Clinical Focus


  • Neonatal-Perinatal Medicine

Professional Education


  • Board Certification: American Board of Pediatrics, Neonatal-Perinatal Medicine (2010)
  • Fellowship: Univ of California San Francisco, School of Medicine (2009) CA United States of America
  • Board Certification: American Board of Pediatrics, Pediatrics (2006)
  • Residency: Univ of California San Francisco, School of Medicine (2006) CA United States of America
  • Internship: Univ of California San Francisco, School of Medicine (2004) CA United States of America
  • Medical Education: University of California at San Francisco School of Medicine (2003) CA

Clinical Trials


  • TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy Not Recruiting

    The TIME study is a randomized, controlled trial to evaluate impact on early measures of neurodevelopment and the safety profile of therapeutic hypothermia in term neonates with Mild Hypoxic-Ischemic Encephalopathy who are < 6 hours of age. Neurodevelopmental outcome will be assessed at 12-14 months of age. The study will enroll 68 neonates randomized to therapeutic hypothermia or normothermia across 5 centers in California.

    Stanford is currently not accepting patients for this trial.

    View full details

2023-24 Courses


All Publications


  • Increasing in-person medical interpreter utilization in the NICU through a bundle of interventions. Journal of perinatology : official journal of the California Perinatal Association Feister, J., Razdan, S., Sharp, D., Punjabi, S., Blecharczyk, E., Escobar, V., Gay, P. M., Scala, M., Bonifacio, S. 2024

    Abstract

    In-person medical interpretation improves communication with patients who have preferred language other than English (PLOE). Multi-dimensional barriers to use of medical interpreters limit their use in the NICU.Medical teams in our NICU were not consistently using in-person medical interpreters, leading to ineffective communication with families with PLOE.Interventions included staff educational sessions and grand rounds regarding equitable language access, distribution of interpreter request cards to families, and allocation of dedicated in-person interpreters for NICU rounds. Interpreter utilization was calculated by total requests per Spanish-speaking person day in the NICU.Interpreter utilization increased five-fold during the intervention period (from 0.2 to 1.0 requests per Spanish-speaking person day).We substantially increased our unit in-person interpreter utilization through a bundle of multifaceted interventions, many of which were low-cost. NICUs should regard dedicated medical interpreters as a critical part of the care team.

    View details for DOI 10.1038/s41372-024-01915-5

    View details for PubMedID 38424233

    View details for PubMedCentralID 1955368

  • Relationship of Neonatal Seizure Burden Prior to Treatment and Response to Initial Anti-Seizure Medication. The Journal of pediatrics Numis, A. L., Glass, H. C., Comstock, B. A., Gonzalez, F., Maitre, N. L., Massey, S. L., Mayock, D. E., Mietzsch, U., Natarajan, N., Sokol, G. M., Bonifacio, S., Van Meurs, K., Thomas, C., Ahmad, K., Heagerty, P., Juul, S. E., Wu, Y. W., Wusthoff, C. J. 2024: 113957

    Abstract

    To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pre-treatment maximal hourly seizure burden and total seizure duration with successful response to initial anti-seizure medication (ASM).Retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between 1/25/2017 and 10/9/2019. We evaluated a cohort of neonates born ≥36 weeks' gestation with moderate to severe HIE who underwent continuous electroencephalogram (EEG) monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1)pre-treatment maximal hourly seizure burden, (2)pre-treatment total seizure duration, (3)time from first seizure to initial ASM, and (4)successful response to initial ASM.Among 39 neonates meeting inclusion criteria, higher pre-treatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pre-treatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (RR 1.007, 95% CI 1.003-1.010).Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

    View details for DOI 10.1016/j.jpeds.2024.113957

    View details for PubMedID 38360261

  • Acute kidney injury in neonates with hypoxic ischemic encephalopathy based on serum creatinine decline compared to KDIGO criteria. Pediatric nephrology (Berlin, Germany) Ahn, H. C., Frymoyer, A., Boothroyd, D. B., Bonifacio, S., Sutherland, S. M., Chock, V. Y. 2024

    Abstract

    Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia (HIE + TH) are at risk for acute kidney injury (AKI). The standardized Kidney Disease Improving Global Outcomes (KDIGO) criteria identifies AKI based on a rise in serum creatinine (SCr) or reduced urine output. This definition is challenging to apply in neonates given the physiologic decline in SCr during the first week of life. Gupta et al. proposed alternative neonatal criteria centered on rate of SCr decline. This study aimed to compare the rate of AKI based on KDIGO and Gupta in neonates with HIE and to examine associations with mortality and morbidity.A retrospective review was performed of neonates with moderate to severe HIE + TH from 2008 to 2020 at a single center. AKI was assessed in the first 7 days after birth by KDIGO and Gupta criteria. Mortality, brain MRI severity of injury, length of stay, and duration of respiratory support were compared between AKI groups.Among 225 neonates, 64 (28%) met KDIGO, 69 (31%) neonates met Gupta but not KDIGO, and 92 (41%) did not meet either definition. Both KDIGO-AKI and GuptaOnly-AKI groups had an increased risk of the composite mortality and/or moderate/severe brain MRI injury along with longer length of stay and prolonged duration of respiratory support compared to those without AKI.AKI in neonates with HIE + TH was common and varied by definition. The Gupta definition based on rate of SCr decline identified additional neonates not captured by KDIGO criteria who are at increased risk for adverse outcomes. Incorporating the rate of SCr decline into the neonatal AKI definition may increase identification of clinically relevant kidney injury in neonates with HIE + TH.

