painintensity and time interval betweenadministration of sucrose and the heelstickprocedure, suggesting that 2 min waiting isunnecessary.▸ Sucrose-induced non-nutritive sucking was theonly variable signiﬁcantly correlated with areduction in pain scores.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841 F167Short research reportgroup.bmj.com on August 2, 2017 - Published by http://fn.bmj.com/Downloaded from Other variables recorded were: gestational age, postnatal age,NNS at time of the prick, number of doses, total volume ofsucrose administered, size of the lance (BD MicrotainerQuickheel Lancet Preemie or Infant), number of heel squeezesand number of pricks needed. All heelsticks were performed bytrained lab personnel, while a nurse or healthcare assistant pro-vided facilitated tucking.Our clinical treatment protocol prescribed the use of sucrose24% with a maximum volume of 0.5 or 2.0 cc in patients withbodyweight <1000 or >1000 g, respectively.Data analysisThe association between PIPP-R and the time interval was esti-mated with Spearman’s rank correlation coefﬁcient. Multiplelinear regression analysis with PIPP-R total score as outcomevariable and the time interval in seconds as predictor variablewas applied. The relevant covariates postnatal age in days, NNS,total volume of sucrose in millilitres and gender were alsoentered into the regression model. Gestational age was notincluded because it is included in the PIPP-R score. A sensitivityanalysis was performed by replacing time interval in secondswith study phase (part A or part B) in the regression model.RESULTSOne hundred and ﬁfty patients were included with a gestationage between 24+1 and 42+1 weeks. One patient in part Breceived a second dose of sucrose during the time interval andwas excluded from the analysis. Table 1 shows backgroundcharacteristics and main study parameters.The correlation between PIPP-R and time interval was 0.11(95% CI −0.05 to 0.27, p=0.17). Large variations in both timeinterval and PIPP-R scores were found (ﬁgure 1).Multivariate analysisIn multiple regression analysis, too, the time interval was notsigniﬁcantly associated with PIPP-R scores, with an estimatedassociation of 0.004 (95% CI −0.005 to 0.013, p=0.37) pointson the PIPP-R per second. NNS was correlated with an averagedecrease in mean PIPP-R score of 3.5 points (95% CI −4.7 to−2.3, p<0.001). Replacing time interval with study phase in theregression model, the PIPP-R score was on average 0.99 pointshigher in part B (95% CI −0.29 to 2.26, p=0.13). Postnatalage, gender and volume of sucrose were not signiﬁcantly corre-lated to PIPP-R scores.DISCUSSIONWe found that in the studied hospitalised newborns, theheelstick-related pain intensity was not correlated with thelength of the time interval between the administration ofsucrose and the heelstick. This is in contradiction with the onlyother comparable study, which led to the worldwide clinicalimplementation of a 2 min time interval.3 In that study,Table 1 Patients’ background characteristics and main study parameters (N=149)Variables Part A (N=100) Part B (N=49) p ValueBoy/girl; N (%) 61 (61)/39 (39) 24 (49)/25 (51) 0.16Gestational age in weeks+days 30+6 (28+5–33+2) 30+6 (26+6–33+2) 0.26Birth weight in grams 1483 (1158–2015) 1280 (888–1950) 0.18Postnatal age in days 4 (2–8) 5 (2–10) 0.11Time interval in seconds 48 (31–79) 127 (107–153) <0.001Non-nutritive sucking; N (%) 48 (48) 23 (47) 0.90Patients with one dose; N (%)* 98 (98%) 44 (90%) 0.27Total volume of sucrose in mL 0.5 (0.5–0.75) 0.5 (0.5–0.75) 0.78Size of the lance: preemie; N (%)/infant; N (%) 12 (12)/88 (88) 7 (14)/42 (86) 0.69Unable to score nasolabial furrow; N (%) 44 (44) 30 (61) 0.05Duration of procedure in seconds 112 (59–191) 154 (97–257) 0.014Number of squeezes 17 (8–28) 22 (13–36) 0.04Analgesics/sedatives; N (%)† 5 (5) 5 (10) 0.23PIPP-R 6 (0–9) 7 (2–9) 0.22Data are presented as median (IQR) for all continuous variables. Part A and part B data were compared using the χ2 test for categorical variables and the Mann-Whitney U test forcontinuous variables.*Patients who received one dose during the total procedure (from sucrose administration until the end of the blood collection).†Patients who received continuous or intermittent morphine/fentanyl and/or midazolam during or <3 hours before the heelstick procedure.PIPP-R, Premature Infant Pain Profile-Revised.Figure 1 Correlation between time interval after sucroseadministration and Premature Infant Pain Proﬁle-Revised (PIPP-R) score(N=149). Reference lines are at the time interval of 120 s and thecut-off score for PIPP-R of 7 or higher. Markers differentiate betweenyes/no non-nutritive sucking.F168 Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841Short research reportgroup.bmj.com on August 2, 2017 - Published by http://fn.bmj.com/Downloaded from however, the primary outcome was ‘crying’ and only healthynewborns were included. We used the validated PIPP-R,4 whichwas not yet available at the time of the previous study andincluded premature and critically ill term neonates.Our ﬁnding does not correspond with the supposition that acertain length of time must elapse to mediate opioid responsesand inhibit nociceptive impulses.5 The absence of a time intervalversus effect relationship in our study suggests that sucroseinduces a change in the patient’s behavioural state rather than apharmacological effect. Thus, our ﬁnding underlines the uncer-tainties concerning the working mechanisms of sucrose.2The PIPP-R was applied during the ﬁrst 30 s following theheelstick, according to the instructions of the instrument, whileblood sampling lasted for a median of 2 min. This way, wefocused on pain related to the insertion of the lance. Accordingto the previous research, the effect of sucrose can persist 5–10 min after a painful stimulus.5 Since time interval aftersucrose administration did not affect relief of the acute painupon insertion of the lance, we expect that likewise it does notaffect relief of the pain related to the preceding squeezingeither. If faster onset of action is received, fewer sucrose dosesmay be needed, which would reduce the possible negative effectof sucrose on neurodevelopment.2Strictly adhering to a 2 min time interval1 was difﬁcult, forexample, when an unstable infant needed time to recover beforethe heelstick procedure could start.The study design led to several limitations with uncontrollableconfounders that could possibly have inﬂuenced time intervaland pain intensity. Potential confounders were, for example, theintensity and number of times the heel was squeezed. Also, wedid not take into account the administration of analgesics andsedatives. In addition, the research nurse observed the total pro-cedure and thus was not blinded to the time interval. Still, thisis the ﬁrst study that questioned if the worldwide implementa-tion of the 2 min time interval based on one study was indeedjustiﬁed. In future studies, blinded coders should score thePIPP-R from video recordings. A blinded randomised controlledtrial comparing different time intervals is underway.CONCLUSIONOur study does not justify the need to wait at least 2 min aftersucrose administration, but needs re-evaluation in a randomisedcontrolled trial. Shorter time intervals importantly improve efﬁ-ciency in busy intensive care units. It is best to give sucrose with apaciﬁer to stimulate sucrose-induced NNS to reduce pain responses.Acknowledgements Ko Hagoort is thanked for editorial assistance.Contributors NM conceptualized and designed the study and data collectioninstruments, carried out data collection and initial analyses, drafted the initialmanuscript and approved the ﬁnal manuscript as submitted. SS conceptualized anddesigned the study, critically reviewed and revised the manuscript and approved theﬁnal manuscript as submitted. JvR supervised initial analyses, critically reviewed andrevised the manuscript and approved the ﬁnal manuscript as submitted. IR criticallyreviewed and revised the manuscript and approved the ﬁnal manuscript assubmitted. JvdA critically reviewed and revised the manuscript and approved theﬁnal manuscript as submitted. MvD conceptualized and designed the study,supervised data collection and initial analyses, critically reviewed and revised themanuscript and approved the ﬁnal manuscript as submitted.Competing interests None declared.Ethics approval METC Erasmus MC.Provenance and peer review Not commissioned; externally peer reviewed.Data sharing statement All data are available upon request.Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/REFERENCES1 Stevens B, Yamada J, Lee GY, et al. Sucrose for analgesia in newborn infantsundergoing painful procedures. Cochrane Database Syst Rev 2013;1:CD001069.2 Committee on Fetus and Newborn and Section on Anesthesiology and PainMedicine. Prevention and management of procedural pain in the neonate: an update.Pediatrics 2016;137:e20154271.3 Blass EM, Shah A. Pain-reducing properties of sucrose in human newborns. ChemSenses 1995;20:29–35.4 Gibbins S, Stevens BJ, Yamada J, et al. Validation of the Premature Infant PainProﬁle-Revised (PIPP-R). Early Hum Dev 2014;90:189–93.5 Gibbins S, Stevens B. Mechanisms of sucrose and non-nutritive sucking in proceduralpain management in infants. Pain Res Manag 2001;6:21–8.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841 F169Short research reportgroup.bmj.com on August 2, 2017 - Published by http://fn.bmj.com/Downloaded from unnecessary?−−administration minutes after sucrose Waiting 2van den Anker and Monique van DijkNaomi Meesters, Sinno Simons, Joost van Rosmalen, Irwin Reiss, Johndoi: 10.1136/archdischild-2016-310841published online October 18, 20162017 102: F167-F169 originallyArch Dis Child Fetal Neonatal Ed  http://fn.bmj.com/content/102/2/F167Updated information and services can be found at: These include:References #BIBLhttp://fn.bmj.com/content/102/2/F167This article cites 5 articles, 1 of which you can access for free at: Open Accesshttp://creativecommons.org/licenses/by-nc/4.0/non-commercial. See: provided the original work is properly cited and the use isnon-commercially, and license their derivative works on different terms, permits others to distribute, remix, adapt, build upon this workCommons Attribution Non Commercial (CC BY-NC 4.0) license, which This is an Open Access article distributed in accordance with the CreativeserviceEmail alertingbox at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in theCollectionsTopic Articles on similar topics can be found in the following collections  (857)Infant health (928)Neonatal health (341)Neonatal and paediatric intensive care (1515)Child health (179)Pain (neurology) (58)Open accessNoteshttp://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:http://journals.bmj.com/cgi/reprintformTo order reprints go to:http://group.bmj.com/subscribe/To subscribe to BMJ go to:group.bmj.com on August 2, 2017 - Published by http://fn.bmj.com/Downloaded from 

