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Medically complex infants experiencing NICU stays can be difficult to manage, exhibiting refractory agitation, disengagement, or both—all signs of delirium, which can present in a hypoactive, hyperactive, or mixed form. Though documented in other settings, delirium is under-recognized in NICUs. Pediatric studies show that a high percentage of patients with delirium are under the age of 12 months. Delirium is associated with increased ventilation days, hospital days, and costs. It negatively affects neurodevelopment and social interaction. Studies show that pediatric nurses are unprepared to recognize delirium. Our nurse-led multidisciplinary group created a best practice recommendation (BPR) focused on detecting delirium and minimizing risk through thoughtful sedation management, promotion of sleep hygiene and mobility, and facilitation of meaningful caregiver presence. Occasionally, medications, including melatonin and risperidone, are helpful. In 2019, we introduced this BPR to reduce delirium risk in our NICU. Practice changes tied to this initiative correlate with a significant reduction in delirium scores and risk including exposure to deliriogenic medications. A multidisciplinary care bundle correlates with decreased delirium screening scores in NICU patients. [ABSTRACT FROM AUTHOR]

Our objective was to evaluate the relationship between congenital gastrointestinal anomalies requiring neonatal surgery and neurodevelopmental outcome. Among the children born in metropolitan Atlanta during 1982-2001 who survived to age 1 year (N = 762,824), we identified children with congenital gastrointestinal anomalies via linkage with the Metropolitan Atlanta Congenital Defects Program and children who received special education services via linkage with the Special Education Database of Metropolitan Atlanta. Several modest increases in special education service use were observed among children with isolated congenital gastrointestinal anomalies; no association was statistically significant. Among children with Hirschsprung disease, gastroschisis, esophageal atresia, intestinal malrotation, bowel atresia, or imperforate anus who had multiple anomalies, we observed statistically significant increases in special education service use.

Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (<26 1 0/ 7 weeks' gestation, <750 g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach. [ABSTRACT FROM AUTHOR]

A persistently patent ductus arteriosus (PDA) in preterm infants can have significant clinical consequences, particularly during the recovery period from respiratory distress syndrome. With improvement of ventilation and oxygenation, the pulmonary vascular resistance decreases early and rapidly, especially in very immature infants with extremely low birth weight (<1000 >). Subsequently, the left-to-right shunt through the ductus arteriosus (DA) is augmented, thereby increasing pulmonary blood flow, which leads to pulmonary edema and overall worsening of cardiopulmonary status. Prolonged ventilation, with the potential risks of volutrauma, barotrauma, and hyperoxygenation, is strongly associated with the development and severity of bronchopulmonary dysplasia/chronic lung disease. Substantial left-to-right shunting through the ductus may also increase the risk of intraventricular hemorrhage, necrotizing enterocolitis, and death. Postnatal ductal closure is regulated by exposure to oxygen and vasodilators; the ensuing vascular responses, mediated by potassium channels, voltage-gated calcium channels, mitochondrial-derived reactive oxygen species, and endothelin 1, depend on gestational age. Platelets are recruited to the luminal aspect of the DA during closure and probably promote thrombotic sealing of the constricted DA. Currently, it is unclear whether and when a conservative, pharmacologic, or surgical approach for PDA closure may be advantageous. Furthermore, it is unknown if prophylactic and/or symptomatic PDA therapy will cause substantive improvements in outcome. In this article we review the mechanisms underlying DA closure, risk factors and comorbidities of significant DA shunting, and current clinical evidence and areas of uncertainty in the diagnosis and treatment of PDA of the preterm infant. [ABSTRACT FROM AUTHOR]

