Premature Infant Pain Profile-Revised Scores Research Articles

Effect of parental touch on relieving acute procedural pain in neonates and parental anxiety (Petal): a multicentre, randomised controlled trial in the UK

Touch interventions such as massage and skin-to-skin contact relieve neonatal pain. The Parental touch trial (Petal) aimed to assess whether parental stroking of their baby before a clinically required heel lance, at a speed of approximately 3 cm/s to optimally activate C-tactile nerve fibres, provides effective pain relief. Petal is a multicentre, randomised, parallel-group interventional superiority trial conducted in the John Radcliffe Hospital (Oxford University Hospitals NHS Foundation Trust, Oxford, UK) and the Royal Devon and Exeter Hospital (Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK). Neonates without neurological abnormalities who were born at 35 weeks gestational age or more and required a blood test via a heel lance in the first week of life were randomly assigned (1:1) to receive parental touch for 10 s either before (intervention group) or after (control group) the clinically required heel lance. Randomisation was managed at the Oxford site using a web-based minimisation algorithm with allocation concealment. The primary outcome measure was the magnitude of noxious-evoked brain activity in response to the heel lance measured with electroencephalography (EEG). Secondary outcome measures were Premature Infant Pain Profile-Revised (PIPP-R) score, development of tachycardia, and parental anxiety score. For all outcomes, the per-protocol effect was estimated via complier average causal effect analysis on the full analysis set. The trial is registered on ISRCTN (ISRCTN14135962) and ClinicalTrials.gov (NCT04901611). Between Sept 1, 2021, and Feb 7, 2023, 159 parents were approached to participate in the study, and 112 neonates were included. 56 neonates were randomly assigned to the intervention group of parental stroking before the heel lance and 56 to the control group of parental stroking after the heel lance. The mean of the magnitude of the heel lance-evoked brain activity was 0·85 arbitrary units (a.u.; SD 0·70; n=39; a scaled magnitude of 1 a.u. represents the expected mean response to a heel lance in term-aged neonates) in the intervention group and 0·91 a.u. (SD 0·76; n=43) in the control group. Therefore, the primary outcome did not differ significantly between groups, with a mean difference of -0·11 a.u. (lower in intervention group; SD 0·77; 95% CI -0·42 to 0·20; p=0·38; n=82). No significant difference was observed across secondary outcomes. The PIPP-R difference in means was 1·10 (higher in intervention group, 95% CI -0·42 to 2·61; p=0·15; n=100); the odds ratio of becoming tachycardic was 2·08 (95% CI 0·46 to 9·46; p=0·34, n=105) in the intervention group with reference to the control group; and the difference in parental State-Trait Anxiety Inventory-State score was -0·44 (higher in control group; SD 6·85; 95% CI -2·91 to 2·02; p=0·72; n=106). One serious adverse event (desaturation) occurred in a neonate randomly assigned to the control group, which was not considered to be related to the study. Parental stroking delivered at an optimal speed to activate C-tactile fibres for a duration of 10 s before the painful procedure did not significantly change neonates' magnitude of pain-related brain activity, PIPP-R score, or development of tachycardia. The trial highlighted the challenge of translating an experimental researcher-led tactile intervention into a parent-led approach, and the value of involving parents in their baby's pain management. Wellcome Trust and Bliss.

The effect of oscillometric blood pressure measurement on pain response in preterm infants.

Preterm neonates are exposed to many painful procedures in neonatal intensive care units. This study aims to evaluate the effect of oscillometric blood pressure (BP) measurement on pain response in preterm infants. This prospective study was performed over 4 months in a level III neonatal intensive care unit. Premature neonates whose gestational age was <34 weeks and postmenstrual age <36 weeks were included if they had no systemic diseases. BP measurement was performed on the right arm. The Premature Infant Pain Profile-Revised (PIPP-R) scores were evaluated three times before, during, and 10 min after BP measurement. During the 5-month period, 100 preterm neonates (53 male infants) were included in the study. Median birth weight and gestational age of the infants were 1148 (IQR: 1015-1300) g and 28 (IQR: 27-30) weeks, respectively. PIPP-R scores were found to be ≥7 in 34% of neonates. PIPP-R scores increased during BP measurement and decreased after. Our results demonstrated that oscillometric BP measurement which is generally accepted as a non-invasive tool for monitoring can produce mild pain in premature neonates of postmenstrual age <36 weeks.