__Background__ Worldwide, oral sucrose is standard of care in many neonatal intensive care units to relieve procedural pain in neonates. This study aims to determine if time interval between sucrose administration and heelstick correlates with pain scores.  

__Methods__ Neonates were prospectively studied with variable time intervals and assessed with the Premature Infant Pain Profile-Revised (PIPP-R).  

__Results__ 150 neonates were included with a median gestational age of 30 +6 (IQR 27 +6-33 +2) weeks and a median time interval of 72 (IQR 39-115) seconds between sucrose administration and heelstick. In multiple regression analysis, this time interval was not significantly related to the PIPP-R (B=0.004, 95% CI â '0.005 to 0.013, p=0.37). Providing non-nutritive sucking combined with sucrose was significantly related to lower PIPP-R scores (B=â '3.50, 95% CI A '4.7 to â '2.3, p<0.001).  

__Conclusions__ Our study suggests that there is no need to wait 2â €.min after sucrose administration before a painful procedure. Sucrose-induced non-nutritive sucking shows a fast pain-relieving effect in neonates

Waiting 2 minutes after sucrose administration—unnecessary?Naomi Meesters,1 Sinno Simons,1 Joost van Rosmalen,2 Irwin Reiss,1John van den Anker,3,4,5 Monique van Dijk1,41Division of Neonatology,Department of Pediatrics,Erasmus MC–Sophia Children’sHospital, Rotterdam, TheNetherlands2Department of Biostatistics,Erasmus MC, Rotterdam, TheNetherlands3Division of Pediatric ClinicalPharmacology, Children’sNational Health System,Washington, USA4Intensive Care andDepartment of PediatricSurgery, Erasmus MC –SophiaChildren’s Hospital, Rotterdam,The Netherlands5Division of PaediatricPharmacology andPharmacometrics, UniversityChildren’s Hospital Basel,Basel, SwitzerlandCorrespondence toNaomi Meesters, Division ofNeonatology Department ofPediatrics, Erasmus MC–SophiaChildren’s Hospital,Wytemaweg 80, Rotterdam3015 CN, The Netherlands;n.meesters@erasmusmc.nlReceived 7 March 2016Revised 7 August 2016Accepted 8 August 2016Published Online First18 October 2016To cite: Meesters N,Simons S, van Rosmalen J,et al. Arch Dis Child FetalNeonatal Ed 2017;102:F167–F169.ABSTRACTBackground Worldwide, oral sucrose is standard ofcare in many neonatal intensive care units to relieveprocedural pain in neonates. This study aims todetermine if time interval between sucrose administrationand heelstick correlates with pain scores.Methods Neonates were prospectively studied withvariable time intervals and assessed with the PrematureInfant Pain Proﬁle-Revised (PIPP-R).Results 150 neonates were included with a mediangestational age of 30+6 (IQR 27+6–33+2) weeks and amedian time interval of 72 (IQR 39–115) secondsbetween sucrose administration and heelstick. In multipleregression analysis, this time interval was notsigniﬁcantly related to the PIPP-R (B=0.004, 95% CI−0.005 to 0.013, p=0.37). Providing non-nutritivesucking combined with sucrose was signiﬁcantly relatedto lower PIPP-R scores (B=−3.50, 95% CI −4.7 to−2.3, p<0.001).Conclusions Our study suggests that there is no needto wait 2 min after sucrose administration before apainful procedure. Sucrose-induced non-nutritive suckingshows a fast pain-relieving effect in neonates.INTRODUCTIONOral administration of sucrose signiﬁcantly reducesprocedural pain in newborns.1 It is most effectivewhen combined with non-nutritive sucking(NNS).1 This intervention is therefore recom-mended in international neonatal pain guidelines.2In most studies, sucrose is administered 2 minprior to the painful procedure.1 To our knowledge,only one study evaluated the effect of this timeinterval and found it optimal.3 Because this studyincluded healthy newborns only, we aimed to testwhether this conclusion also holds true for prema-ture or critically ill neonates.We hypothesised that pain scores for prematureor critically ill term neonates will be lowest when atime interval of approximately 2 min is used. Theaim of the study was to determine if the time inter-val between sucrose administration and heelstick iscorrelated with pain scores.METHODSThis prospective study was conducted fromSeptember 2014 to February 2015 at a level 3 neo-natal intensive care unit. Eligible for inclusion wereall preterm and critically ill term neonates with anindication for blood sampling by heelstick. Patientswere selected by convenience sampling and couldbe included only once. This study consisted of twoconsecutive parts, A and B. In part A, 100 heelstickprocedures were performed without any guidanceon time interval. In part B, the medical team wasinstructed to adhere to a 2 min time interval3during 50 heelstick procedures. This way, weexpected a large variation of time intervals and asufﬁcient population to perform a regression ana-lysis. The institutional ethical review board waivedthe need for approval (MEC-2014-357).Data collectionThe procedure, starting with the commencement ofsucrose administration (T=0), was timed with astopwatch. The paciﬁer was gently applied into themouth and sucrose was administered inside thecheek. Without pressure, the nurse held the paciﬁerin place until the infant started to suck.Primary outcome was the pain score obtainedwith the validated Premature Infant PainProﬁle-Revised (PIPP-R),4 applied during the ﬁrst30 s after the heelstick. A score <7 suggests no orlittle pain, 7–12 slight-to-moderate pain and scores>12 are thought to reﬂect moderate-to-severe pain.All assessments were performed by a research nurse(NM) trained to score the PIPP-R (linearlyweighted kappa compared with a trained neonat-ologist=0.85). If one of the PIPP-R items could notbe assessed, a proportional score was calculated bymultiplying the total score by 7/6.What is already known on this topic?▸ Administration of sucrose to neonates prior toa heelstick procedure signiﬁcantly reduces pain.▸ Sucrose is most effective in combination withnon-nutritive sucking.▸ Most studies and guidelines recommendadministering sucrose at least 2 min before apainful procedure.What this study adds?▸ No correlation was found between painintensity and time interval betweenadministration of sucrose and the heelstickprocedure, suggesting that 2 min waiting isunnecessary.▸ Sucrose-induced non-nutritive sucking was theonly variable signiﬁcantly correlated with areduction in pain scores.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841 F167Short research reportgroup.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from Other variables recorded were: gestational age, postnatal age,NNS at time of the prick, number of doses, total volume ofsucrose administered, size of the lance (BD MicrotainerQuickheel Lancet Preemie or Infant), number of heel squeezesand number of pricks needed. All heelsticks were performed bytrained lab personnel, while a nurse or healthcare assistant pro-vided facilitated tucking.Our clinical treatment protocol prescribed the use of sucrose24% with a maximum volume of 0.5 or 2.0 cc in patients withbodyweight <1000 or >1000 g, respectively.Data analysisThe association between PIPP-R and the time interval was esti-mated with Spearman’s rank correlation coefﬁcient. Multiplelinear regression analysis with PIPP-R total score as outcomevariable and the time interval in seconds as predictor variablewas applied. The relevant covariates postnatal age in days, NNS,total volume of sucrose in millilitres and gender were alsoentered into the regression model. Gestational age was notincluded because it is included in the PIPP-R score. A sensitivityanalysis was performed by replacing time interval in secondswith study phase (part A or part B) in the regression model.RESULTSOne hundred and ﬁfty patients were included with a gestationage between 24+1 and 42+1 weeks. One patient in part Breceived a second dose of sucrose during the time interval andwas excluded from the analysis. Table 1 shows backgroundcharacteristics and main study parameters.The correlation between PIPP-R and time interval was 0.11(95% CI −0.05 to 0.27, p=0.17). Large variations in both timeinterval and PIPP-R scores were found (ﬁgure 1).Multivariate analysisIn multiple regression analysis, too, the time interval was notsigniﬁcantly associated with PIPP-R scores, with an estimatedassociation of 0.004 (95% CI −0.005 to 0.013, p=0.37) pointson the PIPP-R per second. NNS was correlated with an averagedecrease in mean PIPP-R score of 3.5 points (95% CI −4.7 to−2.3, p<0.001). Replacing time interval with study phase in theregression