Ibuprofen enantiomers in premature neonates with patent ductus arteriosus: Preliminary data on an unexpected pharmacokinetic profile of S(+)-ibuprofen.

S(+)-ibuprofen (S-IBU) and R(-)-ibuprofen (R-IBU) concentrations were measured in 16 neonates with patent ductus arteriosus during a cycle of therapy (three intravenous doses of 10-5-5 mg kg-1 at 24-h intervals), at the end of the first infusion and 6, 24, 48, and 72 h later. Data were analyzed with a PK model that included enantiomer elimination rate constants and the R- to S-IBU conversion rate constant. The T½ of S-IBU in the newborn was much longer than in adults (41.8 vs. ≈2 h), whereas the T½ of R-IBU appeared to be the same (2.3 h). The mean fraction of R- to S-IBU conversion was much the same as in adults (0.41 vs. ≈0.60). S-IBU concentrations measured 6 h after the first dose were higher than at the end of the infusion in 10 out of 16 cases, and in five cases, they remained higher even after 24 h. This behavior is unprecedented and may be attributable to a rapid R-to-S conversion overlapping with a slow S-IBU elimination rate. In 13 of the 16 neonates, S-IBU concentrations at 48 and/or 72 h were lower than expected, probably due to the rapid postnatal maturation of the newborn's liver metabolism.

Repeating a dose of sucrose for heel prick procedure in preterms is not effective in reducing pain: a randomised controlled trial.

Oral sucrose is included in almost all recommendations for treatment of pain in newborns, but evidence if multiple doses might be more effective than a single standard dose is lacking. We designed a single-centre, double-blind, randomised, controlled trial. We enrolled preterm infants needing the heel prick procedure. Each enrolled infant was randomised to receive a single standard dose of sucrose 2 min before or a double dose of sucrose 2 min before, and 30 s after heel prick. Primary outcome was the efficacy of the two interventions tested by the premature infant pain profile-PIPP scale obtained at 30 s, 60 s, and 120 s after heel prick. Secondary outcome was the evaluation of the concordance between the PIPP scale and other pain scores more feasible in clinical practice. Seventy-two infants were randomised. No difference in pain perception as measured by the PIPP scale was found between the groups: median PIPP values 4.0(IQR 3.0-4.0) vs 3.0(IQR 3.0-4.0) at baseline; 6.0(IQR 5.0-10.0) vs 6.0(IQR 4.0-8.5) at 30 s; 6.0(IQR 4.0-7.0) vs 5.0(IQR 4.0-8.5) at 60 s and 5.0(IQR 4.0-7.0) vs 5.0(IQR 4.0-7.5) at 2 min, in the experimental and standard treatment groups, respectively (p = 0.9020). There was no correlation between PIPP scores and other pain scales.Conclusion: We do not recommend doubling the dose during heel prick.What is Known:• Oral sucrose is included in almost all international position papers and recommendations for the treatment of mild to moderate pain in newborns, associated with non-nutritive sucking and facilitated tucking• Premature infant pain profile (PIPP) scale is the gold standard for evaluation of pain in preterms but it is difficult to use in clinical practiceWhat is New:• Repeating a dose of 24% sucrose is not effective in reducing pain during the recovery phase of a skin breaking procedure• Other pain scales, easier to use in clinical practice, are not comparable with PIPP for the evaluation of procedural pain in preterms.

Evidence-based clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation.

AIM: This review informed pain control guidelines for clinicians performing mechanical ventilation, nasal continuous positive airway pressure and endotracheal intubation on term and preterm newborn infants. METHODS: We reviewed literature published between 1986 and June 2017 on analgesia and sedation during assisted ventilation and before endotracheal intubation in newborn infants admitted to neonatal intensive care units. The subsequent guidelines were developed using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Our review produced five strong standard of care recommendations. One, reduce neonatal stress and use nonpharmacological analgesia during invasive ventilation. Two, favour intermittent boluses of opioids, administered after pain scores and before invasive procedures, during short expected periods of mechanical ventilation, mainly in preterm infants affected by respiratory distress syndrome. Three, do not use morphine infusion in preterm infants under 27 gestational weeks. Four, always use algometric scores to titrate analgesic drugs doses. Five, use premedication before endotracheal intubation for a more rapid, less painful, less traumatic and safer manoeuvre. We also developed 30 conditional recommendations on therapeutic options. CONCLUSION: Our review produced 35 recommendations on standard care and therapeutic options relating to the analgesia and sedation of newborn infants during ventilation and before endotracheal intubation.