: BackgroundThe objective was to determine the timing and mechanism of brain injury using preoperative and postoperative magnetic resonance imaging (MRI) and three-dimensional MR spectroscopic imaging (MRSI) in newborns with transposition of the great arteries (TGA) repaired with full-flow cardiopulmonary bypass.: MethodsTen term newborns with TGA undergoing an arterial switch operation were studied with MRI, MRSI, and neurologic examination preoperatively and postoperatively at a median of 5 days (2 to 9 days) and 19 days (14 to 26 days) of age, respectively. Five term historical controls were studied at a median of 4 days (3 to 9 days). Lactate/choline (marker of cerebral oxidative metabolism) and N-acetylaspartate (NAA)/choline (marker of cerebral metabolism and density) were measured bilaterally from the basal ganglia, thalamus, and corticospinal tracts.: ResultsFour TGA newborns had brain injury on the preoperative MRI. The only new lesion detected on the postoperative study was a focal white matter lesion in one newborn with a normal preoperative MRI. The MRSI of age-adjusted lactate/choline was quantitatively higher in newborns with TGA compared with those without heart disease (p < 0.0001), even in newborns without MRI evidence of preoperative brain injury. Lactate/choline decreased after surgery but remained elevated compared with controls. In newborns with TGA, those with preoperative brain injury on MRI had lower NAA/choline globally (p = 0.04) than those with normal preoperative MRI. Five newborns had a decline in NAA/choline from the preoperative to postoperative studies.: ConclusionsAbnormal brain metabolism and injury was observed preoperatively in newborns with TGA. Brain injury is not solely related to the operative course. [Copyright &y& Elsevier]

The objective was to determine whether an elevated nucleated red blood cell count at birth after perinatal depression is associated with brain injury as measured by (1) proton magnetic resonance spectroscopy and (2) abnormal neurodevelopmental outcome at 30 months of age. The nucleated red blood cell counts from the first 24 hours of life were statistically analyzed in 33 term infants enrolled in a prospective study of the value of magnetic resonance imaging for the determination of neurodevelopmental outcome after perinatal depression. Nucleated red blood cell counts were elevated in 13/33 (39%). Abnormal outcome (19/33, 54%) was associated with Score for Neonatal Acute Physiology-Perinatal Extension (P = 0.04), decreased N-acetylaspartate to choline ratio in the basal ganglia (P = 0.009), and increased lactate to choline ratio in the basal ganglia (P = 0.02), but not with cord pH, Apgar score, or nucleated red blood cell value. In a logistic regression model, increasing nucleated red blood cell counts did not increase the odds of an abnormal outcome at 30 months of age (OR 1.02, P = 0.17). In a population of neonates with perinatal depression, the nucleated red blood cell count at birth does not correlate with magnetic resonance spectroscopy or 30-month neurodevelopmental outcome. The nucleated red blood cell count should not be used as a surrogate marker for subsequent brain injury. [Copyright &y& Elsevier]

Importance: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high., Objective: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy., Design, Setting, and Participants: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016., Interventions: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83)., Main Outcomes and Measures: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification., Results: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours., Conclusions and Relevance: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C., Trial Registration: clinicaltrials.gov Identifier: NCT01192776.