model, the PIPP-R score was on average 0.99 pointshigher in part B (95% CI −0.29 to 2.26, p=0.13). Postnatalage, gender and volume of sucrose were not signiﬁcantly corre-lated to PIPP-R scores.DISCUSSIONWe found that in the studied hospitalised newborns, theheelstick-related pain intensity was not correlated with thelength of the time interval between the administration ofsucrose and the heelstick. This is in contradiction with the onlyother comparable study, which led to the worldwide clinicalimplementation of a 2 min time interval.3 In that study,Table 1 Patients’ background characteristics and main study parameters (N=149)Variables Part A (N=100) Part B (N=49) p ValueBoy/girl; N (%) 61 (61)/39 (39) 24 (49)/25 (51) 0.16Gestational age in weeks+days 30+6 (28+5–33+2) 30+6 (26+6–33+2) 0.26Birth weight in grams 1483 (1158–2015) 1280 (888–1950) 0.18Postnatal age in days 4 (2–8) 5 (2–10) 0.11Time interval in seconds 48 (31–79) 127 (107–153) <0.001Non-nutritive sucking; N (%) 48 (48) 23 (47) 0.90Patients with one dose; N (%)* 98 (98%) 44 (90%) 0.27Total volume of sucrose in mL 0.5 (0.5–0.75) 0.5 (0.5–0.75) 0.78Size of the lance: preemie; N (%)/infant; N (%) 12 (12)/88 (88) 7 (14)/42 (86) 0.69Unable to score nasolabial furrow; N (%) 44 (44) 30 (61) 0.05Duration of procedure in seconds 112 (59–191) 154 (97–257) 0.014Number of squeezes 17 (8–28) 22 (13–36) 0.04Analgesics/sedatives; N (%)† 5 (5) 5 (10) 0.23PIPP-R 6 (0–9) 7 (2–9) 0.22Data are presented as median (IQR) for all continuous variables. Part A and part B data were compared using the χ2 test for categorical variables and the Mann-Whitney U test forcontinuous variables.*Patients who received one dose during the total procedure (from sucrose administration until the end of the blood collection).†Patients who received continuous or intermittent morphine/fentanyl and/or midazolam during or <3 hours before the heelstick procedure.PIPP-R, Premature Infant Pain Profile-Revised.Figure 1 Correlation between time interval after sucroseadministration and Premature Infant Pain Proﬁle-Revised (PIPP-R) score(N=149). Reference lines are at the time interval of 120 s and thecut-off score for PIPP-R of 7 or higher. Markers differentiate betweenyes/no non-nutritive sucking.F168 Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841Short research reportgroup.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from however, the primary outcome was ‘crying’ and only healthynewborns were included. We used the validated PIPP-R,4 whichwas not yet available at the time of the previous study andincluded premature and critically ill term neonates.Our ﬁnding does not correspond with the supposition that acertain length of time must elapse to mediate opioid responsesand inhibit nociceptive impulses.5 The absence of a time intervalversus effect relationship in our study suggests that sucroseinduces a change in the patient’s behavioural state rather than apharmacological effect. Thus, our ﬁnding underlines the uncer-tainties concerning the working mechanisms of sucrose.2The PIPP-R was applied during the ﬁrst 30 s following theheelstick, according to the instructions of the instrument, whileblood sampling lasted for a median of 2 min. This way, wefocused on pain related to the insertion of the lance. Accordingto the previous research, the effect of sucrose can persist 5–10 min after a painful stimulus.5 Since time interval aftersucrose administration did not affect relief of the acute painupon insertion of the lance, we expect that likewise it does notaffect relief of the pain related to the preceding squeezingeither. If faster onset of action is received, fewer sucrose dosesmay be needed, which would reduce the possible negative effectof sucrose on neurodevelopment.2Strictly adhering to a 2 min time interval1 was difﬁcult, forexample, when an unstable infant needed time to recover beforethe heelstick procedure could start.The study design led to several limitations with uncontrollableconfounders that could possibly have inﬂuenced time intervaland pain intensity. Potential confounders were, for example, theintensity and number of times the heel was squeezed. Also, wedid not take into account the administration of analgesics andsedatives. In addition, the research nurse observed the total pro-cedure and thus was not blinded to the time interval. Still, thisis the ﬁrst study that questioned if the worldwide implementa-tion of the 2 min time interval based on one study was indeedjustiﬁed. In future studies, blinded coders should score thePIPP-R from video recordings. A blinded randomised controlledtrial comparing different time intervals is underway.CONCLUSIONOur study does not justify the need to wait at least 2 min aftersucrose administration, but needs re-evaluation in a randomisedcontrolled trial. Shorter time intervals importantly improve efﬁ-ciency in busy intensive care units. It is best to give sucrose with apaciﬁer to stimulate sucrose-induced NNS to reduce pain responses.Acknowledgements Ko Hagoort is thanked for editorial assistance.Contributors NM conceptualized and designed the study and data collectioninstruments, carried out data collection and initial analyses, drafted the initialmanuscript and approved the ﬁnal manuscript as submitted. SS conceptualized anddesigned the study, critically reviewed and revised the manuscript and approved theﬁnal manuscript as submitted. JvR supervised initial analyses, critically reviewed andrevised the manuscript and approved the ﬁnal manuscript as submitted. IR criticallyreviewed and revised the manuscript and approved the ﬁnal manuscript assubmitted. JvdA critically reviewed and revised the manuscript and approved theﬁnal manuscript as submitted. MvD conceptualized and designed the study,supervised data collection and initial analyses, critically reviewed and revised themanuscript and approved the ﬁnal manuscript as submitted.Competing interests None declared.Ethics approval METC Erasmus MC.Provenance and peer review Not commissioned; externally peer reviewed.Data sharing statement All data are available upon request.Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/REFERENCES1 Stevens B, Yamada J, Lee GY, et al. Sucrose for analgesia in newborn infantsundergoing painful procedures. Cochrane Database Syst Rev 2013;1:CD001069.2 Committee on Fetus and Newborn and Section on Anesthesiology and PainMedicine. Prevention and management of procedural pain in the neonate: an update.Pediatrics 2016;137:e20154271.3 Blass EM, Shah A. Pain-reducing properties of sucrose in human newborns. ChemSenses 1995;20:29–35.4 Gibbins S, Stevens BJ, Yamada J, et al. Validation of the Premature Infant PainProﬁle-Revised (PIPP-R). Early Hum Dev 2014;90:189–93.5 Gibbins S, Stevens B. Mechanisms of sucrose and non-nutritive sucking in proceduralpain management in infants. Pain Res Manag 2001;6:21–8.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841 F169Short research reportgroup.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from unnecessary?−−administration minutes after sucrose Waiting 2van den Anker and Monique van DijkNaomi Meesters, Sinno Simons, Joost van Rosmalen, Irwin Reiss, Johndoi: 10.1136/archdischild-2016-310841published online October 18, 20162017 102: F167-F169 originallyArch Dis Child Fetal Neonatal Ed  http://fn.bmj.com/content/102/2/F167Updated information and services can be found at: These include:References #BIBLhttp://fn.bmj.com/content/102/2/F167This article cites 5 articles, 2 of which you can access for free at: Open Accesshttp://creativecommons.org/licenses/by-nc/4.0/non-commercial. See: provided the original work is properly cited and the use isnon-commercially, and license their derivative works on different terms, permits others to distribute, remix, adapt, build upon this workCommons Attribution Non Commercial (CC BY-NC 4.0) license, which This is an Open Access article distributed in accordance with the CreativeserviceEmail alertingbox at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in theCollectionsTopic Articles on similar topics can be found in the following collections  (857)Infant health (928)Neonatal health (341)Neonatal and paediatric intensive care (1515)Child health (179)Pain (neurology) (55)Open accessNoteshttp://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:http://journals.bmj.com/cgi/reprintformTo order reprints go to:http://group.bmj.com/subscribe/To subscribe to BMJ go to:group.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from 