Literature review informs clinical guidelines for pain management during screening and laser photocoagulation for retinopathy of prematurity.

AIM: The aim of this study was to carry out a literature review and develop clinical guidelines for pain prevention and control during screening and laser photocoagulation for retinopathy of prematurity (ROP) in neonatal intensive care units (NICUs). METHODS: The Italian Society of Neonatology assessed papers published between 1986 and June 2017 and used the Grading of Recommendations, Assessment, Development and Evaluation approach, to develop new guidelines on pain and ROP. RESULTS: The Society's pain experts assessed the full texts of 47 papers, including randomised or quasi-randomised controlled trials and case-control studies on nonpharmacological and pharmacological measures used in NICUs during the screening and laser photocoagulation of neonates for ROP. The literature suggested methods for reducing the stress and pain associated with ROP screening procedures. The panel concluded that the literature showed that it was feasible to provide laser photocoagulation for ROP in spontaneously breathing patients with adequate analgesia. CONCLUSION: This literature review on managing pain in infants with ROP in NICUs led to the development of national guidelines, which will help physicians and nurses to reduce the stress and pain experienced by premature newborn infants during unavoidable screening and treatment for ROP.

Procedural Pain during Insertion of a Continuous Glucose Monitoring Device in Preterm Infants.

Procedural pain was compared between the insertion of a continuous glucose monitoring sensor and heel stick using the Premature Infant Pain Profile in a single-blinded controlled trial in preterm infants (≤32 weeks of gestation or birth weight ≤1500 g) (ClinicalTrials.govNCT02583776). Continuous glucose monitoring insertion was associated with lower pain scores compared with the heel stick.

Systematic review of nonpharmacological analgesic interventions for common needle-related procedure in newborn infants and development of evidence-based clinical guidelines.

The aim of this literature review was to develop clinical guidelines for the prevention and control of needle-related pain in newborn infants. The guidelines were developed by the Italian Society of Neonatology, using the Grading of Recommendations, Assessment, Development and Evaluation approach, based on the assessment of 232 papers published between 1986 and 2015. The quality of the evidence was high or moderate for some behavioural and nonpharmacological interventions. CONCLUSION: There was sufficient evidence to strongly support the use of nonpharmacological interventions for common needle-related procedures in newborn infants. Combined interventions seemed to be more effective in relieving procedural pain.

Assessment of continuous pain in newborns admitted to NICUs in 18 European countries.

AIM: Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown. METHODS: A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission. RESULTS: Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001). CONCLUSION: Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.

Intravenous paracetamol for PDA closure in the preterm: a single-center experience.

UNLABELLED: Increasing recent evidence favors paracetamol use for patent ductus arteriosus (PDA) closure in preterms. Our study aims were (1) to assess efficacy and safety of intravenous (i.v.) paracetamol for PDA closure in a 23-32-week preterm population, as "first-line" (when traditional ibuprofen treatment was contraindicated) or "rescue" treatment (after ibuprofen failed), and (2) to identify predictors of PDA closure. The cumulative efficacy of consecutive cycles of i.v. paracetamol on PDA closure was confirmed after both "first-line" and "rescue" treatment, the overall PDA closure rates being, respectively, 56.7 and 61.1 % (p = 0.7624) after two cycles and 63.3 and 77.8 % (p = 0.2959) after three cycles. No toxicity was apparent after either "first-line" or "rescue" i.v. paracetamol treatment. On multivariate analysis, gestational age (GA) emerged as an independent predictor of PDA closure in the "first-line" i.v. paracetamol treatment group, while clinical risk index for babies (CRIB) score (a patient risk index based on birth weight, GA at birth, sex, patient's temperature on admission, and maximum base excess in first 12 h of life) was an independent predictor of PDA closure failure in the "rescue" group. CONCLUSION: I.V. paracetamol proved effective in our study population. Randomized control trials (RCTs) are warranted to further investigate the efficacy and safety of i.v. paracetamol for PDA closure in preterms. WHAT IS KNOWN: • Oral paracetamol has been judged as effective as oral ibuprofen for PDA closure in the preterm. • To date, only a handful of non-randomized studies exist to support the effectiveness of i.v. paracetamol in PDA closure. What is New: • Our observations confirm the clinical efficacy of i.v. paracetamol for PDA closure in a very low birth weight (VLBW)/extremely low birth weight (ELBW) preterm population. • Gestational age and CRIB score emerge as independent predictors of PDA closure.

