A Delirium Prevention and Management Initiative: Implementing a Best Practice Recommendation for the NICU.

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.

Neonatal Carotid Artery and Internal Jugular Vein Management Practices at Extracorporeal Membrane Oxygenation Decannulation: No Standard Approach.

BACKGROUND: There are currently no commonly accepted standardized guidelines for management of cervical vessels at neonatal extracorporeal membrane oxygenation (ECMO) decannulation. This study investigates neonatal ECMO decannulation practices regarding management of the carotid artery and internal jugular vein, use of post-repair anticoagulation, and follow-up imaging. METHODS: A survey was distributed to the 37 institutions in the Children's Hospitals Neonatal Consortium. Respondents reported their standard approach to carotid artery and internal jugular vein management (ligation or repair) at ECMO decannulation by their pediatric surgery and cardiothoracic (CT) surgery teams as well as post-repair anticoagulation practices and follow-up imaging protocols. RESULTS: The response rate was 95%. Pediatric surgeons performed most neonatal respiratory ECMO cannulations (88%) and decannulations (85%), while all neonatal cardiac ECMO cannulations and decannulations were performed by CT surgeons. Pediatric surgeons overwhelmingly ligate both vessels (90%) while CT surgeons typically repair both vessels at decannulation (83%). Of the responding centers that repair, 28% (7) have a standard anticoagulation protocol after neck vessel repair. While 52% (13) of centers routinely image cervical vessel patency at least once post repair, most do not subsequently repeat neck vessel imaging. CONCLUSIONS: Significant practice differences exist between pediatric and CT surgeons regarding the approach to cervical vessels at neonatal ECMO decannulation. For those centers that do repair the vessels there is little uniformity in post-repair anticoagulation or imaging protocols. There is a need to develop standardized cervical vessel management guidelines for neonatal ECMO patients and to study their impact on both short- and long-term outcomes. LEVEL OF EVIDENCE: IV.

Association of Hospital Resource Utilization With Neurodevelopmental Outcomes in Neonates With Hypoxic-Ischemic Encephalopathy.

Importance: Intercenter variation exists in the management of hypoxic-ischemic encephalopathy (HIE). It is unclear whether increased resource utilization translates into improved neurodevelopmental outcomes. Objective: To determine if higher resource utilization during the first 4 days of age, quantified by hospital costs, is associated with survival without neurodevelopmental impairment (NDI) among infants with HIE. Design, Setting, and Participants: Retrospective cohort analysis of neonates with HIE who underwent therapeutic hypothermia (TH) at US children's hospitals participating in the Children's Hospitals Neonatal Database between 2010 and 2016. Data were analyzed from December 2021 to December 2022. Exposures: Infants who survived to 4 days of age and had neurodevelopmental outcomes assessed at greater than 11 months of age were divided into 2 groups: (1) death or NDI and (2) survived without NDI. Resource utilization was defined as costs of hospitalization including neonatal neurocritical care (NNCC). Data were linked with Pediatric Health Information Systems to quantify standardized costs by terciles. Main Outcomes and Measures: The main outcome was death or NDI. Characteristics, outcomes, hospitalization, and NNCC costs were compared. Results: Among the 381 patients who were included, median (IQR) gestational age was 39 (38-40) weeks; maternal race included 79 (20.7%) Black mothers, 237 (62.2%) White mothers, and 58 (15.2%) mothers with other race; 80 (21%) died, 64 (17%) survived with NDI (combined death or NDI group: 144 patients [38%]), and 237 (62%) survived without NDI. The combined death or NDI group had a higher rate of infants with Apgar score at 10 minutes less than or equal to 5 (65.3% [94 of 144] vs 39.7% [94 of 237]; P < .001) and a lower rate of infants with mild or moderate HIE (36.1% [52 of 144] vs 82.3% [195 of 237]; P < .001) compared with the survived without NDI group. Compared with low-cost centers, there was no association between high- or medium-hospitalization cost centers and death or NDI. High- and medium-EEG cost centers had lower odds of death or NDI compared with low-cost centers (high vs low: OR, 0.30 [95% CI, 0.16-0.57]; medium vs low: OR, 0.29 [95% CI, 0.13-0.62]). High- and medium-laboratory cost centers had higher odds of death or NDI compared with low-cost centers (high vs low: OR, 2.35 [95% CI, 1.19-4.66]; medium vs low: OR, 1.93 [95% CI, 1.07-3.47]). High-antiseizure medication cost centers had higher odds of death or NDI compared with low-cost centers (high vs. low: OR, 3.72 [95% CI, 1.51-9.18]; medium vs low: OR, 1.56 [95% CI, 0.71-3.42]). Conclusions and Relevance: Hospitalization costs during the first 4 days of age in neonates with HIE treated with TH were not associated with neurodevelopmental outcomes. Higher EEG costs were associated with lower odds of death or NDI yet higher laboratory and antiseizure medication costs were not. These findings serve as first steps toward identifying aspects of NNCC that are associated with outcomes.