EUR Research Repository

Waiting 2 minutes after sucrose administration—unnecessary?Naomi Meesters,1 Sinno Simons,1 Joost van Rosmalen,2 Irwin Reiss,1John van den Anker,3,4,5 Monique van Dijk1,41Division of Neonatology,Department of Pediatrics,Erasmus MC–Sophia Children’sHospital, Rotterdam, TheNetherlands2Department of Biostatistics,Erasmus MC, Rotterdam, TheNetherlands3Division of Pediatric ClinicalPharmacology, Children’sNational Health System,Washington, USA4Intensive Care andDepartment of PediatricSurgery, Erasmus MC –SophiaChildren’s Hospital, Rotterdam,The Netherlands5Division of PaediatricPharmacology andPharmacometrics, UniversityChildren’s Hospital Basel,Basel, SwitzerlandCorrespondence toNaomi Meesters, Division ofNeonatology Department ofPediatrics, Erasmus MC–SophiaChildren’s Hospital,Wytemaweg 80, Rotterdam3015 CN, The Netherlands;n.meesters@erasmusmc.nlReceived 7 March 2016Revised 7 August 2016Accepted 8 August 2016Published Online First18 October 2016To cite: Meesters N,Simons S, van Rosmalen J,et al. Arch Dis Child FetalNeonatal Ed 2017;102:F167–F169.ABSTRACTBackground Worldwide, oral sucrose is standard ofcare in many neonatal intensive care units to relieveprocedural pain in neonates. This study aims todetermine if time interval between sucrose administrationand heelstick correlates with pain scores.Methods Neonates were prospectively studied withvariable time intervals and assessed with the PrematureInfant Pain Profile-Revised (PIPP-R).Results 150 neonates were included with a mediangestational age of 30+6 (IQR 27+6–33+2) weeks and amedian time interval of 72 (IQR 39–115) secondsbetween sucrose administration and heelstick. In multipleregression analysis, this time interval was notsignificantly related to the PIPP-R (B=0.004, 95% CI−0.005 to 0.013, p=0.37). Providing non-nutritivesucking combined with sucrose was significantly relatedto lower PIPP-R scores (B=−3.50, 95% CI −4.7 to−2.3, p<0.001).Conclusions Our study suggests that there is no needto wait 2 min after sucrose administration before apainful procedure. Sucrose-induced non-nutritive suckingshows a fast pain-relieving effect in neonates.INTRODUCTIONOral administration of sucrose significantly reducesprocedural pain in newborns.1 It is most effectivewhen combined with non-nutritive sucking(NNS).1 This intervention is therefore recom-mended in international neonatal pain guidelines.2In most studies, sucrose is administered 2 minprior to the painful procedure.1 To our knowledge,only one study evaluated the effect of this timeinterval and found it optimal.3 Because this studyincluded healthy newborns only, we aimed to testwhether this conclusion also holds true for prema-ture or critically ill neonates.We hypothesised that pain scores for prematureor critically ill term neonates will be lowest when atime interval of approximately 2 min is used. Theaim of the study was to determine if the time inter-val between sucrose administration and heelstick iscorrelated with pain scores.METHODSThis prospective study was conducted fromSeptember 2014 to February 2015 at a level 3 neo-natal intensive care unit. Eligible for inclusion wereall preterm and critically ill term neonates with anindication for blood sampling by heelstick. Patientswere selected by convenience sampling and couldbe included only once. This study consisted of twoconsecutive parts, A and B. In part A, 100 heelstickprocedures were performed without any guidanceon time interval. In part B, the medical team wasinstructed to adhere to a 2 min time interval3during 50 heelstick procedures. This way, weexpected a large variation of time intervals and asufficient population to perform a regression ana-lysis. The institutional ethical review board waivedthe need for approval (MEC-2014-357).Data collectionThe procedure, starting with the commencement ofsucrose administration (T=0), was timed with astopwatch. The pacifier was gently applied into themouth and sucrose was administered inside thecheek. Without pressure, the nurse held the pacifierin place until the infant started to suck.Primary outcome was the pain score obtainedwith the validated Premature Infant PainProfile-Revised (PIPP-R),4 applied during the first30 s after the heelstick. A score <7 suggests no orlittle pain, 7–12 slight-to-moderate pain and scores>12 are thought to reflect moderate-to-severe pain.All assessments were performed by a research nurse(NM) trained to score the PIPP-R (linearlyweighted kappa compared with a trained neonat-ologist=0.85). If one of the PIPP-R items could notbe assessed, a proportional score was calculated bymultiplying the total score by 7/6.What is already known on this topic?▸ Administration of sucrose to neonates prior toa heelstick procedure significantly reduces pain.▸ Sucrose is most effective in combination withnon-nutritive sucking.▸ Most studies and guidelines recommendadministering sucrose at least 2 min before apainful procedure.What this study adds?▸ No correlation was found between painintensity and time interval betweenadministration of sucrose and the heelstickprocedure, suggesting that 2 min waiting isunnecessary.▸ Sucrose-induced non-nutritive sucking was theonly variable significantly correlated with areduction in pain scores.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841 F167Short research reportgroup.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from Other variables recorded were: gestational age, postnatal age,NNS at time of the prick, number of doses, total volume ofsucrose administered, size of the lance (BD MicrotainerQuickheel Lancet Preemie or Infant), number of heel squeezesand number of pricks needed. All heelsticks were performed bytrained lab personnel, while a nurse or healthcare assistant pro-vided facilitated tucking.Our clinical treatment protocol prescribed the use of sucrose24% with a maximum volume of 0.5 or 2.0 cc in patients withbodyweight <1000 or >1000 g, respectively.Data analysisThe association between PIPP-R and the time interval was esti-mated with Spearman’s rank correlation coefficient. Multiplelinear regression analysis with PIPP-R total score as outcomevariable and the time interval in seconds as predictor variablewas applied. The relevant covariates postnatal age in days, NNS,total volume of sucrose in millilitres and gender were alsoentered into the regression model. Gestational age was notincluded because it is included in the PIPP-R score. A sensitivityanalysis was performed by replacing time interval in secondswith study phase (part A or part B) in the regression model.RESULTSOne hundred and fifty patients were included with a gestationage between 24+1 and 42+1 weeks. One patient in part Breceived a second dose of sucrose during the time interval andwas excluded from the analysis. Table 1 shows backgroundcharacteristics and main study parameters.The correlation between PIPP-R and time interval was 0.11(95% CI −0.05 to 0.27, p=0.17). Large variations in both timeinterval and PIPP-R scores were found (figure 1).Multivariate analysisIn multiple regression analysis, too, the time interval was notsignificantly associated with PIPP-R scores, with an estimatedassociation of 0.004 (95% CI −0.005 to 0.013, p=0.37) pointson the PIPP-R per second. NNS was correlated with an averagedecrease in mean PIPP-R score of 3.5 points (95% CI −4.7 to−2.3, p<0.001). Replacing time interval with study phase in theregression model, the PIPP-R score was on average 0.99 pointshigher in part B (95% CI −0.29 to 2.26, p=0.13). Postnatalage, gender and volume of sucrose were not significantly corre-lated to PIPP-R scores.DISCUSSIONWe found that in the studied hospitalised newborns, theheelstick-related pain intensity was not correlated with thelength of the time interval between the administration ofsucrose and the heelstick. This is in contradiction with the onlyother comparable study, which led to the worldwide clinicalimplementation of a 2 min time interval.3 In that study,Table 1 Patients’ background characteristics and main study parameters (N=149)Variables Part A (N=100) Part B (N=49) p ValueBoy/girl; N (%) 61 (61)/39 (39) 24 (49)/25 (51) 0.16Gestational age in weeks+days 30+6 (28+5–33+2) 30+6 (26+6–33+2) 0.26Birth weight in grams 1483 (1158–2015) 1280 (888–1950) 0.18Postnatal age in days 4 (2–8) 5 (2–10) 0.11Time interval in seconds 48 (31–79) 127 (107–153) <0.001Non-nutritive sucking; N (%) 48 (48) 23 (47) 0.90Patients with one dose; N (%)* 98 (98%) 44 (90%) 0.27Total volume of sucrose in mL 0.5 (0.5–0.75) 0.5 (0.5–0.75) 0.78Size of the lance: preemie; N (%)/infant; N (%) 12 (12)/88 (88) 7 (14)/42 (86) 0.69Unable to score nasolabial furrow; N (%) 44 (44) 30 (61) 0.05Duration of procedure in seconds 112 (59–191) 154 (97–257) 0.014Number of squeezes 17 (8–28) 22 (13–36) 0.04Analgesics/sedatives; N (%)† 5 (5) 5 (10) 0.23PIPP-R 6 (0–9) 7 (2–9) 0.22Data are presented as median (IQR) for all continuous variables. Part A and part B data were compared using the χ2 test for categorical variables and the Mann-Whitney U test forcontinuous variables.