The effectiveness of repeated sucrose for procedural pain in neonates in a longitudinal observational study.

To determine the analgesic effectiveness of repeated sucrose administration for skin-breaking (SB) procedures over the Neonatal Intensive Care Unit (NICU) hospitalization of preterm infants. Longitudinal observational study, conducted in four level III Canadian NICUs. Eligible infants were <32 weeks gestational age at birth, and <10 days of life at enrollment. Infants received 24% sucrose (0.12 ml) prior to all painful procedures. The Premature Infant Pain Profile - Revised (PIPP-R) was used at 30 and 60 seconds after a medically-required SB procedure as soon as possible after enrollment and weekly up to three additional times for scheduled procedures. 172 infants (57.3% male, gestational age 28.35 (±2.31) weeks) were included. The mean 30 s PIPP-R scores were 6.11 (±3.68), 5.76 (±3.41), 6.48 (±3.67), and 6.81 (±3.69) respectively; there were no statistically significant interactions of study site by time (p = 0.31) or over time (p = 0.15). At 60 s, mean PIPP-R scores were 6.05 (±4.09), 5.74 (±3.67), 6.19 (±3.7), and 5.99 (±3.76) respectively; there were no study site by time interactions (p = 0.14) or differences over time (p = 0.52). There was a statistically significant site difference in the effectiveness of sucrose at 30 and 60 seconds (p < 0.01). Consistently low PIPP-R scores following a skin-breaking procedure indicated that the analgesic effectiveness of the minimal dose of sucrose was sustained over time in the NICU. Further research is required to determine the optimal combination of sucrose and other pain management strategies to improve clinical practice and the impact of consistent use of repeated use of sucrose on neurodevelopment.

Efficacy of Oral Dextrose versus Acetaminophen versus Placebo on Pain Relief during Retinopathy of Prematurity Eye Examinations: A Randomized, Double-Blind Controlled Clinical Trial.

To assess the effect of oral dextrose versus acetaminophen versus placebo in pain relief in retinopathy of prematurity (ROP) examination. In this prospective randomized, double-blind controlled clinical trial study performed in the ophthalmology clinic of Shafa Hospital (referral hospital for eye disease), Kerman, Iran, 105 premature neonates with birth weight ≤2000 g and gestational age between 28 and 34 weeks were studied. Pain score measurement with Premature Infant Pain Profile-Revised (PIPP-R) during ROP examination in three intervention groups, acetaminophen group (15 mg/kg oral acetaminophen), dextrose group (one cc of oral dextrose 50%), and placebo group (one cc of distilled water), was done. Out of 105 infants, 33 infants received acetaminophen drops, 35 infants received dextrose drops, and 37 infants received placebo. The mean pain score of the group receiving acetaminophen was 11.39, dextrose 12.17, and placebo 11.54. The acetaminophen group had a lower average PIPP-R score. This difference was not significant between the three groups (P = 0.38). Acetaminophen and dextrose in comparison with distilled water did not show a significant difference in reducing neonatal pain during ROP examinations. However, the PIPP-R score in the acetaminophen group was lower compared to the other groups.

Effects of white noise on procedural pain-related cortical response and pain score in neonates: A randomized controlled trial

ObjectivesTo evaluate the effects of white noise on pain-related cortical response, pain score, and behavioral and physiological parameters in neonates with procedural pain. MethodsA double-blind, randomized controlled trial was conducted. Sixty-six neonates from the Neonatal Intensive Care Unit in a university-affiliated general hospital were randomly assigned to listen to white noise at 50 dB (experimental group) or 0 dB (control group) 2 min before radial artery blood sampling and continued until 5 min after needle withdrawal. Pain-related cortical response was measured by regional cerebral oxygen saturation (rScO2) monitored with near-infrared spectroscopy, and facial expressions and physiological parameters were recorded by two video cameras. Two assessors scored the Premature Infant Pain Profile-Revised (PIPP-R) independently when viewing the videos. Primary outcomes were pain score and rScO2 during arterial puncture and 5 min after needle withdrawal. Secondary outcomes were pulse oximetric oxygen saturation (SpO2) and heart rate (HR) during arterial puncture, and duration of painful expressions. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2200055571). ResultsSixty neonates (experimental group, n = 29; control group, n = 31) were included in the final analysis. The maximum PIPP-R score in the experimental and control groups was 12.00 (9.50, 13.00), 12.50 (10.50, 13.75), respectively (median difference −0.5, 95% CI −2.0 to 0.5), and minimum rScO2 was (61.22 ± 3.07)%, (61.32 ± 2.79)%, respectively (mean difference −0.325, 95% CI −1.382 to 0.732), without significant differences. During arterial puncture, the mean rScO2, HR, and SpO2 did not differ between groups. After needle withdrawal, the trends for rScO2, PIPP-R score, and facial expression returning to baseline were different between the two groups without statistical significance. ConclusionThe white noise intervention did not show beneficial effects on pain-related cortical response as well as pain score, behavioral and physiological parameters in neonates with procedural pain.