Objective: To quantify intercenter cost variation for perinatal hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia across children's hospitals., Study Design: Prospectively collected data from the Children's Hospitals Neonatal Database and Pediatric Health Information Systems were linked to evaluate intercenter cost variation in total hospitalization costs after adjusting for HIE severity, mortality, length of stay, use of extracorporeal support or nitric oxide, and ventilator days. Secondarily, costs for intensive care unit bed, electroencephalography (EEG), and laboratory and neuroimaging testing were also evaluated. Costs were contextualized by frequency of favorable (survival with normal magnetic resonance imaging) and adverse (death or need for gastric tube feedings at discharge) outcomes to identify centers with relative low costs and favorable outcomes., Results: Of the 822 infants with HIE treated with therapeutic hypothermia at 19 regional neonatal intensive care units, 704 (86%) survived to discharge. The median cost/case for survivors was $58 552 (IQR $32 476-$130 203) and nonsurvivors $29 760 (IQR $16 897-$61 399). Adjusting for illness severity and select interventions, intercenter differences explained 29% of the variation in total hospitalization costs. The widest cost variability across centers was EEG use, although low cost and favorable outcome centers ranked higher with regards to EEG costs., Conclusions: There is marked intercenter cost variation associated with treating HIE across regional children's hospitals. Our investigation may help establish references for cost and enhance quality improvement and resource utilization projects related to HIE., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Cardiac surgery in infants results in a profound inflammatory response secondary to cardiopulmonary bypass (CPB) and the need for blood products. It is not clear how this inflammatory response modulates postoperative course or whether quantification of proinflammatory cytokines can aid with risk stratification. In this study, we prospectively assessed a panel of candidate markers to determine the time course for inflammation and the association of specific markers with clinical outcomes defined as intensive care unit length of stay (LOS)., Methods: We obtained preoperative blood samples from 92 neonates undergoing surgery with CPB and then serially for 5 days after surgery. Numerous interleukins were assayed along with tumor necrosis factor (TNF)-alpha and interferon (INF)-gamma. The most common surgical procedures were arterial switch procedure (n = 35) and Norwood operation (n = 34). Multivariate analysis was performed to determine if inflammatory mediators could independently predict prolonged intensive care unit LOS., Results: Compared with the presurgery level, there were statistically significant increases (p < 0.005) for 8 out of 11 inflammatory markers: INF-gamma, interleukin (IL)-10, IL-13, IL-2, IL-5, IL-8, TNF-alpha, and IL-6 after surgery. The only cytokine on the first postoperative day that was independently associated with prolonged length of stay was IL-8 (p = 0.002). Cytokine values measured on postoperative day 3 were most valuable in predicting prolonged LOS. A model that included use of circulatory arrest, and day 3 measures of IL-6 and IL-8 yielded an area under of the curve of 0.88 (95% confidence interval 0.79 to 0.96) for predicting a prolonged LOS., Conclusions: In summary, neonatal heart surgery for complex lesions elicits a broad inflammatory response. This early inflammatory response appears nonspecific and did not predict clinical course. Persistence of specific inflammatory mediators on the third day after surgery, however, provided important prognostic information. As such, select cytokines may serve as valuable biomarkers in this population. Whether strategies targeting specific cytokines can alter clinical course is not known., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Recent evidence suggests that the current ILCOR guidelines regarding hypothermia for the treatment of neonatal encephalopathy need urgent revision. In 2005 when the current ILCOR guidelines were finalised one large (CoolCap trial, n=235) and one small RCT (n=67), in addition to pilot trials, had been published, and demonstrated that therapeutic hypothermia after perinatal asphyxia was safe. The CoolCap trial showed a borderline overall effect on death and disability at 18 months of age, but significant improvement in a large subset of infants with less severe electroencephalographic changes. Based on this and other available evidence, the 2005 ILCOR guidelines supported post-resuscitation hypothermia in paediatric patients after cardiac arrest, but not after neonatal resuscitation. Subsequently, a whole body cooling trial supported by the NICHD reported a significant overall improvement in death or disability. Further large neonatal trials of hypothermia have stopped recruitment and their final results are likely to be published 2009-2011. Many important questions around the optimal therapeutic use of hypothermia remain to be answered. Nevertheless, independent meta-analyses of the published trials now indicate a consistent, robust beneficial effect of therapeutic hypothermia for moderate to severe neonatal encephalopathy, with a mean NNT between 6 and 8. Given that there is currently no other clinically proven treatment for infants with neonatal encephalopathy we propose that an interim advisory statement should be issued to support and guide the introduction of therapeutic hypothermia into routine clinical practice.

Although cesarean deliveries frequently are performed for anomalous fetal conditions, available data do not always support a fetal benefit from this delivery management. The literature on cesarean delivery for anomalous infants reports insufficient information on comorbid neonatal conditions, so these complications are unknown in this population of newborns. In a minority of cases, a cesarean delivery is reasonable to prevent dystocia or optimize outcome. Areas for future investigation include prospective, randomized, controlled trials of prelabor cesarean compared with vaginal deliveries for myelomeningocele and anterior abdominal wall defects. The rarity of other lesions likely precludes randomized controlled trials.