    View details for DOI 10.1007/s00467-024-06287-8

    View details for PubMedID 38326648

    View details for PubMedCentralID 4209658

  • Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series). Pediatric research Molloy, E. J., El-Dib, M., Soul, J., Juul, S., Gunn, A. J., Bender, M., Gonzalez, F., Bearer, C., Wu, Y., Robertson, N. J., Cotton, M., Branagan, A., Hurley, T., Tan, S., Laptook, A., Austin, T., Mohammad, K., Rogers, E., Luyt, K., Wintermark, P., Bonifacio, S. L. 2023

    Abstract

    The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

    View details for DOI 10.1038/s41390-023-02895-6

    View details for PubMedID 38114609

    View details for PubMedCentralID 7480736

  • Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial. Archives of disease in childhood. Fetal and neonatal edition Mietzsch, U., Kolnik, S. E., Wood, T. R., Natarajan, N., Gonzalez, F. F., Glass, H., Mayock, D. E., Bonifacio, S. L., Van Meurs, K., Comstock, B. A., Heagerty, P. J., Wu, T. W., Wu, Y. W., Juul, S. E. 2023

    Abstract

    To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE).Secondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves.Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA.479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE).Standardised SE was used across sites before and after TH. All providers underwent standardised SE training.Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months.Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe.Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

    View details for DOI 10.1136/archdischild-2023-326102

    View details for PubMedID 38071538

  • Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Mietzsch, U., Kolnik, S. E., Wood, T., Natarajan, N., Gonzalez, F. F., Glass, H., Mayock, D. E., Bonifacio, S. L., Van Meurs, K., Comstock, B. A., Heagerty, P. J., Wu, T., Wu, Y. W., Juul, S. E., HEAL Trial Study Grp 2023
  • Scalp Swelling, a Proxy for "Birth Trauma," Is Not Associated With Neonatal Brain Injury. Neurology Bonifacio, S. L., de Vries, L. S. 2023

    View details for DOI 10.1212/WNL.0000000000208025

    View details for PubMedID 37848335

  • Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia. Neurology Glass, H. C., Numis, A. L., Comstock, B. A., Gonzalez, F. F., Mietzsch, U., Bonifacio, S. L., Massey, S., Thomas, C., Natarajan, N., Mayock, D. E., Sokol, G. M., Van Meurs, K. P., Ahmad, K. A., Maitre, N., Heagerty, P. J., Juul, S. E., Wu, Y. W., Wusthoff, C. J. 2023

    Abstract

    BACKGROUND AND OBJECTIVES: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin (Epo) or placebo for neonates with HIE treated with therapeutic hypothermia.METHODS: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at five one-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire cEEG recording was calculated using the arithmetic mean of the five EEG background ratings (normal=0; discontinuous=1; severely abnormal=2) as follows: "predominantly normal" (mean=0), "normal/discontinuous" (0

    View details for DOI 10.1212/WNL.0000000000207744

    View details for PubMedID 37816642

  • Neonatal encephalopathy and hypoxic-ischemic encephalopathy: moving from controversy to consensus definitions and subclassification. Pediatric research Molloy, E. J., Branagan, A., Hurley, T., Quirke, F., Devane, D., Taneri, P. E., El-Dib, M., Bloomfield, F. H., Maeso, B., Pilon, B., Bonifacio, S. L., Wusthoff, C. J., Chalak, L., Bearer, C., Murray, D. M., Badawi, N., Campbell, S., Mulkey, S., Gressens, P., Ferriero, D. M., de Vries, L. S., Walker, K., Kay, S., Boylan, G., Gale, C., Robertson, N. J., D'Alton, M., Gunn, A., Nelson, K. B. 2023

    View details for DOI 10.1038/s41390-023-02775-z

    View details for PubMedID 37573378

    View details for PubMedCentralID 6477286

  • Association of Primary Language with Very Low Birthweight Outcomes in Hispanic Infants in California. The Journal of pediatrics Feister, J., Kan, P., Bonifacio, S. L., Profit, J., Lee, H. C. 2023: 113527

    Abstract

    To determine the association of Spanish as a primary language for a family with the health outcomes of Hispanic infants with very low birthweight (VLBW, <1500g).Data from the California Perinatal Quality Care Collaborative linked to hospital discharge records were analyzed. Hispanic infants with VLBW born between 2009-2018 with a primary language of English or Spanish were included. Outcomes selected were hypothesized to be sensitive to language barriers. Multivariable logistic regression models and mixed models estimated associations between language and outcomes.Of 18,364 infants meeting inclusion criteria, 27% (n=4,976) were born to families with Spanish as a primary language. In unadjusted analyses, compared with infants of primarily English-speaking families, these infants had higher odds of hospital readmission within 1 year [OR 1.11 (95% CI 1.02-1.21)], higher odds to receive human milk at discharge [OR 1.32 (95% CI 1.23-1.42)], and lower odds of discharge home with oxygen [OR 0.83 (95% CI 0.73-0.94)]. In multivariable analyses, odds of readmission and home oxygen remained significant when adjusting for infant but not maternal and hospital characteristics. Higher odds for receipt of any human milk at discharge were significant in all models. Remaining outcomes did not differ between groups.Significant differences exist between Hispanic infants with VLBW of primarily Spanish- versus English-speaking families. Exploration of strategies to prevent readmissions of infants of families with Spanish as a primary language is warranted.

    View details for DOI 10.1016/j.jpeds.2023.113527

    View details for PubMedID 37263521

  • Early Discontinuation of Phenobarbital After Acute Symptomatic Neonatal Seizures in the Term Newborn. Neurology. Clinical practice Carrasco, M., Bonifacio, S. L., deVeber, G., Chau, V. 2023; 13 (2): e200125

    Abstract

    Acute symptomatic seizures in the term newborn are often seen after perinatal brain injury. Common etiologies include hypoxic-ischemic encephalopathy, ischemic stroke, intracranial hemorrhage, metabolic derangements, and intracranial infections. Neonatal seizures are often treated with phenobarbital, which may cause sedation and may have significant long-term effects on brain development. Recent literature has suggested that phenobarbital may be safely discontinued in some patients before discharge from the neonatal intensive care unit. Optimizing a strategy for selective early phenobarbital discontinuation would be of great value. In this study, we present a unified framework for phenobarbital discontinuation after resolution of acute symptomatic seizures in the setting of brain injury of the newborn.