Efficacy and Safety of Multimodal Analgesic Therapy to Prevent Pain during Screening for Retinopathy of Prematurity

Background: Premature infants admitted to the Neonatal Intensive Care Unit are exposed on average to 14 painful procedures per day, as the retinopathy of prematurity screening. Neonatal pain is often underestimated and insufficiently treated, but there are short-term and long-term deleterious effects in premature infants exposed to repetitive pain. Since premature infants cannot verbalize the pain, the use of validated measurement tools is recommended for its evaluation and measurement of pain. The aim of this study was to determine the usefulness of a multimodal analgesic therapy proposed, to prevent pain in premature infants under retinal evaluation. Methods: We carried out a blinded, randomized clinical trial. Premature infants ≤ 34 weeks of gestational age received standard therapy (one drop of tetracaine in each eye) or proposed multimodal analgesic therapy (paracetamol oral at 15 mg/ kg, 30 minutes prior to retinal evaluation, and intranasal fentanyl 2 μg/kg, 5 minutes prior to retinal screening, as well as warm containment and non-nutritional suction. The primary outcome was the score of Premature Infant Pain Profile-Revised (PIPP-R). The application of the score PIPP-R was performed 35 minutes before the procedure, during, and 15 minutes after the procedure. Results: There were no significant differences in PIPP-R score prior to the retinal screening, however, during the retinal evaluation the PIPP-R score was significantly lower in the proposed multimodal therapy group (14.0 vs 6.5, p=0.0001); and 15 minutes after the procedure, score remained lower in the proposed multimodal therapy group (2.9 vs 1.6 p=0.0001). No adverse effects were documented in neither group. In conclusion, retinal screening cause’s deep pain, the topical tetracaine is insufficient to mitigate it. The proposed multimodal therapy can be useful to prevent the pain caused by the procedure and it does not cause adverse effects.

Breast milk vs 24% sucrose for procedural pain relief in preterm neonates: a non-inferiority randomized controlled trial.

To compare the pain scores between the two groups, breast milk (BM) and 24% sucrose, in preterm neonates undergoing automated heel lance for the blood draw. The study is designed as a randomized, single-blinded, non-inferiority trial. Infants born between 30 1/7weeks and 36 6/7 weeks of gestation were randomly assigned to receive either 24% sucrose or expressed BM. The Premature Infant Pain Profile-Revised (PIPP-R) was utilized to provide pain scores. No differences were noted in the baseline characteristics between the two groups. The quantile regression estimates for PIPP-R scores during the procedure were statistically non-significant at all percentile levels of distribution (50%ile coefficient 0, 95% CI -0.49 to 0.49). We conclude that BM is not inferior to 24% sucrose in providing analgesia during heel lance in moderate and late preterm infants. This trial was registered at www. gov (identifier NCT04898881).

Evaluation of pain and physiological stress during targeted neonatal echocardiography.