Practice variations for fetal and neonatal congenital heart disease within the Children's Hospitals Neonatal Consortium.

BACKGROUND: Many aspects of care for fetuses and neonates with congenital heart disease (CHD) fall outside standard practice guidelines, leading to the potential for significant variation in clinical care for this vulnerable population. METHODS: We conducted a cross-sectional survey of site sponsors of the Children's Hospitals Neonatal Consortium, a multicenter collaborative of 41 Level IV neonatal intensive care units to assess key areas of clinical practice variability for patients with fetal and neonatal CHD. RESULTS: We received responses from 31 centers. Fetal consult services are shared by neonatology and pediatric cardiology at 70% of centers. Three centers (10%) routinely perform fetal magnetic resonance imaging (MRI) for women with pregnancies complicated by fetal CHD. Genetic testing for CHD patients is routine at 76% of centers. Preoperative brain MRI is standard practice at 5 centers (17%), while cerebral NIRS monitoring is regularly used at 14 centers (48%). Use of electroencephalogram (EEG) after major cardiac surgery is routine in 5 centers (17%). Neurodevelopmental follow-up programs are offered at 30 centers (97%). CONCLUSIONS: Many aspects of fetal and neonatal CHD care are highly variable with evolving shared multidisciplinary models. IMPACT: Many aspects of fetal and neonatal CHD care are highly variable. Genetic testing, placental examination, preoperative neuroimaging, and postoperative EEG monitoring carry a high yield of finding abnormalities in patients with CHD and these tests may contribute to more precise prognostication and improve care. Evidence-based standards for prenatal and postnatal CHD care may decrease inter-center variability.

Ventilation Strategies During Extracorporeal Membrane Oxygenation for Neonatal Respiratory Failure: Current Approaches Among Level IV Neonatal ICUs.

To describe ventilation strategies used during extracorporeal membrane oxygenation (ECMO) for neonatal respiratory failure among level IV neonatal ICUs (NICUs). DESIGN: Cross-sectional electronic survey. SETTING: Email-based Research Electronic Data Capture survey. PATIENTS: Neonates undergoing ECMO for respiratory failure at level IV NICUs. INTERVENTIONS: A 40-question survey was sent to site sponsors of regional referral neonatal ECMO centers participating in the Children's Hospitals Neonatal Consortium. Reminder emails were sent at 2- and 4-week intervals. MEASUREMENTS AND MAIN RESULTS: Twenty ECMO centers responded to the survey. Most primarily use venoarterial ECMO (65%); this percentage is higher (90%) for congenital diaphragmatic hernia. Sixty-five percent reported following protocol-based guidelines, with neonatologists primarily responsible for ventilator management (80%). The primary mode of ventilation was pressure control (90%), with synchronized intermittent mechanical ventilation (SIMV) comprising 80%. Common settings included peak inspiratory pressure (PIP) of 16-20 cm H2O (55%), positive end-expiratory pressure (PEEP) of 9-10 cm H2O (40%), I-time 0.5 seconds (55%), rate of 10-15 (60%), and Fio2 22-30% (65%). A minority of sites use high-frequency ventilation (HFV) as the primary mode (5%). During ECMO, 55% of sites target some degree of lung aeration to avoid complete atelectasis. Fifty-five percent discontinue inhaled nitric oxide (iNO) during ECMO, while 60% use iNO when trialing off ECMO. Nonventilator practices to facilitate decannulation include bronchoscopy (50%), exogenous surfactant (25%), and noninhaled pulmonary vasodilators (50%). Common ventilator thresholds for decannulation include PEEP of 6-7 (45%), PIP of 21-25 (55%), and tidal volume 5-5.9 mL/kg (50%). CONCLUSIONS: The majority of level IV NICUs follow internal protocols for ventilator management during neonatal respiratory ECMO, and neonatologists primarily direct management in the NICU. While most centers use pressure-controlled SIMV, there is considerable variability in the range of settings used, with few centers using HFV primarily. Future studies should focus on identifying respiratory management practices that improve outcomes for neonatal ECMO patients.

Current Practices for Genetic Testing in Neonatal Extracorporeal Membrane Oxygenation: Findings from a National survey.