*Patients who received one dose during the total procedure (from sucrose administration until the end of the blood collection).†Patients who received continuous or intermittent morphine/fentanyl and/or midazolam during or <3 hours before the heelstick procedure.PIPP-R, Premature Infant Pain Profile-Revised.Figure 1 Correlation between time interval after sucroseadministration and Premature Infant Pain Profile-Revised (PIPP-R) score(N=149). Reference lines are at the time interval of 120 s and thecut-off score for PIPP-R of 7 or higher. Markers differentiate betweenyes/no non-nutritive sucking.F168 Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841Short research reportgroup.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from however, the primary outcome was ‘crying’ and only healthynewborns were included. We used the validated PIPP-R,4 whichwas not yet available at the time of the previous study andincluded premature and critically ill term neonates.Our finding does not correspond with the supposition that acertain length of time must elapse to mediate opioid responsesand inhibit nociceptive impulses.5 The absence of a time intervalversus effect relationship in our study suggests that sucroseinduces a change in the patient’s behavioural state rather than apharmacological effect. Thus, our finding underlines the uncer-tainties concerning the working mechanisms of sucrose.2The PIPP-R was applied during the first 30 s following theheelstick, according to the instructions of the instrument, whileblood sampling lasted for a median of 2 min. This way, wefocused on pain related to the insertion of the lance. Accordingto the previous research, the effect of sucrose can persist 5–10 min after a painful stimulus.5 Since time interval aftersucrose administration did not affect relief of the acute painupon insertion of the lance, we expect that likewise it does notaffect relief of the pain related to the preceding squeezingeither. If faster onset of action is received, fewer sucrose dosesmay be needed, which would reduce the possible negative effectof sucrose on neurodevelopment.2Strictly adhering to a 2 min time interval1 was difficult, forexample, when an unstable infant needed time to recover beforethe heelstick procedure could start.The study design led to several limitations with uncontrollableconfounders that could possibly have influenced time intervaland pain intensity. Potential confounders were, for example, theintensity and number of times the heel was squeezed. Also, wedid not take into account the administration of analgesics andsedatives. In addition, the research nurse observed the total pro-cedure and thus was not blinded to the time interval. Still, thisis the first study that questioned if the worldwide implementa-tion of the 2 min time interval based on one study was indeedjustified. In future studies, blinded coders should score thePIPP-R from video recordings. A blinded randomised controlledtrial comparing different time intervals is underway.CONCLUSIONOur study does not justify the need to wait at least 2 min aftersucrose administration, but needs re-evaluation in a randomisedcontrolled trial. Shorter time intervals importantly improve effi-ciency in busy intensive care units. It is best to give sucrose with apacifier to stimulate sucrose-induced NNS to reduce pain responses.Acknowledgements Ko Hagoort is thanked for editorial assistance.Contributors NM conceptualized and designed the study and data collectioninstruments, carried out data collection and initial analyses, drafted the initialmanuscript and approved the final manuscript as submitted. SS conceptualized anddesigned the study, critically reviewed and revised the manuscript and approved thefinal manuscript as submitted. JvR supervised initial analyses, critically reviewed andrevised the manuscript and approved the final manuscript as submitted. IR criticallyreviewed and revised the manuscript and approved the final manuscript assubmitted. JvdA critically reviewed and revised the manuscript and approved thefinal manuscript as submitted. MvD conceptualized and designed the study,supervised data collection and initial analyses, critically reviewed and revised themanuscript and approved the final manuscript as submitted.Competing interests None declared.Ethics approval METC Erasmus MC.Provenance and peer review Not commissioned; externally peer reviewed.Data sharing statement All data are available upon request.Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/REFERENCES1 Stevens B, Yamada J, Lee GY, et al. Sucrose for analgesia in newborn infantsundergoing painful procedures. Cochrane Database Syst Rev 2013;1:CD001069.2 Committee on Fetus and Newborn and Section on Anesthesiology and PainMedicine. Prevention and management of procedural pain in the neonate: an update.Pediatrics 2016;137:e20154271.3 Blass EM, Shah A. Pain-reducing properties of sucrose in human newborns. ChemSenses 1995;20:29–35.4 Gibbins S, Stevens BJ, Yamada J, et al. Validation of the Premature Infant PainProfile-Revised (PIPP-R). Early Hum Dev 2014;90:189–93.5 Gibbins S, Stevens B. Mechanisms of sucrose and non-nutritive sucking in proceduralpain management in infants. Pain Res Manag 2001;6:21–8.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F167–F169. doi:10.1136/archdischild-2016-310841 F169Short research reportgroup.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from unnecessary?−−administration minutes after sucrose Waiting 2van den Anker and Monique van DijkNaomi Meesters, Sinno Simons, Joost van Rosmalen, Irwin Reiss, Johndoi: 10.1136/archdischild-2016-310841published online October 18, 20162017 102: F167-F169 originallyArch Dis Child Fetal Neonatal Ed  http://fn.bmj.com/content/102/2/F167Updated information and services can be found at: These include:References #BIBLhttp://fn.bmj.com/content/102/2/F167This article cites 5 articles, 2 of which you can access for free at: Open Accesshttp://creativecommons.org/licenses/by-nc/4.0/non-commercial. See: provided the original work is properly cited and the use isnon-commercially, and license their derivative works on different terms, permits others to distribute, remix, adapt, build upon this workCommons Attribution Non Commercial (CC BY-NC 4.0) license, which This is an Open Access article distributed in accordance with the CreativeserviceEmail alertingbox at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in theCollectionsTopic Articles on similar topics can be found in the following collections  (857)Infant health (928)Neonatal health (341)Neonatal and paediatric intensive care (1515)Child health (179)Pain (neurology) (55)Open accessNoteshttp://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:http://journals.bmj.com/cgi/reprintformTo order reprints go to:http://group.bmj.com/subscribe/To subscribe to BMJ go to:group.bmj.com on March 27, 2017 - Published by http://fn.bmj.com/Downloaded from 