Targeted neonatal echocardiography (Tn-Echo) is a non-invasive examination which may cause pain/discomfort and physiological instability in neonates, but there is little evidence for the same. We conducted this study to evaluate whether targeted neonatal echocardiography causes pain or physiological stress to newborn infants. This cross-sectional study was conducted in a tertiary level NICU. Neonates undergoing targeted neonatal echocardiography were enrolled in this study. Pain was assessed using Premature Infant Pain Profile-Revised (PIPP-R) score before, during and after targeted neonatal echocardiography examination. Heart rate, oxygen saturation, perfusion index and blood pressure were also recorded at the same time points. A total of 88 neonates were enrolled. Mean (SD) PIPP-R score during Tn-Echo was 8.18 (2.6) versus 3.60 (1.8) and 4.24 (2.0) before and after respectively (p value < 0.001). Heart rate and respiratory rate were significantly higher during targeted neonatal echocardiography; oxygen saturation and perfusion index were significantly lower during targeted neonatal echocardiography. Preterm infants had higher PIPP-R score compared to term neonates before, during and after the Tn-Echo [8.76 (2.4) versus 6.81 (2.4); p value < 0.001]. Targeted neonatal echocardiography causes significant pain/discomfort and physiological instability in neonates.

Avoiding use of lid speculum and indentation reduced infantile stress during retinopathy of prematurity examinations.

To study the safety and efficacy of indirect ophthalmoscopy with (Sp) or without (speculum free, SpF) the use of lid speculum and scleral indentation for retinopathy of prematurity (ROP) screening. In this crossover randomized controlled trial, preterm infants received either the Sp on their first and the SpF technique on their second examination a week later or vice versa. Video recordings of the infants' reactions were assessed by two observers, using Premature Infant Pain Profile-Revised score and the crying score of the Bernese Pain Scale for Neonates. Fundoscopy adequacy, its duration and adverse events within the first 24 hr postscreening were also recorded. Thirty-seven infants with median (interquartile range) gestational age of 28.7 (28.0, 30.2) weeks and mean (standard deviation, SD) birth weight 1225 (377) grams were enrolled. The mydriasis-induced stress was similar between the Sp and SpF exam (mean difference [MD]: 0.78, 95% confidence interval [CI]: -0.83, 2.38; p = 0.33). The stress induced by fundoscopy (MD: 4.98, 95% CI: 3.58, 6.37; p < 0.001) and examination overall (MD: 2.32, 95% CI: 0.96, 3.67; p = 0.001) were higher in the Sp than in the SpF exam, and so was the crying score during fundoscopy (MD: 1.31, 95% CI: 1.06, 1.56; p < 0.001). Adverse events in the two groups were similar (p = 0.13). Fundoscopy was adequate in identifying the absence of treatment-requiring ROP in all cases, and lasted longer in the Sp than in the SpF exam (p < 0.001). Our study suggests that the use of speculum and indentation should be reserved for the few cases where fundus visualization is insufficient for excluding the presence of severe ROP.

Evaluation of the Premature Infant Pain Profile-Revised (PIPP-R) e-Learning Module: Immediate and Sustained Competency.

Electronic health (e-health) learning is a potential avenue to educate health professionals about accurately using infant pain assessment tools, although little is known about the impact of e-health interventions on clinical competence. To evaluate whether an e-health learning module for teaching the accurate use of the Premature Infant Pain Profile-Revised (PIPP-R) pain assessment tool results in immediate and sustained competency to assess infant pain. Neonatal intensive care unit (NICU) nurses who participated in a larger study across 2 tertiary NICUs in Canada examining the implementation and clinical utility of the PIPP-R e-learning module completed 2 follow-up evaluations at 1 week and 3 months. Participants were asked to view a video recording of an infant undergoing a painful procedure and to assess the infant's pain intensity response using the PIPP-R measure. Immediate and sustained competency was assessed via interrater consensus of participant-reported PIPP-R scores compared with those of an experienced trained coder. Of the 25 eligible nurses, 22 completed 1-week and 3-month follow-up evaluations. At the 1-week follow-up, 84% of nurses scored the video accurately compared with 50% at 3 months. Behavioral pain indicators were more likely to be scored incorrectly than physiological indicators. Follow-up training after completion of the initial e-learning module training may improve competency related to the clinical use of the PIPP-R tool to assess infant pain over time. Additional study regarding the need and timing of e-health training to optimize sustained competency in infant pain assessment is warranted.