    View details for DOI 10.1212/CPJ.0000000000200125

    View details for PubMedID 36891461

    View details for PubMedCentralID PMC9987207

  • Neuromonitoring in neonatal critical care part I: neonatal encephalopathy and neonates with possible seizures. Pediatric research El-Dib, M., Abend, N. S., Austin, T., Boylan, G., Chock, V., Cilio, M. R., Greisen, G., Hellström-Westas, L., Lemmers, P., Pellicer, A., Pressler, R. M., Sansevere, A., Tsuchida, T., Vanhatalo, S., Wusthoff, C. J. 2022

    Abstract

    The blooming of neonatal neurocritical care over the last decade reflects substantial advances in neuromonitoring and neuroprotection. The most commonly used brain monitoring tools in the neonatal intensive care unit (NICU) are amplitude integrated EEG (aEEG), full multichannel continuous EEG (cEEG), and near-infrared spectroscopy (NIRS). While some published guidelines address individual tools, there is no consensus on consistent, efficient, and beneficial use of these modalities in common NICU scenarios. This work reviews current evidence to assist decision making for best utilization of neuromonitoring modalities in neonates with encephalopathy or with possible seizures. Neuromonitoring approaches in extremely premature and critically ill neonates are discussed separately in the companion paper. IMPACT: Neuromonitoring techniques hold promise for improving neonatal care. For neonatal encephalopathy, aEEG can assist in screening for eligibility for therapeutic hypothermia, though should not be used to exclude otherwise eligible neonates. Continuous cEEG, aEEG and NIRS through rewarming can assist in prognostication. For neonates with possible seizures, cEEG is the gold standard for detection and diagnosis. If not available, aEEG as a screening tool is superior to clinical assessment alone. The use of seizure detection algorithms can help with timely seizures detection at the bedside.

    View details for DOI 10.1038/s41390-022-02393-1

    View details for PubMedID 36476747

  • Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo. Pediatric research Glass, H. C., Wusthoff, C. J., Comstock, B. A., Numis, A. L., Gonzalez, F. F., Maitre, N., Massey, S. L., Mayock, D. E., Mietzsch, U., Natarajan, N., Sokol, G. M., Bonifacio, S. L., Van Meurs, K. P., Thomas, C., Ahmad, K. A., Heagerty, P. J., Juul, S. E., Wu, Y. W. 2022

    Abstract

    An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo.Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models.Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo).In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia.In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

    View details for DOI 10.1038/s41390-022-02398-w

    View details for PubMedID 36470964

  • Neuromonitoring in neonatal critical care part II: extremely premature infants and critically ill neonates. Pediatric research El-Dib, M., Abend, N. S., Austin, T., Boylan, G., Chock, V., Cilio, M. R., Greisen, G., Hellstrom-Westas, L., Lemmers, P., Pellicer, A., Pressler, R. M., Sansevere, A., Szakmar, E., Tsuchida, T., Vanhatalo, S., Wusthoff, C. J., Newborn Brain Society Guidelines and Publications Committee, Bonifacio, S., Wintermark, P., Aly, H., Chang, T., Chau, V., Glass, H., Lemmon, M., Massaro, A., Wusthoff, C., deVeber, G., Pardo, A., McCaul, M. C. 2022

    Abstract

    Neonatal intensive care has expanded from cardiorespiratory care to a holistic approach emphasizing brain health. To best understand and monitor brain function and physiology in the neonatal intensive care unit (NICU), the most commonly used tools are amplitude-integrated EEG, full multichannel continuous EEG, and near-infrared spectroscopy. Each of these modalities has unique characteristics and functions. While some of these tools have been the subject of expert consensus statements or guidelines, there is no overarching agreement on the optimal approach to neuromonitoring in the NICU. This work reviews current evidence to assist decision making for the best utilization of these neuromonitoring tools to promote neuroprotective care in extremely premature infants and in critically ill neonates. Neuromonitoring approaches in neonatal encephalopathy and neonates with possible seizures are discussed separately in the companion paper. IMPACT: For extremely premature infants, NIRS monitoring has a potential role in individualized brain-oriented care, and selective use of aEEG and cEEG can assist in seizure detection and prognostication. For critically ill neonates, NIRS can monitor cerebral perfusion, oxygen delivery, and extraction associated with disease processes as well as respiratory and hypodynamic management. Selective use of aEEG and cEEG is important in those with a high risk of seizures and brain injury. Continuous multimodal monitoring as well as monitoring of sleep, sleep-wake cycling, and autonomic nervous system have a promising role in neonatal neurocritical care.

    View details for DOI 10.1038/s41390-022-02392-2

    View details for PubMedID 36434203

  • Neuroprotective therapies in the NICU in term infants: present and future. Pediatric research Molloy, E. J., El-Dib, M., Juul, S. E., Benders, M., Gonzalez, F., Bearer, C., Wu, Y. W., Robertson, N. J., Hurley, T., Branagan, A., Michael Cotten, C., Tan, S., Laptook, A., Austin, T., Mohammad, K., Rogers, E., Luyt, K., Bonifacio, S., Soul, J. S., Gunn, A. J., Newborn Brain Society Guidelines and Publications Committee, Bonifacio, S., Wintermark, P., Aly, H., Chang, T., Chau, V., Glass, H., Lemmon, M., Massaro, A., Wusthoff, C., deVeber, G., Pardo, A., McCaul, M. C. 2022

    Abstract

    Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

    View details for DOI 10.1038/s41390-022-02295-2

    View details for PubMedID 36195634

  • Altered biventricular function in neonatal hypoxic-ischaemic encephalopathy: a case-control echocardiographic study. Cardiology in the young Altit, G., Bonifacio, S. L., Guimaraes, C. V., Sivakumar, G., Yan, B., Chock, V., Van Meurs, K., Bhombal, S. 2022: 1-10

    Abstract

    BACKGROUND: In newborns with hypoxic-ischaemic encephalopathy, more profound altered right and left ventricular function has been associated with mortality or brain injury. Mechanisms underlying cardiac dysfunction in this population are thought to be related to the persistence of increased pulmonary vascular resistance and myocardial ischaemia. We sought to compare cardiac function in newborns with hypoxic-ischaemic encephalopathy to controls using echocardiography.METHODS: We did a retrospective case-control study with moderate or severe hypoxic-ischaemic encephalopathy between 2008 and 2017. Conventional and speckle-tracking echocardiography measures were extracted to quantify right and left ventricular systolic and diastolic function. Fifty-five newborns with hypoxic-ischaemic encephalopathy were compared to 28 controls.RESULTS: Hypoxic-ischaemic encephalopathy newborns had higher estimated systolic pulmonary pressure (62.5 ± 15.0 versus 43.8 ± 17.3 mmHg, p < 0.0001) and higher systolic pulmonary artery pressure/systolic blood pressure ratio [101 ± 16 (iso-systemic) versus 71 ± 27 (2/3 systemic range) %, p < 0.0001]. Tricuspid annular plane systolic excursion was decreased (7.5 ± 2.2 versus 9.0 ± 1.4 mm, p = 0.002), E/e' increased (7.9 ± 3.3 versus 5.8 ± 2.0, p = 0.01), and right ventricle-myocardial performance index increased (68.1 ± 21.5 versus 47.8 ± 9.5, p = 0.0001) in hypoxic-ischaemic encephalopathy. Conventional markers of left ventricle systolic function were similar, but e' velocity (0.059 ± 0.019 versus 0.070 ± 0.01, p = 0.03) and left ventricle-myocardial performance index were statistically different (77.9 ± 26.2 versus 57.9 ± 11.2, p = 0.001). The hypoxic-ischaemic encephalopathy group had significantly altered right and left ventricular deformation parameters by speckle-tracking echocardiography. Those with decreased right ventricle-peak longitudinal strain were more likely to have depressed left ventricle-peak longitudinal strain.CONCLUSION: Newborns with hypoxic-ischaemic encephalopathy have signs of increased pulmonary pressures and altered biventricular systolic and diastolic function.