English

Background Worldwide, oral sucrose is standard of care in many neonatal intensive care units to relieve procedural pain in neonates. This study aims to determine if time interval between sucrose administration and heelstick correlates with pain scores.  Methods Neonates were prospectively studied with variable time intervals and assessed with the Premature Infant Pain Profile-Revised (PIPP-R).  Results 150 neonates were included with a median gestational age of 30+6 (IQR 27+6–33+2) weeks and a median time interval of 72 (IQR 39–115) seconds between sucrose administration and heelstick. In multiple regression analysis, this time interval was not significantly related to the PIPP-R (B=0.004, 95% CI −0.005 to 0.013, p=0.37). Providing non-nutritive sucking combined with sucrose was significantly related to lower PIPP-R scores (B=−3.50, 95% CI −4.7 to −2.3, p\u3c0.001).  Conclusions Our study suggests that there is no need to wait 2 min after sucrose administration before a painful procedure. Sucrose-induced non-nutritive sucking shows a fast pain-relieving effect in neonates

Simons, Sinno

George Washington University: Health Sciences Research Commons (HSRC)

Himmelfarb Health Sciences Library, The George Washington UniversityHealth Sciences Research CommonsPediatrics Faculty Publications Pediatrics3-2017Waiting 2 minutes after sucroseadministration—unnecessary?Naomi MeestersSinno SimonsJoost van RosmalenIrwin ReissJohn van den AnkerGeorge Washington UniversitySee next page for additional authorsFollow this and additional works at: https://hsrc.himmelfarb.gwu.edu/smhs_peds_facpubsPart of the Critical Care Commons, Maternal and Child Health Commons, and the PediatricsCommonsThis Journal Article is brought to you for free and open access by the Pediatrics at Health Sciences Research Commons. It has been accepted forinclusion in Pediatrics Faculty Publications by an authorized administrator of Health Sciences Research Commons. For more information, pleasecontact hsrc@gwu.edu.APA CitationMeesters, N., Simons, S., van Rosmalen, J., Reiss, I., van den Anker, J., & van Dijk, M. (2017). Waiting 2 minutes after sucroseadministration—unnecessary?. ADC Fetal and Neonatal Edition, 102 (2). http://dx.doi.org/10.1136/archdischild-2016-310841AuthorsNaomi Meesters, Sinno Simons, Joost van Rosmalen, Irwin Reiss, John van den Anker, and Monique van DijkThis journal article is available at Health Sciences Research Commons: https://hsrc.himmelfarb.gwu.edu/smhs_peds_facpubs/1781Waiting 2 minutes after sucrose administration—unnecessary?Naomi Meesters,1 Sinno Simons,1 Joost van Rosmalen,2 Irwin Reiss,1John van den Anker,3,4,5 Monique van Dijk1,41Division of Neonatology,Department of Pediatrics,Erasmus MC–Sophia Children’sHospital, Rotterdam, TheNetherlands2Department of Biostatistics,Erasmus MC, Rotterdam, TheNetherlands3Division of Pediatric ClinicalPharmacology, Children’sNational Health System,Washington, USA4Intensive Care andDepartment of PediatricSurgery, Erasmus MC –SophiaChildren’s Hospital, Rotterdam,The Netherlands5Division of PaediatricPharmacology andPharmacometrics, UniversityChildren’s Hospital Basel,Basel, SwitzerlandCorrespondence toNaomi Meesters, Division ofNeonatology Department ofPediatrics, Erasmus MC–SophiaChildren’s Hospital,Wytemaweg 80, Rotterdam3015 CN, The Netherlands;n.meesters@erasmusmc.nlReceived 7 March 2016Revised 7 August 2016Accepted 8 August 2016To cite: Meesters N,Simons S, van Rosmalen J,et al. Arch Dis Child FetalNeonatal Ed PublishedOnline First: [please includeDay Month Year]doi:10.1136/archdischild-2016-310841ABSTRACTBackground Worldwide, oral sucrose is standard ofcare in many neonatal intensive care units to relieveprocedural pain in neonates. This study aims todetermine if time interval between sucrose administrationand heelstick correlates with pain scores.Methods Neonates were prospectively studied withvariable time intervals and assessed with the PrematureInfant Pain Profile-Revised (PIPP-R).Results 150 neonates were included with a mediangestational age of 30+6 (IQR 27+6–33+2) weeks and amedian time interval of 72 (IQR 39–115) secondsbetween sucrose administration and heelstick. In multipleregression analysis, this time interval was notsignificantly related to the PIPP-R (B=0.004, 95% CI−0.005 to 0.013, p=0.37). Providing non-nutritivesucking combined with sucrose was significantly relatedto lower PIPP-R scores (B=−3.50, 95% CI −4.7 to−2.3, p<0.001).Conclusions Our study suggests that there is no needto wait 2 min after sucrose administration before apainful procedure. Sucrose-induced non-nutritive suckingshows a fast pain-relieving effect in neonates.INTRODUCTIONOral administration of sucrose significantly reducesprocedural pain in newborns.1 It is most effectivewhen combined with non-nutritive sucking(NNS).1 This intervention is therefore recom-mended in international neonatal pain guidelines.2In most studies, sucrose is administered 2 minprior to the painful procedure.1 To our knowledge,only one study evaluated the effect of this timeinterval and found it optimal.3 Because this studyincluded healthy newborns only, we aimed to testwhether this conclusion also holds true for prema-ture or critically ill neonates.We hypothesised that pain scores for prematureor critically ill term neonates will be lowest when atime interval of approximately 2 min is used. Theaim of the study was to determine if the time inter-val between sucrose administration and heelstick iscorrelated with pain scores.METHODSThis prospective study was conducted fromSeptember 2014 to February 2015 at a level 3 neo-natal intensive care unit. Eligible for inclusion wereall preterm and critically ill term neonates with anindication for blood sampling by heelstick. Patientswere selected by convenience sampling and couldbe included only once. This study consisted of twoconsecutive parts, A and B. In part A, 100 heelstickprocedures were performed without any guidanceon time interval. In part B, the medical team wasinstructed to adhere to a 2 min time interval3during 50 heelstick procedures. This way, weexpected a large variation of time intervals and asufficient population to perform a regression ana-lysis. The institutional ethical review board waivedthe need for approval (MEC-2014-357).Data collectionThe procedure, starting with the commencement ofsucrose administration (T=0), was timed with astopwatch. The pacifier was gently applied into themouth and sucrose was administered inside thecheek. Without pressure, the nurse held the pacifierin place until the infant started to suck.Primary outcome was the pain score obtainedwith the validated Premature Infant PainProfile-Revised (PIPP-R),4 applied during the first30 s after the heelstick. A score <7 suggests no orlittle pain, 7–12 slight-to-moderate pain and scores>12 are thought to reflect moderate-to-severe pain.All assessments were performed by a research nurse(NM) trained to score the PIPP-R (linearlyweighted kappa compared with a trained neonat-ologist=0.85). If one of the PIPP-R items could notbe assessed, a proportional score was calculated bymultiplying the total score by 7/6.What is already known on this topic?