The influence of breastfeeding on cortical and bio-behavioural indicators of procedural pain in newborns: Findings of a randomized controlled trial

AimsThe objective of this study was to compare the influence of breastfeeding and 24% oral sucrose on pain-related electrophysiologic activity, bio-behavioural pain scores, physiologic recovery, and adverse events during heel lance. Study designSingle-blind randomized controlled trial. Subjects39 full-term infants were randomized to receive breastfeeding or 0.24 mL of 24% oral sucrose plus offered non-nutritive sucking 2 min prior to heel lance. Outcome measuresThe primary outcome of pain-related potential was recorded on electroencephalogram. Secondary outcomes included Premature Infant Pain Profile – Revised (PIPP-R) score, physiologic recovery, and adverse events. Data were analyzed per protocol (ClinicalTrials.gov: NCT03272594). ResultsBetween November 2017 and January 2019, 20 infants were randomized to breastfeeding and 19 infants to receive oral sucrose. Infants who were breastfeeding had an appreciably smaller, yet not statistically different (F[1,15.9] = 0.58, p = 0.64, SE = 11.79), amplitude pain-related potential (peak amplitude 0.29 μV) following heel lance compared to infants who received oral sucrose (peak amplitude 8.97 μV). Mean PIPP-R scores were not statistically significantly different between groups following heel lance, however, they were indicative of low pain across groups. Mean time in seconds to physiologic recovery was faster in breastfeeding infants (M = 17.5, SD = 31.1) compared to oral sucrose (M = 70.8, SD = 144.3). There were no safety concerns. DiscussionBreastfeeding and oral sucrose both reduce bio-behavioural responses to pain, however, may differentially modulate pain response in the infant brain. Further research to understand the neurophysiologic effects of these interventions during acute painful procedures is needed.

The newborn infant parasympathetic evaluation index for acute procedural pain assessment in preterm infants.

Accurate assessments of pain in hospitalized preterm infants present a major challenge in improving the short- and long-term consequences associated with painful experiences. We evaluated the ability of the newborn infant parasympathetic evaluation (NIPE) index to detect acute procedural pain in preterm infants. Different painful and stressful interventions were prospectively observed in preterm infants born at 25 + 0 to 35 + 6 weeks gestation. Pain responses were measured using the composite Premature Infant Pain Profile Revised (PIPP-R) scale, the NIPE index, and skin conductance responses (SCR). Outcome measures were correlations between the NIPE index, the PIPP-R score, and the SCR. Sensitivity/specificity analyses tested the accuracy of the NIPE index and SCR. Two hundred and fifty-four procedures were recorded in 90 preterm infants. No significant correlation was found between PIPP-R and the NIPE index. PIPP-R and SCR were positively correlated (r = 0.27, P < 0.001), with stronger correlations for painful procedures (r = 0.68, P < 0.001) and especially for skin-breaking procedures (r = 0.82, P < 0.001). The NIPE index and SCR had high sensitivity and high negative predictive values to predict PIPP-R > 10, especially for skin-breaking painful procedures. We found no significant correlation between the NIPE index and PIPP-R during routine painful or stressful procedures in preterm infants. Exposure to repetitive pain can lead to neurodevelopmental sequelae. Behavior-based pain scales have limited clinical utility, especially for preterm infants. New devices for monitoring physiological responses to pain have not been validated sufficiently in preterm infants. This study found that the NIPE index was not significantly correlated to the validated PIPP-R scale during acute procedural pain. Secondary analysis of this study showed that NIPE index and SCRs may help to exclude severe pain in preterm infants. In clinical practice, measurements of physiological parameters should be combined with behavior-based scales for multidimensional pain assessments.

Intranasal fentanyl for pain management during screening for retinopathy of prematurity in preterm infants: a randomized controlled trial.

To study the efficacy of intranasal fentanyl as an adjunct for pain management during screening for retinopathy of prematurity (ROP) in preterm infants. In this single center, double blinded, randomized controlled trial, preterm neonates between 30 and 34 weeks postmenstrual age received either intranasal fentanyl (2 mcg/kg) or intranasal normal saline through a mucosal atomization device 5 min prior to the first ROP-screening examination. Both the groups received standard pain relief strategies (oral sucrose, 0.5% proparacaine eye drops and physical containment). The primary outcome was premature infant pain profile-revised (PIPP-R) score during the screening. A total of 111 infants were enrolled. PIPP-R score during the retinal examination was significantly lower in the fentanyl group (8.3 versus 11.5, mean difference: 3.2 (2.46-4.06), P < 0.001). There was no significant difference in the incidence of adverse effects. Intranasal fentanyl significantly reduced the pain associated with retinal examination without increasing the risk of respiratory depression. Large RCTs are required to verify the efficacy and safety of intranasal fentanyl for acute procedural pain in neonates. CTRI/2017/12/011016.