    View details for DOI 10.1017/S1047951122002839

    View details for PubMedID 36065722

  • Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. The New England journal of medicine Wu, Y. W., Comstock, B. A., Gonzalez, F. F., Mayock, D. E., Goodman, A. M., Maitre, N. L., Chang, T., Van Meurs, K. P., Lampland, A. L., Bendel-Stenzel, E., Mathur, A. M., Wu, T., Riley, D., Mietzsch, U., Chalak, L., Flibotte, J., Weitkamp, J., Ahmad, K. A., Yanowitz, T. D., Baserga, M., Poindexter, B. B., Rogers, E. E., Lowe, J. R., Kuban, K. C., O'Shea, T. M., Wisnowski, J. L., McKinstry, R. C., Bluml, S., Bonifacio, S., Benninger, K. L., Rao, R., Smyser, C. D., Sokol, G. M., Merhar, S., Schreiber, M. D., Glass, H. C., Heagerty, P. J., Juul, S. E., HEAL Consortium, Juul, S. E., Wu, Y. W., Heagerty, P. J., Ahmad, K. A., Baserga, M., Bendel-Stenzel, E., Benninger, K. L., Chalak, L., Chang, T., Flibotte, J., Gonzalez, F. F., Lampland, A. L., Maitre, N. L., Mathur, A. M., Mayock, D. E., Merhar, S., Mietzsch, U., Poindexter, B. B., Rao, R., Riley, D., Smyser, C. D., Sokol, G. M., Van Meurs, K. P., Weitkamp, J., Wu, T., Yanowitz, T. D., Agthe, A. G., Andescavage, N., Bonifacio, S., Chapman, R., Dysart, K., Eichenwald, E., Engelstad, L., Ferriero, D. M., Gano, D., Glass, H. C., Henderson, C., Hintz, S., Ho, E., Isaza, N., Jackson, C., Jackson, L., Johnson, Y., Lawrence, R., Machie, M., Mahmood, B., Massaro, A., Miller, C., Morris, E. A., Morris, H. F., Naik, M., Nedrelow, J., Neumaier, J. R., O'Donnell, B., Rogers, E. E., Sanchez, P. J., Shepherd, J., Thomas, J., Tsuchida, T., Vesoulis, Z., Vijayamadhavan, V., Winter, S., Bataglia, K., Batterson, N., Bernstein, B., Blankenship, S., Burrows, F., Christopher, L., Corrales, A., Cunningham, S., D'Agostino, J. A., DeAnda, M., DeBattista, A., Demauro, S. B., Drury, G., Duncan, A. F., ElTers, N., Neis Farrell, C., Fierro, M., Forero, N., Frey, C., Blanc Friedman, K., Friedman, S., Fuller, J., George, T., Gerdes, M., German, A., German, K., Gogliotti, S., Goldenshteyn, M., Goode, R. H., Haman, M., Hawthorne, C., Hay, A., Hayden, Y., Heyne, R., Hines, A., Hoffman, C., Hutchon, B., Jensen, E., Johnson, B., Keener, K., Kramer, A., Krueger, C., Lawrence, A., Lee, M., Lehman, K., Liebowitz, M., Liggett, M., Lorenzi-Quigley, L., Lundequam, P., Malmud, E., McCall, S., McHugh, K., Morshedzadeh, G., Mouvery, A. L., Myers, E., Natarajan, N., Neel, M. L., Nelin, M. A., Oakes, C., Patel, J., Pietruszewski, L., Plummer, E., Powers, D. A., Rapoport, R., Rauda, H., Rick, L., Scott, L., Siqveland, E., Slaughter, L. A., Stonebraker, L., Stout, K., Stuart, A., Taylor, H., Tolentino-Plata, K., Vanderbilt, D., Vecchiarelli, J., Vierling, A. N., Wager, N., Watkins, D., Wing, S., Wolfe-Christensen, C., Zorn, E., Autelli, V., Baker, S., Ball, B., Barton, A., Bassett, K., Cole Bledsoe, L., Boyle, F., Clopp, B., Corry, K., Drummond, M., Dudley, J., Espinoza, A., Esposito, I., Feltner, J., Fine, D., Fisher, M., Gossett, A., Grisby, C., Hauge, S., Houston, K., Kaletka, B., Kleinman, S., Kohlleppel, K., Lee, L., Li, P., McGowan, M., Nelson, K., Nikirk, S., O'Kane, A., Oskoui, T., Purnell, J., Rakow, H., Rau, C., Reichert, E., Rogers, T., Roth, E., Sepulveda, P., Silvia, A., Stacey, S., Strait, E., Thomas, D., Toda-Eng, B., Weinberg, D. D., Wells, S., Widmayer, A., Worwa, C., Wuertz, S., Yarnell, A., Ziolkowski, K., Comstock, B. A., Heagerty, P. J., Konodi, M. A., Nefcy, C., Ballard, R., Goodman, A. M., Schreiber, M. D., Kuban, K. C., Lowe, J. R., O'Shea, T. M., Bluml, S., McKinstry, R. C., Panigrahy, A., Wisnowski, J. L., Bammler, T., Numis, A. L. 2022; 387 (2): 148-159

    Abstract

    BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P=0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

    View details for DOI 10.1056/NEJMoa2119660

    View details for PubMedID 35830641

  • Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network. Seminars in perinatology Bonifacio, S. L., Chalak, L. F., Van Meurs, K. P., Laptook, A. R., Shankaran, S. 2022: 151639

    Abstract

    Therapeutic hypothermia (TH) is now well established as the standard of care treatment for moderate to severe neonatal encephalopathy secondary to perinatal hypoxic ischemic encephalopathy (HIE) in infants ≥36 weeks gestation in high income countries. The Neonatal Research Network (NRN) contributed greatly to the study of TH as a neuroprotectant with three trials now completed in infants ≥36 weeks gestation and the only large randomized-controlled trial of TH in preterm infants now in the follow-up phase. Data from the first NRN TH trial combined with data from other large trials of TH affirm the safety and neuroprotective qualities of TH and highlight the importance of providing TH to all infants who qualify. In this review we will highlight the findings of the three NRN trials of TH in the term infant population and the secondary analyses that continue to inform the care of patients with HIE.