▸ Administration of sucrose to neonates prior toa heelstick procedure significantly reduces pain.▸ Sucrose is most effective in combination withnon-nutritive sucking.▸ Most studies and guidelines recommendadministering sucrose at least 2 min before apainful procedure.What this study adds?▸ No correlation was found between painintensity and time interval betweenadministration of sucrose and the heelstickprocedure, suggesting that 2 min waiting isunnecessary.▸ Sucrose-induced non-nutritive sucking was theonly variable significantly correlated with areduction in pain scores.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F3. doi:10.1136/archdischild-2016-310841 F1Short report ADC-FNN Online First, published on October 18, 2016 as 10.1136/archdischild-2016-310841Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence. group.bmj.com on December 28, 2016 - Published by http://fn.bmj.com/Downloaded from Other variables recorded were: gestational age, postnatal age,NNS at time of the prick, number of doses, total volume ofsucrose administered, size of the lance (BD MicrotainerQuickheel Lancet Preemie or Infant), number of heel squeezesand number of pricks needed. All heelsticks were performed bytrained lab personnel, while a nurse or healthcare assistant pro-vided facilitated tucking.Our clinical treatment protocol prescribed the use of sucrose24% with a maximum volume of 0.5 or 2.0 cc in patients withbodyweight <1000 or >1000 g, respectively.Data analysisThe association between PIPP-R and the time interval was esti-mated with Spearman’s rank correlation coefficient. Multiplelinear regression analysis with PIPP-R total score as outcomevariable and the time interval in seconds as predictor variablewas applied. The relevant covariates postnatal age in days, NNS,total volume of sucrose in millilitres and gender were alsoentered into the regression model. Gestational age was notincluded because it is included in the PIPP-R score. A sensitivityanalysis was performed by replacing time interval in secondswith study phase (part A or part B) in the regression model.RESULTSOne hundred and fifty patients were included with a gestationage between 24+1 and 42+1 weeks. One patient in part Breceived a second dose of sucrose during the time interval andwas excluded from the analysis. Table 1 shows backgroundcharacteristics and main study parameters.The correlation between PIPP-R and time interval was 0.11(95% CI −0.05 to 0.27, p=0.17). Large variations in both timeinterval and PIPP-R scores were found (figure 1).Multivariate analysisIn multiple regression analysis, too, the time interval was notsignificantly associated with PIPP-R scores, with an estimatedassociation of 0.004 (95% CI −0.005 to 0.013, p=0.37) pointson the PIPP-R per second. NNS was correlated with an averagedecrease in mean PIPP-R score of 3.5 points (95% CI −4.7 to−2.3, p<0.001). Replacing time interval with study phase in theregression model, the PIPP-R score was on average 0.99 pointshigher in part B (95% CI −0.29 to 2.26, p=0.13). Postnatalage, gender and volume of sucrose were not significantly corre-lated to PIPP-R scores.DISCUSSIONWe found that in the studied hospitalised newborns, theheelstick-related pain intensity was not correlated with thelength of the time interval between the administration ofsucrose and the heelstick. This is in contradiction with the onlyother comparable study, which led to the worldwide clinicalimplementation of a 2 min time interval.3 In that study,Table 1 Patients’ background characteristics and main study parameters (N=149)Variables Part A (N=100) Part B (N=49) p ValueBoy/girl; N (%) 61 (61)/39 (39) 24 (49)/25 (51) 0.16Gestational age in weeks+days 30+6 (28+5–33+2) 30+6 (26+6–33+2) 0.26Birth weight in grams 1483 (1158–2015) 1280 (888–1950) 0.18Postnatal age in days 4 (2–8) 5 (2–10) 0.11Time interval in seconds 48 (31–79) 127 (107–153) <0.001Non-nutritive sucking; N (%) 48 (48) 23 (47) 0.90Patients with one dose; N (%)* 98 (98%) 44 (90%) 0.27Total volume of sucrose in mL 0.5 (0.5–0.75) 0.5 (0.5–0.75) 0.78Size of the lance: preemie; N (%)/infant; N (%) 12 (12)/88 (88) 7 (14)/42 (86) 0.69Unable to score nasolabial furrow; N (%) 44 (44) 30 (61) 0.05Duration of procedure in seconds 112 (59–191) 154 (97–257) 0.014Number of squeezes 17 (8–28) 22 (13–36) 0.04Analgesics/sedatives; N (%)† 5 (5) 5 (10) 0.23PIPP-R 6 (0–9) 7 (2–9) 0.22Data are presented as median (IQR) for all continuous variables. Part A and part B data were compared using the χ2 test for categorical variables and the Mann-Whitney U test forcontinuous variables.*Patients who received one dose during the total procedure (from sucrose administration until the end of the blood collection).