The Current State of Neonatal Neurodevelopmental Follow-up Programs in North America: A Children's Hospitals Neonatal Consortium Report.

OBJECTIVE: This study aimed to determine neonatal neurodevelopmental follow-up (NDFU) practices across academic centers. STUDY DESIGN: This study was a cross-sectional survey that addressed center-specific neonatal NDFU practices within the Children's Hospitals Neonatal Consortium (CHNC). RESULTS: Survey response rate was 76%, and 97% of respondents had a formal NDFU program. Programs were commonly staffed by neonatologists (80%), physical therapists (77%), and nurse practitioners (74%). Median gestational age at birth identified for follow-up was ≤32 weeks (range 26-36). Median duration was 3 years (range 2-18). Ninety-seven percent of sites used Bayley Scales of Infant and Toddler Development, but instruments used varied across ages. Scores were recorded in discrete electronic data fields at 43% of sites. Social determinants of health data were collected by 63%. Care coordination and telehealth services were not universally available. CONCLUSION: NDFU clinics are almost universal within CHNC centers. Commonalities and variances in practice highlight opportunities for data sharing and development of best practices. KEY POINTS: · Neonatal NDFU clinics help transition high-risk infants home.. · Interdisciplinary neonatal intensive care unit follow-up brings together previously separated outpatient service lines.. · This study reviews the current state of neonatal NDFU in North America..

Phenobarbital as a Sedation Strategy to Reduce Opioid and Benzodiazepine Burden in Neonatal Extracorporeal Membrane Oxygenation.

OBJECTIVE: The study aims to describe our experience with the implementation of phenobarbital as a primary sedation strategy during neonatal extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: Retrospective chart review in a level IV neonatal intensive care unit between 2011 and 2021 comparing neonatal ECMO patients before and after the implementation of a sedation-analgesia (SA) protocol using scheduled phenobarbital as the primary sedative. Groups were compared for neonatal and ECMO characteristics, cumulative SA doses, and in-hospital outcomes. Comparison between groups was performed using Mann-Whitney test on continuous variables and chi-square on nominal variables. RESULTS: Forty-two patients were included, 23 preprotocol and 19 postprotocol. Birth, pre-ECMO, and ECMO clinical characteristics were similar between groups except for a lower birth weight in the postprotocol group (p = 0.024). After standardization of phenobarbital SA protocol, there was a statistically significant reduction in median total morphine dose (31.38-17.65 mg/kg, p = 0.006) and median total midazolam dose (36.21-6.36 mg/kg, p < 0.001). There was also a reduction in median total days on morphine by 7.5 days (p = 0.026) and midazolam by 6.6 days (p = 0.003). There were no differences in ECMO duration or in-hospital outcomes between groups. CONCLUSION: In this cohort, short-term use of phenobarbital as primary sedation strategy during neonatal ECMO was associated with reduced opioid and midazolam burden. Such reduction, however, did not affect in-hospital outcomes. KEY POINTS: · Prolonged sedation on ECMO puts infants at risk for iatrogenic withdrawal.. · Phenobarbital is a feasible sedation strategy for ECMO.. · Phenobarbital sedation strategy may mitigate risk by decreasing opioid and midazolam burden..

Extracorporeal Membrane Oxygenation (ECMO) for suspected neonatal genetic diagnoses with cardiorespiratory failure.

Recent data describe an increasing use of extracorporeal membrane oxygenation (ECMO) in neonates with various clinical conditions besides primary respiratory or cardiac diagnoses. Infants with underlying genetic disorders characterized by cardiopulmonary failure pose unique management challenges. When pathognomonic dysmorphic features for common genetic diagnoses are not present, the prognosis is uncertain at best when determining ECMO candidacy. Lengthy turnaround times of genetic testing often delay definitive diagnosis during the ECMO course. Clinical management pathways to guide practice and evidence to support the use of ECMO in rare genetic conditions are lacking. The decision to initiate ECMO is daunting but may be of benefit if the subsequent genetic diagnosis is non-lethal. In lethal genetic cases warranting discontinuation of care, the time spent on ECMO may still be advantageous as a bridge to diagnosis while allowing for parental bonding with the terminally ill infant. Diagnostic confirmation may also facilitate the attainment of closure for these parents. Here, we report our experience providing ECMO to three neonates presenting with cardiorespiratory failure and later diagnosed with rare genetic syndromes. We share the challenges faced, lessons learned, and outcomes of these critically ill neonates.