    View details for DOI 10.1016/j.semperi.2022.151639

    View details for PubMedID 35835616

  • Continuous EEG monitoring still recommended for neonatal seizure management: commentary on NEST trial. Pediatric research Soul, J. S., Glass, H. C., Mohammad, K., Ment, L. R., Smyser, C. D., Bonifacio, S. L., Massaro, A. N., El-Dib, M. 2022

    View details for DOI 10.1038/s41390-022-02138-0

    View details for PubMedID 35681096

  • Association between multi-organ dysfunction and adverse outcome in infants with hypoxic ischemic encephalopathy. Journal of perinatology : official journal of the California Perinatal Association Yan, E. S., Chock, V. Y., Bonifacio, S. L., Dahlen, A., Guimaraes, C. V., Altit, G., Bhombal, S., Van Meurs, K. 2022

    Abstract

    OBJECTIVE: To evaluate multi-organ dysfunction (MOD) in newborns treated with therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE), and to compare MOD in those with normal/mild magnetic resonance imaging (MRI) findings to those with moderate to severe MRI findings or death.STUDY DESIGN: Retrospective single-center observational study of infants treated with TH. A total of 16 parameters across 7 organ systems were analyzed. Primary outcome was death or moderate to severe brain injury on MRI.RESULT: Of 157 infants treated with TH, 77% had ≥2 organ systems with dysfunction. The number of organ systems with dysfunction was strongly associated with death or moderate-to-severe brain injury (p<0.0001). Hematologic (68%) and hepatic (65%) dysfunction were most common. Neurologic and renal dysfunction were most strongly associated with the primary outcome (OR 13.5 [6.1-29.8] and 11.2 [4.1-30.3], respectively), while pulmonary hypertension was not.CONCLUSION: MOD is prevalent in infants undergoing TH for HIE, and the association between MOD and adverse outcomes may impact clinical care and counseling.

    View details for DOI 10.1038/s41372-022-01413-6

    View details for PubMedID 35578019

  • Hypoxic ischemic encephalopathy: Do peripartum risk factors account for observed changes in incidence? Minor, K. C., Liu, J., El-Sayed, Y. Y., Druzin, M. L., Profit, J., Hintz, S., Bonifacio, S., Karakash, S. MOSBY-ELSEVIER. 2022: S210
  • Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations. Experimental neurology Reiss, J. D., Peterson, L. S., Nesamoney, S. N., Chang, A. L., Pasca, A. M., Marić, I., Shaw, G. M., Gaudilliere, B., Wong, R. J., Sylvester, K. G., Bonifacio, S. L., Aghaeepour, N., Gibbs, R. S., Stevenson, D. K. 2022: 113988

    Abstract

    Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.

    View details for DOI 10.1016/j.expneurol.2022.113988

    View details for PubMedID 35081400

  • Does magnesium sulfate for hypertensive disease reduce the risk of neonatal hypoxic ischemic encephalopathy? Minor, K. C., Liu, J., El-Sayed, Y. Y., Druzin, M. L., Profit, J., Hintz, S., Bonifacio, S., Leonard, S. A., Karakash, S. MOSBY-ELSEVIER. 2022: S526
  • Neonatal Seizures: Challenges and the Road Ahead. Pediatric neurology Chau, V., Bonifacio, S. L., Wintermark, P., Newborn Brain Society Guidelines and Publications Committee 1800
  • Standardized Evaluation of Cord Gases in Neonates at Risk for Hypoxic Ischemic Encephalopathy. Hospital pediatrics Blecharczyk, E., Lee, L., Birnie, K., Gupta, A., Davis, A., Van Meurs, K., Bonifacio, S., Frymoyer, A. 2021

    Abstract

    BACKGROUND: Umbilical-cord acidemia may indicate perinatal asphyxia and places a neonate at increased risk for hypoxic ischemic encephalopathy (HIE). Our specific aim was to develop a standardized clinical care pathway, ensuring timely identification and evaluation of neonates with umbilical-cord acidemia at risk for HIE.METHODS: A standardized clinical care pathway to screen inborn neonates ≥36 weeks with abnormal cord blood gases (a pH of ≤7.0 or base deficit of ≥10) for HIE was implemented in January 2016. Abnormal cord blood gases resulted in a direct notification from the laboratory to an on-call physician. Evaluation included a modified Sarnat examination, postnatal blood gas, and standardized documentation. The percentage of neonates in which physician notification, documented Sarnat examination, and postnatal blood gas occurred was examined for 6 months before and 35 months after implementation.RESULTS: Of 203 neonates with abnormal cord gases in the post-quality improvement (QI) period, physician notification occurred in 92%. In the post-QI period, 94% had a documented Sarnat examination, and 94% had postnatal blood gas, compared with 16% and 11%, respectively, of 87 neonates in the pre-QI period. In the post-QI period, of those evaluated, >96% were documented within 4 hours of birth. In the post-QI period, 15 (7.4%) neonates were cooled; 13 were in the NICU at time of identification, but 2 were identified in the newborn nursery and redirected to the NICU for cooling.CONCLUSIONS: A standardized screening pathway in neonates with umbilical-cord acidemia led to timely identification and evaluation of neonates at risk for HIE.