†Patients who received continuous or intermittent morphine/fentanyl and/or midazolam during or <3 hours before the heelstick procedure.PIPP-R, Premature Infant Pain Profile-Revised.Figure 1 Correlation between time interval after sucroseadministration and Premature Infant Pain Profile-Revised (PIPP-R) score(N=149). Reference lines are at the time interval of 120 s and thecut-off score for PIPP-R of 7 or higher. Markers differentiate betweenyes/no non-nutritive sucking.F2 Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F3. doi:10.1136/archdischild-2016-310841Short reportgroup.bmj.com on December 28, 2016 - Published by http://fn.bmj.com/Downloaded from however, the primary outcome was ‘crying’ and only healthynewborns were included. We used the validated PIPP-R,4 whichwas not yet available at the time of the previous study andincluded premature and critically ill term neonates.Our finding does not correspond with the supposition that acertain length of time must elapse to mediate opioid responsesand inhibit nociceptive impulses.5 The absence of a time intervalversus effect relationship in our study suggests that sucroseinduces a change in the patient’s behavioural state rather than apharmacological effect. Thus, our finding underlines the uncer-tainties concerning the working mechanisms of sucrose.2The PIPP-R was applied during the first 30 s following theheelstick, according to the instructions of the instrument, whileblood sampling lasted for a median of 2 min. This way, wefocused on pain related to the insertion of the lance. Accordingto the previous research, the effect of sucrose can persist 5–10 min after a painful stimulus.5 Since time interval aftersucrose administration did not affect relief of the acute painupon insertion of the lance, we expect that likewise it does notaffect relief of the pain related to the preceding squeezingeither. If faster onset of action is received, fewer sucrose dosesmay be needed, which would reduce the possible negative effectof sucrose on neurodevelopment.2Strictly adhering to a 2 min time interval1 was difficult, forexample, when an unstable infant needed time to recover beforethe heelstick procedure could start.The study design led to several limitations with uncontrollableconfounders that could possibly have influenced time intervaland pain intensity. Potential confounders were, for example, theintensity and number of times the heel was squeezed. Also, wedid not take into account the administration of analgesics andsedatives. In addition, the research nurse observed the total pro-cedure and thus was not blinded to the time interval. Still, thisis the first study that questioned if the worldwide implementa-tion of the 2 min time interval based on one study was indeedjustified. In future studies, blinded coders should score thePIPP-R from video recordings. A blinded randomised controlledtrial comparing different time intervals is underway.CONCLUSIONOur study does not justify the need to wait at least 2 min aftersucrose administration, but needs re-evaluation in a randomisedcontrolled trial. Shorter time intervals importantly improve effi-ciency in busy intensive care units. It is best to give sucrose with apacifier to stimulate sucrose-induced NNS to reduce pain responses.Acknowledgements Ko Hagoort is thanked for editorial assistance.Contributors NM conceptualized and designed the study and data collectioninstruments, carried out data collection and initial analyses, drafted the initialmanuscript and approved the final manuscript as submitted. SS conceptualized anddesigned the study, critically reviewed and revised the manuscript and approved thefinal manuscript as submitted. JvR supervised initial analyses, critically reviewed andrevised the manuscript and approved the final manuscript as submitted. IR criticallyreviewed and revised the manuscript and approved the final manuscript assubmitted. JvdA critically reviewed and revised the manuscript and approved thefinal manuscript as submitted. MvD conceptualized and designed the study,supervised data collection and initial analyses, critically reviewed and revised themanuscript and approved the final manuscript as submitted.Competing interests None declared.Ethics approval METC Erasmus MC.Provenance and peer review Not commissioned; externally peer reviewed.Data sharing statement All data are available upon request.Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/REFERENCES1 Stevens B, Yamada J, Lee GY, et al. Sucrose for analgesia in newborn infantsundergoing painful procedures. Cochrane Database Syst Rev 2013;1:CD001069.2 Committee on Fetus and Newborn and Section on Anesthesiology and PainMedicine. Prevention and management of procedural pain in the neonate: an update.Pediatrics 2016;137:e20154271.3 Blass EM, Shah A. Pain-reducing properties of sucrose in human newborns. ChemSenses 1995;20:29–35.4 Gibbins S, Stevens BJ, Yamada J, et al. Validation of the Premature Infant PainProfile-Revised (PIPP-R). Early Hum Dev 2014;90:189–93.5 Gibbins S, Stevens B. Mechanisms of sucrose and non-nutritive sucking in proceduralpain management in infants. Pain Res Manag 2001;6:21–8.Meesters N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F3. doi:10.1136/archdischild-2016-310841 F3Short reportgroup.bmj.com on December 28, 2016 - Published by http://fn.bmj.com/Downloaded from unnecessary?−−administration minutes after sucrose Waiting 2van den Anker and Monique van DijkNaomi Meesters, Sinno Simons, Joost van Rosmalen, Irwin Reiss, John published online October 18, 2016Arch Dis Child Fetal Neonatal Ed  http://fn.bmj.com/content/early/2016/10/18/archdischild-2016-310841Updated information and services can be found at: These include:References #BIBLhttp://fn.bmj.com/content/early/2016/10/18/archdischild-2016-310841This article cites 5 articles, 2 of which you can access for free at: Open Accesshttp://creativecommons.org/licenses/by-nc/4.0/non-commercial. See: provided the original work is properly cited and the use isnon-commercially, and license their derivative works on different terms, permits others to distribute, remix, adapt, build upon this workCommons Attribution Non Commercial (CC BY-NC 4.0) license, which This is an Open Access article distributed in accordance with the CreativeserviceEmail alertingbox at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in theCollectionsTopic Articles on similar topics can be found in the following collections  (857)Infant health (928)Neonatal health (341)Neonatal and paediatric intensive care (1515)Child health (179)Pain (neurology) (54)Open accessNoteshttp://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:http://journals.bmj.com/cgi/reprintformTo order reprints go to:http://group.bmj.com/subscribe/To subscribe to BMJ go to:group.bmj.com on December 28, 2016 - Published by http://fn.bmj.com/Downloaded from 

Undetermined

https://repub.eur.nl/pub/93902/REPUB_93902_OA.pdf

Waiting 2 minutes after sucrose administration-unnecessary?

Abstract

Similar works

Full text

Available Versions

Erasmus University Digital Repository

Crossref

NARCIS

Erasmus University Digital Repository

Erasmus University Digital Repository

EUR Research Repository

George Washington University: Health Sciences Research Commons (HSRC)

EUR Research Repository