Use of vasopressin in persistent pulmonary hypertension of the newborn: A case series.

Treatment of neonates with persistent pulmonary hypertension of newborn includes optimization of ventilatory support, use of pulmonary vasodilators, and/or inotropic support. If refractory to this management, some may require extracorporeal membrane oxygenation. We describe a case series of 10 neonates with refractory persistent pulmonary hypertension of newborn treated with vasopressin in a single tertiary center. Mean initiation time of vasopressin was at 30 h of life with a dose ranging from 10 to 85 milliunits/kg/h. Oxygenation index decreased after 12 h of vasopressin exposure (25 to 11) and mean arterial pressure improved after 1 h (45 to 58 mm Hg). Extracorporeal membrane oxygenation was averted in 50% of the cases with transient hyponatremia as the only notable side effect. Although our findings are exploratory and further research is needed to establish safety and efficacy, our experience suggests that vasopressin may have rescue properties in the management of refractory persistent pulmonary hypertension of newborn.

Bleeding Complications in Neonates Receiving Extracorporeal Membrane Oxygenation and Controlled Hypothermia.

OBJECTIVE: Safety and efficacy data on controlled hypothermia (CH) for neonates with moderate to severe hypoxic ischemic encephalopathy has been extrapolated to a subgroup of these patients who also require extracorporeal membrane oxygenation for refractory persistent pulmonary hypertension of the newborn (PPHN). However, safety data on the concomitant use of CH and extracorporeal membrane oxygenation (ECMO) are lacking. METHODS: This is a single-center retrospective study of neonates ≥35 weeks' gestation with refractory PPHN who required ECMO between January 2010 and December 2020. Study groups were divided into those receiving CH/ECMO versus ECMO only. Baseline characteristics, short-term outcomes, and brain magnetic resonance imaging (MRI) data were compared. RESULTS: A total of 36 neonates who received ECMO for refractory PPHN were included. Of these, 44.4% (n = 16) received CH/ECMO and 55.6% (n = 20) received ECMO only. Bleeding complications were more common in CH/ECMO group 50% (n = 8) versus ECMO only 15% (n = 3, p = 0.023). T1 brain MRI severity scores were higher in CH/ECMO group versus ECMO only group, however, there were no statistical difference in T2 and diffusion-weighted image scores. Functional status and survival to discharge were comparable between groups. CONCLUSION: In our cohort, neonates who received CH/ECMO had higher bleeding complications than ECMO only group with comparable functional status and survival at discharge. KEY POINTS: · Safety data on the concomitant use of CH and ECMO are lacking in neonates.. · In our cohort, neonates who received CH/ECMO had higher bleeding complications than ECMO only group.. · Functional status and survival to discharge were no differences between the two groups..

Severe Pulmonary Hemorrhage in a Neonate With Hypoxic Ischemic Encephalopathy and Sepsis Managed on Extracorporeal Membrane Oxygenation.

Pulmonary hemorrhage (PH) is an infrequent and potentially fatal event in term neonates. Reports of successful management of PH on extracorporeal membrane oxygenation (ECMO) are limited, given the accentuated risk of mortality imposed by the use of heparin to prevent thrombosis on ECMO. We present a case of a term neonate with hypoxic ischemic encephalopathy undergoing controlled hypothermia who developed hypoxic respiratory failure, hemodynamic instability, Enterobacter cloacae pneumonia and sepsis complicated by severe PH who required support with veno-arterial ECMO. We describe the therapeutic strategies used on veno-arterial ECMO to successfully manage this infant, including clamping the endotracheal tube, aggressive correction of coagulopathy, and use of dornase alfa, as well as elaborate on the subtle changes in ECMO parameters during the run that preceded worsening pneumonia with sepsis.

Improving timeliness of newborn screens in the neonatal intensive care unit: a quality improvement initiative.

BACKGROUND: Despite the established utility of newborn screening tests (NBS), achieving timely specimen transit is a challenge for neonatal intensive care units (NICU). METHODS: This project was conducted between September 2017 and July 2020 using the Plan-Do-Study-Act (PDSA) tool. Our primary aim was to increase the percent of NBS samples reaching the state laboratory within 1 day of collection by 20% by April 2020. Process, outcome, and balancing measures were monitored. RESULTS: Five hundred and eighty-five NBS were collected. There was special cause variation with improvement in the percent of samples received within 1 day of collection from 28 to 77%. Special cause variation was also observed in the process measures without an increase in the percent of unacceptable samples. CONCLUSIONS: Standardizing the NBS collection processes by adopting a sample collection window and same day courier pickup ensures timely specimen transit without adversely affecting the quality of samples collected.