Heated, Humidified High-Flow Nasal Cannulae as a Form of Noninvasive Respiratory Support for Preterm Infants and Children with Acute Respiratory Failure.

Heated, humidified high-flow delivered by nasal cannulae (HHHFNC) is increasingly used for noninvasive respiratory support in preterm infants and critically ill children due to its perceived effectiveness and ease of use. Evidence from randomized controlled trials suggests that HHHFNC and continuous positive airway pressure (CPAP) are equally effective as postextubation support in preterm infants. HHHFNC is also used for weaning preterm infants from CPAP. Data on HHHFNC used as the primary support for treating respiratory distress syndrome are conflicting. HHHFNC use in preterm infants is associated with reduced nasal trauma. Inability to measure the pressure generated by HHHFNC systems is a concern because overexpansion can lead to an air leak and lung injury. Great caution is warranted when HHHFNC is used in extremely low-birth-weight infants (who were rarely included in these randomized controlled trials) because a recent retrospective study found its use is associated with a higher likelihood of bronchopulmonary dysplasia or death in this population. HHHFNC has also become popular in pediatric intensive care units and pediatric wards as a method for delivering oxygen and noninvasive respiratory support. Most published studies were conducted on infants and young children with bronchiolitis. The results of a few observational studies and two randomized trials suggest that HHHFNC therapy is effective in the treatment of bronchiolitis. This review discusses the proposed mechanisms of action behind HHHFNC, the results of observational studies, and the evidence emerging from clinical trials on the use of HHHFNC in preterm infants and children critically ill with bronchiolitis.

Failure mode and effective analysis ameliorate awareness of medical errors: a 4-year prospective observational study in critically ill children.

BACKGROUND: Errors in are estimated to occur with an incidence of 3.7-16.6% in hospitalized patients. The application of systems for detection of adverse events is becoming a widespread reality in healthcare. Incident reporting (IR) and failure mode and effective analysis (FMEA) are strategies widely used to detect errors, but no studies have combined them in the setting of a pediatric intensive care unit (PICU). AIM: The aim of our study was to describe the trend of IR in a PICU and evaluate the effect of FMEA application on the number and severity of the errors detected. METHODS: With this prospective observational study, we evaluated the frequency IR documented in standard IR forms completed from January 2009 to December 2012 in the PICU of Woman's and Child's Health Department of Padova. On the basis of their severity, errors were classified as: without outcome (55%), with minor outcome (16%), with moderate outcome (10%), and with major outcome (3%); 16% of reported incidents were 'near misses'. We compared the data before and after the introduction of FMEA. RESULTS: Sixty-nine errors were registered, 59 (86%) concerning drug therapy (83% during prescription). Compared to 2009-2010, in 2011-2012, we noted an increase of reported errors (43 vs 26) with a reduction of their severity (21% vs 8% 'near misses' and 65% vs 38% errors with no outcome). CONCLUSION: With the introduction of FMEA, we obtained an increased awareness in error reporting. Application of these systems will improve the quality of healthcare services.

Congenital Pulmonary Airway Malformation in Preterm Infants: A Case Report and Review of the Literature.

Congenital pulmonary airway malformations (CPAMs) represent a well-known cluster of rare lung malformations affecting 1 in 2500 live births. The natural history of many CPAMs is to increase their size in the second trimester, reach a plateau, and, in about 50% of cases, regress and to become barely detectable during the third trimester. Little is known about cases of affected neonates born prematurely: only six cases are described in the literature, recording different conduct and outcomes. Herein, we report the case of a very low birth weight infant born at GW 28 without antenatal findings and presenting at birth with severe respiratory distress, requiring ventilation. Chest X-rays and a CT scan showed the presence of a solid mass in the left lung. An initial conservative approach was adopted as the baby gained respiratory stability within the first days of life. Routine ultrasound (US) showed a progressive reduction of the lesion, mimicking the process of involution that CPAM can exhibit during late gestation. The rarity of the condition does not allow the formulation of any suggestions regarding one type of management over the other. An initial conservative approach seems to be appropriate with regards to the outcome and possible intra- and post-operative complications.

Parents in Neonatal Pain Management-An International Survey of Parent-Delivered Interventions and Parental Pain Assessment.