Introduction: Comprehensive genetic testing with whole-exome (WES) or whole-genome (WGS) sequencing facilitates diagnosis, can optimize treatment, and may improve outcomes in critically ill neonates, including those requiring extracorporeal membrane oxygenation (ECMO) for respiratory failure. Our objective was to describe practice variation and barriers to the utilization of comprehensive genetic testing for neonates on ECMO.Methods: We performed a cross-sectional survey of Level IV neonatal intensive care units in the United States across the Children's Hospitals Neonatal Consortium (CHNC).Results: Common indications for WES and WGS included concerning phenotype, severity of disease, unexpected postnatal clinical course, and inability to wean from ECMO support. Unexpected severity of disease on ECMO was the most common indication for rapid genetic testing. Cost of utilization was the primary barrier to testing. If rapid WES or WGS were readily available, 63% of centers would consider incorporating universal screening for neonates upon ECMO cannulation.Conclusion: Despite variation in the use of WES and WGS, universal testing may offer earlier diagnosis and influence the treatment course among neonates on ECMO. Cost is the primary barrier to utilization and most centers would consider incorporating universal screening on ECMO if readily available.

Patterns of acute kidney and hepatic injury and association with adverse outcomes in infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

OBJECTIVE: To describe patterns of renal and hepatic injury in infants with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Retrospective cohort of infants receiving therapeutic hypothermia for HIE was classified into groups based on organ injury: neither acute kidney injury (AKI) nor acute hepatic injury (AHI), isolated AKI, isolated AHI, or both AKI/AHI. Biomarkers and outcomes were described and analyzed. RESULTS: Among 188 infants, 55% had no AKI nor AHI, 7% had only AKI, 22% had only AHI and 16% had both AKI and AHI. Infants with both AKI/AHI had the highest mortality (47%) and worse outcomes, compared to other injury groups, although AKI/AHI was not significantly associated with mortality (hazard ratio 2.5; 95% CI 0.9-6.9), after accounting for severity of HIE. For surviving infants, biomarkers of organ injury, on average, normalized by discharge. CONCLUSION: Infants with HIE with both AKI/AHI have worse outcomes than infants with AKI or AHI alone.

Opioid exposure during therapeutic hypothermia and short-term outcomes in neonatal encephalopathy.

OBJECTIVE: To assess the association between opioid exposure during therapeutic hypothermia (TH) for perinatal hypoxic-ischemic encephalopathy (HIE) and in-hospital outcomes. STUDY DESIGN: In this retrospective cohort study, linked data were accessed on infants ≥36 weeks gestation, who underwent TH for HIE, born from 2010-2016 in 23 Neonatal Intensive Care Units participating in Children's Hospitals Neonatal Consortium and Pediatric Health Information Systems. We excluded infants who received opioids for >5 days. RESULTS: The cohort (n = 1484) was categorized as No opioid [240(16.2%)], Low opioid (1-2 days) [574 (38.7%)] and High opioid group (HOG, 3-5 days) [670 (45.2%)]. After adjusting for HIE severity, opioids were not associated with abnormal MRI, but were associated with decreased likelihood of complete oral feeds at discharge. HOG had increased likelihood of prolonged hospital stay and ventilation. CONCLUSION: Opioid exposure during TH was not associated with abnormal MRI; its association with adverse short-term outcomes suggests need for cautious empiric use.

Training pathways and careers for neonatologists interested in cardiovascular care.

Neonatologists and neonatal-perinatal trainees continue to be invested in the cardiovascular care of the newborn, many focusing their careers in this area of expertise. Multiple formalized structured and non-structured training pathways have evolved for neonatologists caring for infants with congenital heart disease and other cardiovascular pathologies. Furthermore, the evolution of neonatal hemodynamic science over the past decade has also spawned a formal training pathway in hemodynamics consultation to enhance standard of care and guide the management of infants at risk for cardiovascular compromise. Neonatologists have also chosen to expand upon on their neonatology training with clinical and research exposure to enhance their roles in neonatal cardiovascular care, including fetal care consultation, delivery room management, and perioperative cardiac intensive care consultation. To provide insight and career guidance to interested neonatal trainees and early career physicians, this perspective article highlights several different pathways in the care of neonates with cardiovascular disease.

Utilization of Therapeutic Hypothermia and Neurological Injury in Neonates with Mild Hypoxic-Ischemic Encephalopathy: A Report from Children's Hospital Neonatal Consortium.