ECMO as a Platform for Rapid Ammonia Removal in a Neonate with Multienzyme Urea Cycle Disorder.

Since the initial deployment of neonatal extracorporeal membrane oxygenation (ECMO) for respiratory failure, the use of ECMO in this population has diversified. We present a term female infant with carbamoyl phosphate synthetase 1 and partial N-acetylglutamate synthase deficiencies who developed severe hyperammonemia refractory to medical management requiring venoarterial ECMO-driven continuous veno-venous hemodiafiltration for ammonia detoxification. This case report illustrates a subpopulation where neonatal ECMO may improve survival and neurodevelopmental outcomes. To our knowledge, this is the first reported case of a urea cycle defect arising from two proximal enzyme deficiencies. Also, this is one of the few reported patients with UCD associated with peak ammonia levels >2,000 µmol/L who survived to hospital discharge after the successful use of ECMO for ammonia reduction. This case will add to the existing scant literature supporting the use of ECMO as a platform for rapid removal of serum ammonia.

Streptococcus pyogenes purpura fulminans and septic shock: A case highlighting the ethical considerations of high-risk extracorporeal membrane oxygenation.

Separately, refractory septic shock and purpura fulminans have very poor outcomes. The ethics involved in offering extracorporeal membrane oxygenation to very high-risk patients is complex. We report a novel case of refractory shock requiring veno-arterial extracorporeal membrane oxygenation and continuous renal replacement therapy due to Streptococcus pyogenes bacteremia with purpura fulminans to highlight the ethical challenges in offering extracorporeal membrane oxygenation to a patient with such a poor likelihood of survival.

Management Strategies during a VA ECMO Run in a Neonate with E. Coli Septic Shock Masquerading as Hypoxic Ischemic Encephalopathy.

Advances in neonatal care for hypoxic respiratory failure, with high-frequency ventilation and inhaled nitric oxide, have led to a decreased need for extracorporeal membrane oxygenation (ECMO). However, neonates resistant to such therapies are more complex and at higher risk of mortality. One such population includes those with hypoxic ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). We present a challenging case of a full-term neonate with inotrope-resistant Escherichia coli septic shock, profound coagulopathy, hypoxic respiratory failure, and HIE requiring CH and venoarterial (VA) ECMO. We illustrate that family-centered decision-making, ECMO, primary team, and subspecialist support is critical to success. In addition, we share the strategic medical interventions concomitantly used with VA ECMO to aid in the survival of this high-risk infant such as continuous veno-venous hemofiltration with AN69 membrane for cytokine and fluid removal, prostaglandin use to relieve right ventricular strain in malignant pulmonary hypertension, and cautious use of bronchoscopy to assist in lung recruitment.

Newborn Infant With Mothball Toxicity Due to Maternal Ingestion.

Naphthalene poisoning due to exposure to mothballs is a common cause of toxicity in children worldwide. Naphthalene toxicity is known to cause hemolytic anemia, methemoglobinemia, and hepatic and renal injury. Neonates are more susceptible to the effects of oxidative stress from naphthalene because of their low glutathione stores and immaturity of hepatic enzymes. However, there are no reported cases of chronic fetal exposure to naphthalene during pregnancy. We report a novel case of chronic fetal exposure to naphthalene-containing mothballs that occurred from the second trimester through the third trimester of pregnancy. Our patient presented with hyperbilirubinemia, requiring exchange transfusion, severe hemolytic anemia, pulmonary hypertension, respiratory failure, and renal failure and progressed to develop "bronze baby" syndrome. Pregnant mothers should be diligently screened for such exposures and if found should receive psychiatric evaluation and counseling to prevent such devastating effects in neonates.

Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic-Ischemic Encephalopathy Receiving Controlled Hypothermia.