BACKGROUND: While parent-delivered pain management has been demonstrated to effectively reduce neonatal procedural pain responses, little is known about to what extent it is utilized. Our aim was to explore the utilization of parents in neonatal pain management and investigate whether local guidelines promote parent-delivered interventions. METHODS: A web-based survey was distributed to neonatal units worldwide. RESULTS: The majority of the 303 responding neonatal intensive care units (NICUs) from 44 countries were situated in high-income countries from Europe and Central Asia. Of the responding units, 67% had local guidelines about neonatal pain management, and of these, 40% answered that parental involvement was recommended, 27% answered that the role of parents in pain management was mentioned as optional, and 32% responded that it was not mentioned in the guidelines. According to the free-text responses, parent-delivered interventions of skin-to-skin contact, breastfeeding, and parental live singing were the most frequently performed in the NICUs. Of the responding units, 65% answered that parents performed some form of pain management regularly or always. CONCLUSIONS: There appears to be some practice uptake of parent-delivered pain management to reduce neonatal pain in high-income countries. Additional incorporation of these interventions into NICU pain guidelines is needed, as well as a better understanding of the use of parent-delivered pain management in low- and middle-income countries.

Nasal intermittent positive pressure ventilation during less invasive surfactant administration in preterm infants: An open-label randomized controlled study.

INTRODUCTION: Approximately half of very preterm infants with respiratory distress syndrome (RDS) fail treatment with nasal continuous positive airway pressure (NCPAP) and need mechanical ventilation (MV). OBJECTIVES: Our aim with this study was to evaluate if nasal intermittent positive pressure ventilation (NIPPV) during less invasive surfactant treatment (LISA) can improve respiratory outcome compared with NCPAP. MATERIALS AND METHODS: We carried out an open-label randomized controlled trial at tertiary neonatal intensive care units in which infants with RDS born at 25+0-31+6 weeks of gestation between December 1, 2020 and October 31, 2022 were supported with NCPAP before and after surfactant administration and received NIPPV or NCPAP during LISA. The primary endpoint was the need for a second dose of surfactant or MV in the first 72 h of life. Other endpoints were need and duration of invasive and noninvasive respiratory supports, changes in SpO2/FiO2 ratio after LISA, and adverse effect rate. RESULTS: We enrolled 101 infants in the NIPPV group and 99 in the NCPAP group. The unadjusted odds ratio for the composite primary outcome was 0.873 (95% confidence interval: 0.456-1.671; p = .681). We found that the SpO2/FiO2 ratio was transiently higher in the LISA plus NIPPV than in the LISA plus NCPAP group, while adverse effects of LISA had similar occurrence in the two arms. CONCLUSIONS: The application of NIPPV or NCPAP during LISA in very preterm infants supported with NCPAP before and after surfactant administration had similar effects on the short-term respiratory outcome and are both safe. Our study does not support the use of NIPPV during LISA.

SARS-CoV-2 perinatal transmission and neonatal outcomes across four different waves of COVID-19 pandemic: A nationwide prospective cohort study from the Italian Society of Neonatology.

OBJECTIVES: To describe how SARS-CoV-2 infection at the time of delivery affected maternal and neonatal outcomes across four major waves of the COVID-19 pandemic in Italy. METHODS: This is a large, prospective, nationwide cohort study collecting maternal and neonatal data in case of maternal peripartum SARS-CoV-2 infection between February 2020 and March 2022. Data were stratified across the four observed pandemic waves. RESULTS: Among 5201 COVID-19-positive mothers, the risk of being symptomatic at delivery was significantly higher in the first and third waves (20.8-20.8%) than in the second and fourth (13.2-12.2%). Among their 5284 neonates, the risk of prematurity (gestational age <37 weeks) was significantly higher in the first and third waves (15.6-12.5%). The risk of intrauterine transmission was always very low, while the risk of postnatal transmission during rooming-in was higher and peaked at 4.5% during the fourth wave. A total of 80% of positive neonates were asymptomatic. CONCLUSION: The risk of adverse maternal and neonatal outcomes was significantly higher during the first and third waves, dominated by unsequenced variants and the Delta variant, respectively. Postnatal transmission accounted for most neonatal infections and was more frequent during the Omicron period. However, the paucity of symptoms in infected neonates should lead us not to separate the dyad.

Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates: 2-Year Follow-Up of a Randomized Clinical Trial.