OBJECTIVE: This study was aimed to describe utilization of therapeutic hypothermia (TH) in neonates presenting with mild hypoxic-ischemic encephalopathy (HIE) and associated neurological injury on magnetic resonance imaging (MRI) scans in these infants. STUDY DESIGN: Neonates ≥ 36 weeks' gestation with mild HIE and available MRI scans were identified. Mild HIE status was assigned to hyper alert infants with an exaggerated response to arousal and mild HIE as the highest grade of encephalopathy recorded. MRI scans were dichotomized as "injury" versus "no injury." RESULTS: A total of 94.5% (257/272) neonates with mild HIE, referred for evaluation, received TH. MRI injury occurred in 38.2% (104/272) neonates and affected predominantly the white matter (49.0%, n = 51). Injury to the deep nuclear gray matter was identified in (10.1%) 20 infants, and to the cortex in 13.4% (n = 14 infants). In regression analyses (odds ratio [OR]; 95% confidence interval [CI]), history of fetal distress (OR = 0.52; 95% CI: 0.28-0.99) and delivery by caesarian section (OR = 0.54; 95% CI: 0.31-0.92) were associated with lower odds, whereas medical comorbidities during and after cooling were associated with higher odds of brain injury (OR = 2.31; 95% CI: 1.37-3.89). CONCLUSION: Majority of neonates with mild HIE referred for evaluation are being treated with TH. Odds of neurological injury are over two-fold higher in those with comorbidities during and after cooling. Brain injury predominantly involved the white matter. KEY POINTS: · Increasingly, neonates with mild HIE are being referred for consideration for hypothermia therapy.. · Drift in clinical practice shows growing number of neonates treated with hypothermia as having mild HIE.. · MRI data show that 38% of neonates with mild HIE have brain injury, predominantly in the white matter..

Association between anti-seizure medication and outcomes in infants.

OBJECTIVE: To compare treatment failure between: (1) infants treated with phenobarbital versus levetiracetam for first-line treatment and (2) infants treated with phenytoin versus levetiracetam for second-line treatment following phenobarbital. STUDY DESIGN: This retrospective cohort study included infants with seizures receiving phenobarbital or levetiracetam as the initial anti-seizure medication. Treatment failure was defined as the need for additional anti-seizure medication within 24-72 h and compared using mixed-effect logistic regression after adjustment for confounding factors, including center. RESULTS: In this cohort of 6842 infants, the incidence of treatment failure was 31% vs. 38% in infants receiving first-line phenobarbital versus levetiracetam (adjusted OR: 0.70; 95% CI 0.58-0.84). There was no significant difference in second-line treatment failure (adjusted OR: 1.31; 95% CI 0.92-1.86). CONCLUSIONS: First-line treatment of neonatal seizures with phenobarbital is associated with a lower rate of treatment failure than levetiracetam. There was no significant difference in second-line treatment failure.

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study.

Importance: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, Setting, and Participants: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main Outcomes and Measures: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and Relevance: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial Registration: ClinicalTrials.gov Identifier: NCT01192776.

Noninvasive neurocritical care monitoring for neonates on extracorporeal membrane oxygenation: where do we stand?

OBJECTIVE: To determine practice variation in the utilization of neuromonitoring modalities in neonatal extracorporeal membrane oxygenation (ECMO) patients across Level IV neonatal intensive care units (NICUs). STUDY DESIGN: Cross-sectional survey design using electronic surveys sent to site sponsors of a multicenter collaborative of 34 Level IV NICUs of the Children's Hospitals Neonatal Consortium (CHNC) from June to August 2018. RESULTS: We had 22 survey respondents from CHNC ECMO centers. Twenty-seven percent of respondents routinely monitored for seizures using electroencephalogram. Cerebral near infrared spectroscopy was used by 50%. Head ultrasound was performed by 95% but the frequency, duration, and type of views varied. Post ECMO screening brain MRI prior to hospital discharge was routinely performed by 77% of respondents. A majority of centers (95%) performed neurodevelopmental follow-up after hospital discharge. CONCLUSIONS: There is variation in neuromonitoring practices in Level IV NICUs performing ECMO. Lack of evidence and clear outcome benefits has contributed to practice variation across institutions.

Patent Ductus Arteriosus of the Preterm Infant.

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 + 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.

Antimicrobial therapy utilization in neonates with hypoxic-ischemic encephalopathy (HIE): a report from the Children's Hospital Neonatal Database (CHND).

OBJECTIVE(S): Quantify antimicrobial therapy (AMT) use in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia (HIE/TH). STUDY DESIGN: Newborns with HIE/TH were identified from the Children's Hospital Neonatal Database (CHND). Early infection (onset ≤7 days of life) was defined as "confirmed" (culture proven) or "suspected infection" (culture negative but treated) and compared with a "no infection" group. RESULTS: 1501/1534 (97.8%) neonates received AMT. 36 (2.3%) had confirmed, 255 (16.6%) suspected, and 1243 (81.0%) had no infection. The median (IQR) AMT duration was 13 (8-21), 8 (7-10), and 3 (3-7) days for the three groups, respectively (p < 0.001). AMT duration of use varied significantly across centers, adjusted for covariates (OR 1.88, 95% CI: 1.43-2.46). CONCLUSION(S): Incidence of early confirmed infection in neonates with HIE/TH (23/1000) is significantly higher than reported rates of early onset sepsis in term and near term infants (0.5-1.0/1000 live births). Antimicrobial-stewardship opportunities exist in infants with negative cultures.