OBJECTIVE: Identify population pharmacokinetics and pharmacodynamic target attainment of gentamicin in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). DESIGN: Prospective open-label pharmacokinetic study. Gentamicin concentrations were modeled and dosing regimens simulated for a 5000-patient neonatal population with HIE receiving CH using PMetrics, a nonparametric, pharmacometric modeling, and simulation package for R. SETTING: A 189-bed children's tertiary care teaching hospital. RESULTS: Twelve patients, 5 (42%) females and 7 (58%) males, met inclusion criteria with a median gestation age of 39.9 weeks (interquartile range [IQR] 38.5-40.2 wks) and a median birthweight (BW) of 3.3 kg (IQR 3.1-3.7 kg). Gentamicin concentrations were best described by a two-compartment model with first-order elimination with BW as a covariate on volume of distribution (Vd). The mean total body population clearance (CL) was 2.2 ± 0.7 ml/minute/kg, and the volume of the central compartment was 0.44 ± 0.06 L/kg. The R2 , bias, and precision for the observed versus population predicted model were 0.917, 1.15, and 10.9 µg/ml; the R2 , bias, and precision for the observed versus individual predicted model were 0.982, -0.132, and 0.932 µg/ml, respectively. The calculated mean population estimate for the total Vd was 0.96 ± 0.4 L/kg. The dosing regimen that most consistently produced a maximum concentration (Cmax ) in the range of 10-12 mg/L with a minimum concentration (Cmin ) level less than 2 mg/L was 5 mg/kg/dose given every 36 hours. CONCLUSION: These data suggest the population pharmacokinetics of gentamicin in neonates with HIE receiving CH have an increase in gentamicin CL and are different from previous reports in neonates with HIE not receiving CH and/or neonates without HIE. This analysis suggests a dosing regimen of 5 mg/kg/dose every 36 hours results in a gentamicin Cmax within the range of 10-12 mg/L with a Cmin lower than 2 mg/L, which is appropriate for treating susceptible gram-negative organisms with minimum inhibitory concentrations of 1 mg/L or lower.

Diagnostic Potential of Neural Exosome Cargo as Biomarkers for Acute Brain Injury.

Objective: Neuronal exosomes purified from peripheral blood samples have been proposed as diagnostic tool in the setting of acute brain injury but never tested clinically. We hypothesized that exosome protein biomarkers would change over time following acute hypoxic brain injury and would predict response to therapy. Methods: Synaptopodin (SYNPO), an actin-associated protein present in postsynaptic spines, was evaluated as a potential biomarker as well as: synaptophysin, neuron-specific enolase, and mitochondrial cytochrome c oxidase. A secondary analysis was performed on neonatal samples collected at 8, 10, and 14 h after the initiation of therapeutic-controlled hypothermia for acute hypoxic-ischemic encephalopathy (n = 14). Neuronal exosomes were purified from serum and protein levels were quantified using standard ELISA methods. The primary study outcomes were length of stay (LOS), discharge on seizure medication (DCMED), and composite neuroimaging score (NIS). Results: The slope of change in neuronal exosome SYNPO between 8 and 14 h appeared to be the most promising biomarker for all three clinical study outcomes. SYNPO was highly correlated with LOS (-0.91, P < 0.001). SYNPO increased in 6/8 without DCMED and was worse or neutral in 5/5 with DCMED (P = 0.02). All four neonates with an abnormal NIS had neutral or decreasing SYNPO (P = 0.055). Other candidate biomarkers were not associated with outcomes. Interpretation: This report provides the first clinical evidence that neural exosomes turn over rapidly enough in the peripheral circulation to be used as a "troponin-like" test following acute brain injury. Optimal sampling and biomarkers likely vary with type of brain injury.

Transition to Routine Premedication for Nonemergent Intubations in a Level IV Neonatal Intensive Care Unit.

OBJECTIVE: This study aims to test whether implementing a guideline for nonemergent intubation improves the rate of premedication for nonemergent intubations in an academic level IV neonatal intensive care unit (NICU). We further sought to test the hypothesis that neonates who receive premedication for a nonemergent intubation have decreased pain scores at the time of intubation, fewer intubation attempts, and no associated adverse events. STUDY DESIGN: This was a prospective observational study with ongoing audit and feedback as well as statistical process control analysis. Data collection began on October 1, 2014. Clinical guideline implementation began in October 2015. A percent "P"-chart spanning seven-quarters was constructed with statistical process control analysis plotting premedication rates over time. Student's t-tests or Wilcoxon rank-sum tests were used for secondary outcomes. RESULTS: The mean number of nonemergent intubations given premedications increased from 34 to 82%. The mean pain score was lower when premedications were given: 0.34 (95% confidence interval [CI]: 0.10-0.58) versus 2.8 (95% CI: 1.9-3.6) (p < 0.001). The number of intubation attempts did not differ with premedications. CONCLUSION: Adopting a guideline with supporting educational initiatives to standardize premedication before nonemergent intubations increased this practice. This regimen lowered clinical pain scores with no difference in the number of intubation attempts.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Ampicillin in Neonates with Hypoxemic-Ischemic Encephalopathy in the Setting of Controlled Hypothermia.