    View details for DOI 10.1542/hpeds.2021-006135

    View details for PubMedID 34854918

  • Characteristics of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multi-Center Study. The Journal of pediatrics Massey, S. L., Glass, H. C., Shellhaas, R. A., Bonifacio, S., Chang, T., Chu, C., Cilio, M. R., Lemmon, M. E., McCulloch, C. E., Soul, J. S., Thomas, C., Wusthoff, C. J., Xiao, R., Abend, N. S. 2021

    Abstract

    OBJECTIVE: To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease (CPD).STUDY DESIGN: The Neonatal Seizure Registry (NSR-1) is a multicenter, prospectively acquired cohort of neonates with clinical or EEG-confirmed seizures. CPD was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous electroencephalographic monitoring (cEEG) strategy, seizure characteristics, seizure management, and outcomes for neonates with and without CPD.RESULTS: We evaluated 83 neonates with CPD and 271 neonates without CPD. Neonates with CPD were more likely to have EEG-only seizures (40% vs. 21%, P <.001) and experience their first seizure later than those without CPD (174 vs. 21 hours of age, p<0.001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs. 43%, p=0.27). Phenobarbital was the primary initial antiseizure medication (ASM) for both groups (90%), and both groups had similarly high rates of incomplete response to initial ASM administration (66% vs. 68%, p=0.75). Neonates with CPD were discharged from the hospital later (hazard ratio 0.34, 95%CI 0.25-0.45, p<0.001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95%CI 0.66-1.94, p=0.64).CONCLUSION: Neonates with and without CPD had a similarly high seizure exposure, but neonates with CPD were more likely to experience EEG-only seizures and had seizure onset later in the clinical course. Phenobarbital was the most common seizure treatment, but seizures were often refractory to initial ASM. These data support guidelines recommending cEEG in neonates with CPD and indicate a need for optimized therapeutic strategies.

    View details for DOI 10.1016/j.jpeds.2021.10.058

    View details for PubMedID 34728234

  • Neuroimaging in the term newborn with neonatal encephalopathy. Seminars in fetal & neonatal medicine Wisnowski, J. L., Wintermark, P., Bonifacio, S. L., Smyser, C. D., Barkovich, A. J., Edwards, A. D., de Vries, L. S., Inder, T. E., Chau, V., Newborn Brain Society Guidelines and Publications Committee 2021: 101304

    Abstract

    Neuroimaging is widely used to aid in the diagnosis and clinical management of neonates with neonatal encephalopathy (NE). Yet, despite widespread use clinically, there are few published guidelines on neuroimaging for neonates with NE. This review outlines the primary patterns of brain injury associated with hypoxic-ischemic injury in neonates with NE and their frequency, associated neuropathological features, and risk factors. In addition, it provides an overview of neuroimaging methods, including the most widely used scoring systems used to characterize brain injury in these neonates and their utility as predictive biomarkers. Last, recommendations for neuroimaging in neonates with NE are presented.

    View details for DOI 10.1016/j.siny.2021.101304

    View details for PubMedID 34736808

  • Proposing a care practice bundle for neonatal encephalopathy during therapeutic hypothermia. Seminars in fetal & neonatal medicine Wintermark, P., Mohammad, K., Bonifacio, S. L., Newborn Brain Society Guidelines and Publications Committee. Electronic address: publications@newbornbrainsociety.org,, 2021: 101303

    Abstract

    Neonates with neonatal encephalopathy (NE) often present with multi-organ dysfunction that requires multidisciplinary specialized management. Care of the neonate with NE is thus complex with interaction between the brain and various organ systems. Illness severity during the first days of birth, and not only during the initial hypoxia-ischemia event, is a significant predictor of adverse outcomes in neonates with NE treated with therapeutic hypothermia (TH). We thus propose a care practice bundle dedicated to support the injured neonatal brain that is based on the current best evidence for each organ system. The impact of using such bundle on outcomes in NE remains to be demonstrated.

    View details for DOI 10.1016/j.siny.2021.101303

    View details for PubMedID 34711527

  • Cardiac Dysfunction in Neonatal HIE Is Associated with Increased Mortality and Brain Injury by MRI. American journal of perinatology Altit, G., Bonifacio, S. L., Guimaraes, C. V., Bhombal, S., Sivakumar, G., Yan, B., Chock, V., Meurs, K. V. 2021

    Abstract

    OBJECTIVE: Describe the association between cardiac dysfunction and death or moderate-to-severe abnormalities on brain magnetic resonance imaging (MRI) in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE).STUDY DESIGN: Retrospective study in neonates with moderate or severe HIE undergoing therapeutic hypothermia between 2008 and 2017. Primary outcome was death or moderate-to-severe brain injury using the Barkovich score. Conventional and speckle-tracking echocardiography measures were extracted from available echocardiograms to quantify right (RV) and left (LV) ventricular functions.RESULTS: A total of 166 newborns underwent therapeutic hypothermia of which 53 (36.5%) had echocardiography performed. Ten (19%) died prior to hospital discharge, and 11 (26%) had moderate-to-severe brain injury. There was no difference in chronologic age at echocardiography between the normal and adverse outcome groups (22 [±19] vs. 28 [±21] hours, p=0.35). Cardiac findings in newborns with abnormal outcome included lower systolic and diastolic blood pressure (BP) at echocardiography (p=0.004) and decreased tricuspid annular plane systolic excursion (a marker of RV systolic function; p=0.01), while the ratio of systolic pulmonary artery (PA) pressure to systolic BP indicated isosystemic pressures (>2/3 systemic) in both groups. A multilogistic regression analysis, adjusting for weight and seizure status, indicated an association between abnormal outcome and LV function by longitudinal strain, as well as by ejection fraction.CONCLUSION: Newborns who died or had moderate-to-severe brain injury had a higher incidence of cardiac dysfunction but similar PA pressures when compared with those who survived with mild or no MRI abnormalities.KEY POINTS: · Newborns with HIE with functional LV/RV dysfunction are at risk for death or brain injury.. · All neonates with HIE had elevated pulmonary pressure, but neonates with poor outcome had RV dysfunction.. · When evaluating newborns with HIE by echocardiography, beyond estimation of pulmonary pressure, it is important to assess biventricular function..