Neurophysiological and behavioral measures of pain during neonatal hip examination.

IntroductionThe aim of this study was to test the hypothesis that neonatal hip examination causes pain in newborns. Pain assessment using instruments such as the Premature Infant Pain Profile‐Revised (PIPP‐R) scale is recommended, but recently physiological and neurophysiological measures, for example, near‐infrared spectroscopy (NIRS) and galvanic skin response (GSR), have been used as well.MethodsHeart auscultation and hip examination were performed, and the response of the newborn was registered by NIRS optodes, GSR electrodes, and a pulse oximeter probe attached to the infant. The face of the newborn was filmed. Heart auscultation was used as a nonpainful reference.ResultsThe pain scores for hip examination were higher than for the heart auscultation. Near‐infrared spectroscopy showed a significant higher increase from baseline in oxygenated hemoglobin (HbO2) on both sides of the cortex at hip examination compared with at heart auscultation (P = .011 and P = .017). Mean PIPP‐R scores for the hip examination compared with heart auscultation increased from 3.0 to 8.1 (P = .000). The GSR analyses of hip examination compared with heart auscultation showed a significant increase in area under small peaks during the hip examination (P = .016), however, not when measured in peaks per second (P = .104). Interrater reliability was calculated for the NIRS interpretations, with an intraclass correlation coefficient (ICC) range of 0.93‐1.0 (P = .000).DiscussionPain in newborns can have negative consequences, and pain prevention and treatment are therefore important. We conclude that neonatal hip examinations are painful and that the pain should be treated, for example, with oral sweet solution. This is a change from present routines during neonatal hip examination and is hoped to lead to a change in national guidelines.

Oral morphine analgesia for preventing pain during invasive procedures in non-ventilated premature infants in hospital: the Poppi RCT

Background Identifying better pain management strategies for painful procedures performed in neonatal care is a clinical priority. Retinopathy of prematurity screening and heel-lance blood tests are essential clinical procedures, but adequate pain relief is not currently provided because of a lack of evidence-based analgesia. Morphine provides effective analgesia in older children and adults, but efficacy in infants is controversial. Morphine is, however, commonly used intravenously for sedation in ventilated infants. Objective The primary objective was to investigate whether or not a single 100 µg/kg morphine sulphate dose administered orally prior to painful clinical procedures provides effective analgesia. Design Single-centre, prospective, randomised controlled trial. Setting John Radcliffe Hospital, Oxford, UK. Participants Thirty-one infants of 34–42 weeks’ gestational age, requiring a heel lance and retinopathy of prematurity screening on the same test occasion. Interventions The study interventions were 100 µg/kg of oral morphine sulphate (intervention arm) or placebo (control arm) 1 hour before the clinically required procedures. Main outcome measures There were two co-primary outcomes: Premature Infant Pain Profile-Revised score (a higher score implies more nociceptive processing) during the 30-second period after retinopathy of prematurity screening, and the magnitude of noxious-evoked brain activity (a higher activity implies more nociceptive processing) following the heel lance. Physiological stability and safety were secondary outcomes. Results After 31 participants were randomised (30 studied and one withdrew), the predefined safety stopping boundary was passed as 3 of the 15 infants who received morphine had apnoeas requiring resuscitation with non-invasive positive-pressure ventilation in the 24 hours after drug administration, compared with 0 of the 15 infants who received placebo [difference in proportion 0.2, 80% confidence interval (adjusted to allow for planned multiple analyses) 0.05 to 1.00; p = 0.085]. The trial was therefore stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. There was no significant difference between the trial arms for either primary outcome (Premature Infant Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – morphine: 11.1 ± 3.2; Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – placebo: 10.5 ± 3.4; mean difference in Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening score 0.5, 95% confidence interval –2.0 to 3.0, p = 0.66; noxious-evoked brain activity following heel lancing median activity – morphine: 0.99, interquartile range 0.40–1.56; noxious-evoked brain activity following heel lancing median activity – placebo: 0.75, interquartile range 0.33–1.22; and median difference in noxious-evoked brain activity following heel lancing 0.25, 95% confidence interval –0.16 to 0.80, p = 0.25). Limitations The trial lacked power for the primary outcome measures because of early cessation. However, there was a trend across modalities favouring placebo, suggesting that it was unlikely that a clinically significant analgesic benefit would have been detected in the original proposed sample of 156 infants. Conclusions The administration of 100 µg/kg of oral morphine to non-ventilated premature infants has the potential for harm without analgesic benefit. Oral morphine is not recommended for retinopathy of prematurity screening, and caution is strongly advised if this is being considering for other acute painful procedures in non-ventilated premature infants. Future work Further clinical trials are essential to ascertain effective pain management for retinopathy of prematurity screening. Using multimodal measures with detailed physiological recordings provides a rigorous approach to assess analgesic efficacy and adverse effects, leading to greater mechanistic understanding of the drug effects. This is essential in future clinical trials of analgesics in infants. Patient and public involvement The research team worked closely with an on-site charity during the trial design, conduct, oversight and dissemination. Trial registration Clinical Controlled Trials ISRCTN82342359; EudraCT 2014-003237-25. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. Funding was also received for the trial from the Wellcome Trust (reference numbers 095802 and 102076). The report will be published in full in Efficacy and Mechanism; Vol. 6, No. 9. See the National Institute for Health Research’s Journals Library website for further project information.