STUDY OBJECTIVE: To describe the population pharmacokinetics and pharmacodynamic target attainment of ampicillin in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). DESIGN: Prospective, open-label pharmacokinetic study. SETTING: A 189-bed, freestanding children's tertiary care teaching hospital. PATIENTS: Thirteen neonates (three females and 10 males) with HIE encephalopathy receiving CH and ampicillin 100 mg/kg/dose intravenously every 8 hours who were admitted to the neonatal intensive care unit between May 2013 and June 2014. INTERVENTION: Blood (0.5 ml) was collected at 8, 10, and 14 hours of life coinciding with other scheduled laboratory investigations for ampicillin concentration analysis, providing a total of three ampicillin serum concentrations/patient. MEASUREMENTS AND MAIN RESULTS: The patients had a median gestational age of 39 weeks, mean ± SD birth weight of 3.34 ± 0.61 kg, and mean ± SD estimated glomerular filtration rate of 43 ± 12.6 ml/minute/1.73 m2 . Ampicillin concentrations were best described by a two-compartment model with gestational age as a covariate with allometric scaling on total body clearance. The mean ± SD total body clearance for the population was 0.43 ± 0.12 ml/minute/kg (median 0.36 ml/min/kg), volume of the central compartment was 0.35 ± 0.46 L/kg, and the calculated population estimate for the total volume of distribution (Vd ) was 0.52 ± 0.28 L/kg. The R2 , bias, and precision were 0.497, 0.538, and 10.5 µg/ml and 0.972, -0.125, and 0.938 µg/ml for the observed versus population and observed versus individual predicted concentrations, respectively. Monte Carlo simulation was conducted to determine the probability of target attainment for 12 simulated ampicillin dosing regimens using 50% and 100% of the dosing interval that free drug concentration remains above the minimum inhibitory concentration (fT > MIC) in 5000 simulated neonates with HIE receiving CH. Dosing regimens of 25 and 50 mg/kg/dose every 24 hours provided for an appropriate pharmacodynamic target attainment of 50% and 100% fT > MIC. CONCLUSION: To our knowledge, this study describes the first pharmacokinetic data of ampicillin in neonates with HIE receiving CH and demonstrates a reduced total body clearance and an increased Vd for ampicillin. Based on these data, modifications to the ampicillin dosing regimens seem appropriate during the period of CH. Dosing regimens of ampicillin 25 and 50 mg/kg/day were able achieve optimal probability of target attainment against all susceptible gram-negative and gram-positive bacteria in a population of neonates with HIE receiving CH for 50% and 100% fT > MIC.

The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice.

Neonatal colonization by microbes, which begins immediately after birth, is influenced by gestational age and the mother's microbiota and is modified by exposure to antibiotics. In neonates, prolonged duration of antibiotic therapy is associated with increased risk of late-onset sepsis (LOS), a disorder controlled by neutrophils. A role for the microbiota in regulating neutrophil development and susceptibility to sepsis in the neonate remains unclear. We exposed pregnant mouse dams to antibiotics in drinking water to limit transfer of maternal microbes to the neonates. Antibiotic exposure of dams decreased the total number and composition of microbes in the intestine of the neonates. This was associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage-restricted progenitor cells in the bone marrow of antibiotic-treated and germ-free neonates. Antibiotic exposure of dams reduced the number of interleukin-17 (IL-17)-producing cells in the intestine and production of granulocyte colony-stimulating factor (G-CSF). Granulocytopenia was associated with impaired host defense and increased susceptibility to Escherichia coli K1 and Klebsiella pneumoniae sepsis in antibiotic-treated neonates, which could be partially reversed by administration of G-CSF. Transfer of a normal microbiota into antibiotic-treated neonates induced IL-17 production by group 3 innate lymphoid cells (ILCs) in the intestine, increasing plasma G-CSF levels and neutrophil numbers in a Toll-like receptor 4 (TLR4)- and myeloid differentiation factor 88 (MyD88)-dependent manner and restored IL-17-dependent resistance to sepsis. Specific depletion of ILCs prevented IL-17- and G-CSF-dependent granulocytosis and resistance to sepsis. These data support a role for the intestinal microbiota in regulation of granulocytosis, neutrophil homeostasis and host resistance to sepsis in neonates.