    View details for DOI 10.1055/s-0041-1735618

    View details for PubMedID 34492719

  • The Term Newborn: Evaluation for Hypoxic-Ischemic Encephalopathy. Clinics in perinatology Bonifacio, S. L., Hutson, S. 2021; 48 (3): 681-695

    Abstract

    Neonatal encephalopathy due to perinatal hypoxia-ischemia (hypoxic-ischemic encephalopathy [HIE]) occurs at a rate of 1 to 3 per 1000 live births. Therapeutic hypothermia is the standard of care and the only currently available therapy to reduce the risk of death or disability in newborns with moderate to severe HIE. Hypothermia therapy needs to be initiated within 6hours after birth in order to provide the best chance for neuroprotection. All pediatricians and delivery room attendants should be trained to recognize encephalopathy and understand the eligibility criteria for treatment. The modified Sarnat examination is the most frequently used tool to assess the degree of encephalopathy and has six categories, each of which can have mild, moderate, severe abnormalities. Apart from historical and biochemical criteria, a neonate must have 3 of 6 categories scored in the moderate or severe range in order to qualify for hypothermia as was done in the randomized trials. Whether an infant qualifies or there is concern that an infant might have HIE, transfer to a center that can perform treatment should be initiated immediately. Hypothermia significantly reduces the risk of death or moderate to severe impairments at 2years and at school age. On average, only 7 neonates need to be treated for one neonate to benefit. Although easy in concept, implementation of hypothermia does require expertise and should be carried out under the guidance of a neonatologist. If infants are passively cooled prior to transport, core temperature needs to be closely monitored with a target of 33.5°C±0.5°C. Maintenance of homeostasis is important in order to prevent conditions that may result in additional brain injury. Seizures are common in neonates with HIE, but electrographic seizures are rare in the first few hours after birth if the insult occurred during labor and delivery. Prophylactic antiepileptic drugs should not be administered. Brain monitoring in the form of electroencephalogram (EEG) and or amplitude-integrated EEG should be implemented as soon as possible to help with prognosis and to accurately diagnose seizures.

    View details for DOI 10.1016/j.clp.2021.05.014

    View details for PubMedID 34353587

  • Unanswered questions in neonates with NE. Seminars in fetal & neonatal medicine Wintermark, P., El Dib, M., Bonifacio, S. L., Newborn Brain Society Guidelines and Publications Committee 2021: 101260

    View details for DOI 10.1016/j.siny.2021.101260

    View details for PubMedID 34154944

  • Issues in the daily management of neonates with NE. Seminars in fetal & neonatal medicine Wintermark, P., El Dib, M., Bonifacio, S. L., Newborn Brain Society Guidelines and Publications Committee 2021: 101255

    View details for DOI 10.1016/j.siny.2021.101255

    View details for PubMedID 34144932

  • Unanswered questions regarding therapeutic hypothermia for neonates with neonatal encephalopathy. Seminars in fetal & neonatal medicine Sabir, H., Bonifacio, S. L., Gunn, A. J., Thoresen, M., Chalak, L. F., Newborn Brain Society Guidelines and Publications Committee 2021: 101257

    Abstract

    Therapeutic hypothermia (TH) is now well established to improve intact survival after neonatal encephalopathy (NE). However, many questions could not be addressed by the randomized controlled trials. Should late preterm newborns with NE be cooled? Is cooling beneficial for mild NE? Is the current therapeutic time window optimal, or could it be shortened or prolonged? Will either milder or deeper hypothermia be effective? Does infection/inflammation exposure in the perinatal period in combination with NE offer potentially beneficial preconditioning or might it obviate hypothermic neuroprotection? In the present review, we dissect the evidence, for whom, when and how can TH best be delivered, and highlight areas that need further research.

    View details for DOI 10.1016/j.siny.2021.101257

    View details for PubMedID 34144931

  • Seizure Control in Neonates Undergoing Screening vs Confirmatory EEG Monitoring. Neurology Wusthoff, C. J., Sundaram, V., Abend, N. S., Massey, S. L., Lemmon, M. E., Thomas, C., McCulloch, C. E., Chang, T., Soul, J. S., Chu, C. J., Rogers, E. E., Bonifacio, S. L., Cilio, M. R., Glass, H. C., Shellhaas, R. A., Neonatal Seizure Registry Group 2021

    Abstract

    OBJECTIVE: To determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures.METHODS: We included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR), a prospective, multicenter cohort of neonates with seizures. We compared two cEEG approaches: (1) Screening cEEG, initiated for indications of encephalopathy or paralysis without suspected clinical seizures, and (2) Confirmatory cEEG, initiated for the indication of clinical events suspicious for seizures, either alone or in addition to other indications. The primary outcome was successful response to initial seizure treatment, defined as seizures resolved without recurrence within 30 minutes after initial loading dose of anti-seizure medicine. Multivariable logistic regression analyses assessed the association between cEEG approach and successful seizure treatment.RESULTS: Among 514 neonates included, 161 (31%) had screening cEEG and 353 (69%) had confirmatory cEEG. Neonates with screening cEEG had a higher proportion of successful initial seizure treatment than neonates with confirmatory cEEG (39% versus 18%; p<0.0001). After adjusting for covariates, there remained a greater odds ratio (OR) for successful initial seizure treatment in the screening vs. confirmatory cEEG groups (adjusted OR 2.44, 95% CI: 1.45-4.11, p=0.0008).CONCLUSIONS: These findings provide evidence from a large, contemporary cohort of neonates that a screening cEEG approach may improve odds of successful treatment of acute seizures.CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for neonates a screening CEEG approach, compared to a confirmatory EEG approach, increases the probability of successful treatment of acute seizures.

    View details for DOI 10.1212/WNL.0000000000012293

    View details for PubMedID 34078719

  • Outcomes of infants with hypoxic ischemic encephalopathy and persistent pulmonary hypertension of the newborn: results from three NICHD studies. Journal of perinatology : official journal of the California Perinatal Association Agarwal, P., Shankaran, S., Laptook, A. R., Chowdhury, D., Lakshminrusimha, S., Bonifacio, S. L., Natarajan, G., Chawla, S., Keszler, M., Heyne, R. J., Ambalavanan, N., Walsh, M. C., Das, A., Van Meurs, K. P., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network 2021

    Abstract

    OBJECTIVE: To determine the association of persistent pulmonary hypertension of the newborn (PPHN) with death or disability among infants with moderate or severe hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia.METHODS: We compared infants with and without PPHN enrolled in the hypothermia arm from three randomized controlled trials (RCTs): Induced Hypothermia trial, "usual care" arm of Optimizing Cooling trial, and Late Hypothermia trial. Primary outcome was death or disability at 18-22 months adjusted for severity of HIE, center, and RCT.RESULTS: Among 280 infants, 67 (24%) were diagnosed with PPHN. Among infants with and without PPHN, death or disability was 47% vs. 29% (adjusted OR: 1.65, 0.86-3.14) and death was 26% vs. 12% (adjusted OR: 2.04, 0.92-4.53), respectively.CONCLUSIONS: PPHN in infants with moderate or severe HIE was not associated with a statistically significant increase in primary outcome. These results should be interpreted with caution given the limited sample size.