Background: Preoperative brain injury is common in neonates with transposition of the great arteries (TGA). The objective of this study is to determine risk factors for preoperative brain injury in neonates with TGA., Methods and Results: Twenty-nine term neonates with TGA were studied with MRI before cardiac surgery in a prospective cohort study. Twelve patients (41%) had brain injury on preoperative MRI, and all injuries were focal or multifocal. None of the patients had birth asphyxia. Nineteen patients (66%) required preoperative balloon atrial septostomy (BAS). All patients with brain injury had BAS (12 of 19; risk difference, 63%; 95% confidence interval, 41 to 85; P=0.001). As expected on the basis of the need for BAS, these neonates had lower systemic arterial hemoglobin saturation (Sao2) (P=0.05). The risk of injury was not modified by the cannulation site for septostomy (umbilical versus femoral, P=0.8) or by the presence of a central venous catheter (P=0.4)., Conclusions: BAS is a major identifiable risk factor for preoperative focal brain injury in neonates with TGA. Imaging characteristics of identified brain injuries were consistent with embolism; however, the mechanism is more complex than site of vascular access for BAS or exposure to central venous catheters. These findings have implications for the indications for BAS, timing of surgical repair, and use of anticoagulation in TGA.

Objectives: To determine if the incidence of sonographically detected cystic periventricular leukomalacia (PVL) and periventricular hemorrhagic infarction (PVHI) have changed over the past decade and to determine if a decline in cystic PVL was associated with a change in neurodevelopmental outcome., Study Design: Premature newborn infants admitted to our intensive care nursery from 1992 to 2002 were identified in a comprehensive nursery database. Premature newborn infants had routine neurosonography by means of a standardized protocol. Infants weighing < or =1500 g at birth surviving to nursery discharge were enrolled in a nursery follow-up clinic., Results: Adjusting for gestational age, there was a significant decrease in cystic PVL from 1992 to 2002 (P=.003) without a concurrent decrease in PVHI (P=0.5). Cystic PVL and PVHI accounted for only 9 of the 28 cases of cerebral palsy and 12 of 90 cases of abnormal Developmental Scores in infants weighing <1500 g at birth. The decline in cystic PVL was not associated with improved developmental outcome from 1992 to 2002., Conclusions: The incidence of cystic PVL declined significantly from 1992 to 2002 at our center. Cystic PVL was detected by ultrasound in a minority of infants with abnormal neurodevelopmental outcome, indicating that other forms of cerebral injury account for the majority of abnormal neurodevelopmental outcomes in premature newborn infants.

This report describes the case of a neonate who underwent fetal surgery for congenital diaphragmatic hernia (CDH) and pulmonary sequestration. His postnatal management was complicated by the additional diagnosis of transposition of the great arteries (TGA). TGA is particularly difficult to diagnose in the fetus. This triad has not previously been documented in the literature. Clinicians should have a high index of suspicion for associated anomalies, especially cardiac, when evaluating and counseling a pregnancy complicated by CDH., (Copyright 2004 S. Karger AG, Basel)

Stroke is a devastating condition occurring in at least 1 in 4000 live births in the neonatal period. Since hypoxia-inducible factor (HIF)-1alpha can modulate ischemic injury via induction of target genes that may protect cells against ischemia, and is induced after preconditioning by hypoxia in the neonatal rat brain hypoxia-ischemia model, we evaluated whether HIF-1alpha is induced after focal ischemia-reperfusion, a model for neonatal stroke. We developed an ischemia-reperfusion model in postnatal day 10 (P10) rats by transiently occluding the middle cerebral artery (MCA) for 1.5 h. The MCA territory was reperfused for 0, 4, 8, or 24 h and the expression of HIF-1alpha and its target gene, vascular endothelial growth factor (VEGF), were delineated. HIF-1alpha protein and VEGF protein peaked at 8 h, and declined subsequently at 24 h in injured cortex following 1.5 h of MCA occlusion. Double-immunolabeling indicated that both HIF-1alpha and VEGF are expressed together in neurons with a similar time course of expression. The presence of HIF-1alpha and VEGF after moderate ischemia-reperfusion injury suggests potential avenues to exploit for neuroprotection.

Purpose of Review: Perinatal hypoxia-ischemia is responsible for significant morbidity and mortality in term infants. The developing brain is uniquely vulnerable to hypoxic-ischemic injury, with a complex evolution of injury that affords opportunities for intervention, yet potentially jeopardizes normal maturational processes., Recent Findings: Data published over the past year have provided insights into the evolution of injury, and have suggested a greater role for oxidants and inflammatory mediators., Summary: The search for ideal neuroprotective agents and techniques for timely injury detection is actively progressing and has led to advances in our understanding of pathogenesis.