Importance: A multicenter randomized clinical trial (RCT) showed a lung recruitment maneuver using high-frequency oscillatory ventilation just before surfactant administration (ie, intubate-recruit-surfactant-extubate [IN-REC-SUR-E]) improved the efficacy of treatment compared with the standard intubate-surfactant-extubate (IN-SUR-E) technique without increasing the risk of adverse neonatal outcomes. Objective: To examine follow-up outcomes at corrected postnatal age (cPNA) 2 years of preterm infants previously enrolled in an RCT and treated with IN-REC-SUR-E or IN-SUR-E in 35 tertiary neonatal intensive care units. Design, Setting, and Participants: This was a follow-up study of infants recruited into the primary RCT from 2015 to 2018 at 35 tertiary neonatal intensive care units (NICUs) in Italy. Follow-up examinations included neurodevelopmental, growth, and respiratory outcomes of these children at cPNA 2 years. Participants included spontaneously breathing extremely preterm neonates (24 0/7 to 27 6/7 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 hours of life. Data were analyzed from April 2023 to January 2024. Intervention: Infants were randomly assigned (1:1) to IN-REC-SUR-E or IN-SUR-E and then followed up. Main Outcomes and Measures: The primary outcome was the occurrence of death after discharge or major disability at cPNA 2 years. Secondary outcomes were neurodevelopmental outcomes (major disability, cerebral palsy, cognitive impairment, visual deficit, or auditory deficit), anthropometric measurements (weight, length, and head circumference), and recurrent respiratory infections and hospitalizations because of respiratory causes at 2y cPNA. Results: A total of 137 extremely preterm infants (median [IQR] gestational age, 26.5 [25.3-27.5] weeks and 75 [54.7%] female), initially enrolled in the original RCT, were followed up at cPNA 2 years, including 64 infants in the IN-SUR-E group and 73 infants in the IN-REC-SUR-E group. There were no significant differences in the occurrence of death after discharge or major disability at cPNA 2 years (IN-SUR-E: 13 children [20.3%] vs IN-REC-SUR-E: 10 children [13.7%]; P = .36). There were no significant differences in incidence of disability, cerebral palsy, or cognitive impairment in the IN-REC-SUR-E group compared with the IN-SUR-E group. There were no significant differences in anthropometric measurements (weight, length, and head circumference) between groups. There were no significant differences in the incidence of recurrent respiratory infections or in hospitalizations because of respiratory causes between groups. Conclusions and Relevance: In this RCT of lung recruitment before surfactant vs standard care there were no significant differences between the 2 groups in death, neurodevelopmental outcomes, anthropometric measurements, or recurrent respiratory infections at the 2-year follow-up. These findings can aid clinicians in decision-making for the best strategy to administer surfactant, considering long-term outcomes.

Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation.

OBJECTIVE: To evaluate the analgesic superiority and the safety equivalence of continuous fentanyl infusions versus fentanyl boluses in preterm infants on mechanical ventilation. STUDY DESIGN: In this multicenter, double-blind, randomized controlled trial, mechanically ventilated newborns (≤ 32(+6) weeks gestational age) were randomized to fentanyl (continuous infusion of fentanyl plus open-label boluses of fentanyl) or placebo (continuous infusion of placebo plus open-label boluses of fentanyl). The primary endpoint was analgesic efficacy, as evaluated by the Echelle Douleur Inconfort Nouveau-Né (EDIN) and Premature Infant Pain Profile scales. Safety variables were evaluated as well. RESULTS: Sixty-four infants were allocated to the fentanyl group, and 67 were allocated to the placebo group. The need for open-label boluses of fentanyl was similar in the 2 groups (P = .949). EDIN scores were comparable in the 2 groups; 65 of 961 (6.8%) EDIN scores were >6 in the fentanyl group and 91 of 857 (10.6%) in the placebo group (P = .003). The median Premature Infant Pain Profile score was clinically and statistically higher in the placebo group compared with the fentanyl group on days 1, 2, and 3 of treatment (P < .05). Mechanical ventilation at age 1 week was required in 27 of 64 infants in the fentanyl group (42.2%), compared with 17 of 67 infants in the placebo group (25.4%) (P = .042). The first cycle of mechanical ventilation was longer and the first meconium passage occurred later in the fentanyl group (P = .019 and .027, respectively). CONCLUSION: In very preterm infants on mechanical ventilation, continuous fentanyl infusion plus open-label boluses of fentanyl does not reduce prolonged pain, but does reduce acute pain and increase side effects compared with open-label boluses of fentanyl alone.

Procedural pain in neonates: the state of the art in the implementation of national guidelines in Italy.