Safety of Rectal Administration of Acetaminophen in Neonates

On the basis of pharmacokinetic modelling, high-dose acetaminophen by rectal administration has been recommended for neonates needing antipyretic or analgesic therapy, but the safety and efficacy of this approach have not been established in vivo. The primary objective was to assess the safety of rectal acetaminophen administration for neonates, as indicated by changes in the results of hepatic and renal function tests. The secondary objective was to assess the efficacy of rectal acetaminophen administration in terms of the Premature Infant Pain Profile-Revised (PIPP-R) score. This single-centre retrospective chart analysis was conducted in the neonatal intensive care unit at a quaternary care children's hospital. Neonates who received all prescribed doses of acetaminophen by continu - ous rectal administration for 24 h or more, from January 1, 2011, to December 31, 2012, were included. For the primary objective, hepatotoxicity was assessed in terms of changes in liver enzyme levels, and nephrotoxicity was assessed in terms of changes from baseline serum creatinine values. Twenty-five patients, who received a total of 27 courses of acetaminophen by rectal administration, met the inclusion criteria. Median gestational age at initiation of acetaminophen was 37.0 weeks (interquartile range 35.0-39.8 weeks). Values of alanine aminotransferase remained within normal limits during acetaminophen therapy for all but 3 patients, for whom the changes were attributable to confounding factors. Renal function remained unchanged. The secondary outcome of efficacy (based on PIPP-R score) could not be evaluated because of concurrent use of opioids for most patients. Continuous rectal administration of acetaminophen over a short period (< 48 h) appeared to be well tolerated. The conclusions that can be drawn from these results are limited because of small sample size, the prescribing of doses lower than those recommended by the hospital's formulary, and limited blood sampling. Further studies are required.

Use of morphine before retinopathy of prematurity examinations

Use of morphine before retinopathy of prematurity examinations

Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trial

SummaryBackgroundInfant pain has immediate and long-term effects but is undertreated because of a paucity of evidence-based analgesics. Although morphine is often used to sedate ventilated infants, its analgesic efficacy is unclear. We aimed to establish whether oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedural pain.MethodsIn this single-centre masked trial, 31 infants at the John Radcliffe Hospital, Oxford, UK, were randomly allocated using a web-based facility with a minimisation algorithm to either 100 μg/kg oral morphine sulphate or placebo 1 h before a clinically required heel lance and retinopathy of prematurity screening examination, on the same occasion. Eligible infants were born prematurely at less than 32 weeks' gestation or with a birthweight lower than 1501 g and had a gestational age of 34–42 weeks at the time of the study. The co-primary outcome measures were the Premature Infant Pain Profile–Revised (PIPP-R) score after retinopathy of prematurity screening and the magnitude of noxious-evoked brain activity after heel lancing. Secondary outcome measures assessed physiological stability and safety. This trial is registered with the European Clinical Trials Database (number 2014-003237-25).FindingsBetween Oct 30, 2016, and Nov 17, 2017, 15 infants were randomly allocated to morphine and 16 to placebo; one infant assigned placebo was withdrawn from the study before monitoring began. The predefined stopping boundary was crossed, and trial recruitment stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. None of the co-primary outcome measures differed significantly between groups. PIPP-R score after retinopathy of prematurity screening was mean 11·1 (SD 3·2) with morphine and 10·5 (3·4) with placebo (mean difference 0·5, 95% CI −2·0 to 3·0; p=0·66). Noxious-evoked brain activity after heel lancing was median 0·99 (IQR 0·40–1·56) with morphine and 0·75 (0·33–1·22) with placebo (median difference 0·25, 95% CI −0·16 to 0·80; p=0·25).InterpretationAdministration of oral morphine (100 μg/kg) to non-ventilated premature infants has the potential for harm without analgesic efficacy. We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants.FundingWellcome Trust and National Institute for Health Research.

Remifentanil versus Fentanyl for pain control during elective endotracheal intubation for surfactant administration in preterm infants

Introduction: Today, the reality of pain in neonates is an undisputed fact, but pain management in clinical practice remains a challenging issue. All neonatal units should have a pain management protocol. The aim of this study was to compare the effectiveness of Remifentanil versus Fentanyl in pain control during elective endotracheal intubation for surfactant administration in preterm infants. Materials and methods: Preterm infants with gestational age between 28 weeks and 34 weeks + 6 days with Respiratory Distress Syndrome (RDS) who needed surfactant administration were divided into two groups using a random sampling method. Neonates in the first group received 2 μg/kg intravenous Fentanyl infusion and neonates in group 2 received 1 μg/kg intravenous Remifentanil before elective endotracheal intubation for surfactant therapy. The vital signs, including heart rate, oxygen saturation, mean arterial blood pressure and change in facial grimace were documented in an unnamed Premature Infant Pain Profile-Revised (PIPP-R) scoring sheet individually. Video recording was performed in both groups before, during and after the endotracheal intubation. All videos and data were interpreted and scored by two Newborn Individualized Developmental Care and Assessment Program (NIDCAP) professionals. Results: The mean PIPP-R score in the Fentanyl-treated group was 13.06 ± 3.55 and in the Remifentanil-treated group was 10.75 ± 2.93, with no statistically significant difference (p = 0.054). There was less need for Naloxone use in the Remifentanil group (p < 0.001). Incidence of apnea, severe drop in oxygen saturation, Intra-Ventricular Hemorrhage (IVH) and chest rigidity were not significantly different between the two groups. Conclusion: Although the difference was not statistically significant, Remifentanil reduced the pain score more than Fentanyl during elective endotracheal intubation in preterm infants. We recommend conducting further studies with larger study populations to determine the better drug and the optimal dosage of these drugs in neonates.

The minimally effective dose of sucrose for procedural pain relief in neonates: a randomized controlled trial

BackgroundOrally 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 is wide variability in sucrose doses examined in research, and more than a 20-fold variation across neonatal care settings. The aim of this study was to determine the minimally effective dose of 24% sucrose for reducing pain in hospitalized neonates undergoing a single skin-breaking heel lance procedure.MethodsA total of 245 neonates from 4 Canadian tertiary neonatal intensive care units (NICUs), born between 24 and 42 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 the Premature Infant Pain Profile-Revised (PIPP-R). The secondary outcome was the incidence of adverse events. Analysis of covariance models, adjusting for GA and study site examined between group differences in pain intensity across intervention groups.ResultsThere was no difference in mean pain intensity PIPP-R scores between treatment groups at 30 s (P = .97) and 60 s (P = .93); however, pain was not fully eliminated during the heel lance procedure. There were 5 reported adverse events 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.ConclusionsThe minimally effective dose of 24% sucrose required to treat pain associated with a single heel lance in neonates was 0.1 ml. Further evaluation regarding the sustained effectiveness of this dose in reducing pain intensity in neonates for repeated painful procedures is warranted.Trial registrationClinicalTrials.gov: NCT02134873. Date: May 5, 2014 (retrospectively registered).