BACKGROUND: National and international guidelines have been published on pain control and prevention in the newborn, but data on compliance with these guidelines are lacking. AIM: To document current hospital practices for analgesia at neonatal intensive care units (NICUs) 5 years after national guidelines were published in Italy. METHODS: A computer-based questionnaire was sent to all registered Italian level II and level III NICUs to investigate their routine pain control practices. MAIN OUTCOME MEASURES: The analgesia and sedation currently used for invasive procedures as compared with best practices. RESULTS: The questionnaire was returned by 103 of the 118 NICUs (87.3%), most of which (85.4%) knew of the national guidelines on procedural pain control and prevention, and used some analgesic measures during invasive procedures. One or more nonpharmacological interventions were only used routinely by 64.1% of the NICUs for heel pricks and venipuncture, 56.0% for percutaneous insertion of central catheters, 69.7% for nasal CPAP, and 62.4% for eye tests to screen for retinopathy of prematurity. Pain medication was routinely administered at 34.3% NICUs for tracheal intubation, 46.6% for mechanical ventilation (MV), 12.9% for tracheal aspiration, 71.4% for chest tube insertion, 33.0% for lumbar puncture, and 64.0% for postoperative pain. Pain was routinely monitored at only 22.7% of the units during MV, 12.1% for nCPAP, and 21.8% postoperatively. CONCLUSION: This survey showed that most Italian NICUs provide some form of analgesia and sedation for invasive procedures in accordance with national guidelines, but their routine adherence to best practices for pain control and monitoring is still suboptimal.

Neurodevelopmental outcomes of very low birth weight preterms in preschool childhood: a prospective cohort study.

BACKGROUND: Preterm birth is a risk factor for a child's neurological development. Preterm children have unusual neurodevelopmental profiles with executive, visual-motor functions, fine and gross motor skills, language and behavior that affect learning. In this study, we analyzed the neurodevelopmental outcomes of a cohort of very low birth weight infants admitted to the Treviso Neonatal Intensive Care Unit (NICU) between 2014 and 2016 and followed up to preschool childhood. METHOD: This is a prospective cohort study. Infants were followed at birth and after NICU discharge at two- and four-year follow-ups. The two-year assessment was conducted with Bayley III, and at four years with the Wechsler Preschool and Primary Scale of Intelligence - III scales and Movement Assessment Battery for Children - 2. RESULTS: The cohort consisted of 207 subjects with a mean gestational age of 28.9 weeks, and a mean birth weight of 1097.2 g. At two years of age, children without disabilities were 90 (59.6%), those with minor disabilities 47 (31.1%), and those with major disabilities 14 (9.3%); at four years, 58.4% of children without previous disabilities, presented problems with verbal tests and manual dexterity: aiming, grasping and balance at movement assessment. There was significant alteration in processing speed (p < 0.001). Furthermore, there was a strong correlation between processing speed and manual dexterity (p < 0.001) and between processing speed and aiming and grasping (p = 0.0059). CONCLUSIONS: We found that more than half the children free of disability at two years, at four years had deficit often involving the oculo-motor coordination and processing speed. These motor profile alterations limit the expression of cognitive abilities and the achievement of expected school performance, thus resulting in behavioral disorders, typical of preterm children. Early professional follow-up could improve the expected educational outcomes.

Continuous Fentanyl Infusion in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia: Background, Aims, and Study Protocol for Time-Concentration Profiles.

Therapeutic hypothermia (TH) is the standard of care for newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE). Discomfort and pain during treatment are common and may affect the therapeutic efficacy of TH. Opioid sedation and analgesia (SA) are generally used in clinical practice, and fentanyl is one of the most frequently administered drugs. However, although fentanyl's pharmacokinetics (PKs) may be altered by hypothermic treatment, the PK behavior of this opioid drug in cooled newborns with HIE has been poorly investigated. The aim of this phase 1 study protocol (Trial ID: FentanylTH; EUDRACT number: 2020-000836-23) is to evaluate the fentanyl time-concentration profiles of full-term newborns with HIE who have been treated with TH. Newborns undergoing TH receive a standard fentanyl regimen (2 mcg/Kg of fentanyl as a loading dose, followed by a continuous infusion-1 mcg/kg/h-during the 72 h of TH and subsequent rewarming). Fentanyl plasma concentrations before bolus administration, at the end of the loading dose, and 24-48-72-96 h after infusion are measured. The median, maximum, and minimum plasma concentrations, together with drug clearance, are determined. This study will explore the fentanyl time-concentration profiles of cooled, full-term newborns with HIE, thereby helping to optimize the fentanyl SA dosing regimen during TH.