    View details for DOI 10.1038/s41372-020-00905-7

    View details for PubMedID 33402707

  • Early MRI Predicts 30-Month Outcomes After Therapeutic Hypothermia for Neonatal Encephalopathy. The Journal of pediatrics Bach, A. M., Fang, A. Y., Bonifacio, S., Rogers, E. E., Scheffler, A., Partridge, J. C., Xu, D., Barkovich, A. J., Ferriero, D. M., Glass, H. C., Gano, D. 2021

    Abstract

    To evaluate the association of therapeutic hypothermia with magnetic resonance imaging (MRI) findings and 30-month neurodevelopment in term neonatal encephalopathy.Cross-sectional analysis of 30-month neurodevelopment (IQR:19.0-31.4) in a prospective cohort of mild-to-severe NE imaged on day 4 (1993-2017 with institutional implementation of TH in 2007). MRI injury was classified as normal, watershed or basal ganglia/thalamus. Abnormal motor outcome was defined as Bayley-II psychomotor developmental index<70, Bayley-III motor score<85 or functional motor deficit. Abnormal cognitive outcome was defined as Bayley-II mental developmental index<70 or Bayley-III cognitive score<85. Abnormal composite outcome was defined as abnormal motor and/or cognitive outcome, or death. The association of TH with MRI and outcomes was evaluated with multivariable logistic regression adjusted for propensity to receive TH.Follow-up was available in 317 (78%) surviving children, of whom 155 (49%) received TH. Adjusting for propensity, TH was independently associated with decreased odds of abnormal motor (OR:0.15,95%-CI 0.06-0.40, P < .001) and cognitive (OR:0.11,95%-CI 0.04-0.33,P<0.001) outcomes. This association remained statistically significant after adjustment for injury pattern. The predictive accuracy of MRI pattern for abnormal composite outcome was unchanged between TH-treated (AUROC:0.76;95%-CI 0.61-0.91) and untreated (AUROC:0.74; 95%-CI 0.67-0.81) infants. The negative predictive value of normal MRI was high in TH-treated and untreated infants (motor:96%-vs-90%; cognitive:99%-vs-95%).Therapeutic hypothermia is associated with lower rates of brain injury and adverse 30-month outcomes after neonatal encephalopathy. The predictive accuracy of MRI in the first week of life is unchanged by TH. Normal MRI remains reassuring for normal 30-month outcome after TH.

    View details for DOI 10.1016/j.jpeds.2021.07.003

    View details for PubMedID 34237346

  • Seizure Severity and Treatment Response in Newborn Infants with Seizures Attributed to Intracranial Hemorrhage. The Journal of pediatrics Herzberg, E. M., Machie, M., Glass, H. C., Shellhaas, R. A., Wusthoff, C. J., Chang, T., Abend, N. S., Chu, C. J., Cilio, M. R., Bonifacio, S. L., Massey, S. L., McCulloch, C. E., Soul, J. S. 2021

    Abstract

    To characterize intracranial hemorrhage (ICH) as a seizure etiology in infants born at term and preterm. For term infants, to compare seizure severity and treatment response for multi-site vs single-site ICH and hypoxic-ischemic encephalopathy (HIE) with vs. without ICH.We studied 112 newborn infants with seizures attributed to ICH, and 201 infants born at term with seizures attributed to HIE, using a cohort of consecutive infants with clinically diagnosed and/or electrographic seizures prospectively enrolled in the multicenter Neonatal Seizure Registry. We compared seizure severity and treatment response among infants with complicated ICH, defined as multi-site vs. single-site ICH and HIE with vs. without ICH.ICH was a more common seizure etiology in infants born preterm vs. term (27% vs. 10%, p<0.001). Most infants had subclinical seizures (74%) and an incomplete response to initial antiseizure medication (ASM) (68%). In infants born term, multi-site ICH was associated with more subclinical seizures than single-site ICH (93% vs. 66%, p=0.05) and an incomplete response to the initial ASM (100% vs. 66%, p=0.02). Status epilepticus was more common in HIE with ICH vs. HIE alone (38% vs. 17%, P = .05).Seizure severity was higher and treatment response was lower among infants born term with complicated ICH. These data support the use of continuous video electroencephalogram monitoring to accurately detect seizures and a multi-step treatment plan that considers early use of multiple ASMs, particularly with parenchymal and high-grade intraventricular hemorrhage and complicated ICH.

    View details for DOI 10.1016/j.jpeds.2021.11.012

    View details for PubMedID 34780777

  • Associations between Infant and Parent Characteristics and Measures of Family Well-Being in Neonates with Seizures: A Cohort Study. The Journal of pediatrics Franck, L. S., Shellhaas, R. A., Lemmon, M. n., Sturza, J. n., Soul, J. S., Chang, T. n., Wusthoff, C. J., Chu, C. J., Massey, S. L., Abend, N. S., Thomas, C. n., Rogers, E. E., McCulloch, C. E., Grant, K. n., Grossbauer, L. n., Pawlowski, K. n., Glass, H. C. 2020; 221: 64–71.e4

    Abstract

    To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures.This prospective, observational cohort study enrolled 144 parent-infant dyads among neonates with acute symptomatic seizures from 9 pediatric hospitals in the Neonatal Seizure Registry. One parent per family completed a discharge survey, which included measures of anxiety and depression, health-related quality of life, and impact on the family. Multivariable regression analyses adjusted for site were constructed to examine parent and infant characteristics associated with well-being.At discharge, 54% of parents reported symptoms of anxiety and 32% reported symptoms of depression. Parents of infants with hypoxic-ischemic encephalopathy reported more depression and worse quality of life than parents of infants with other seizure etiologies. Parental quality of life was also lower with greater infant age at discharge. A higher level of maternal education was associated with greater impact on the family. All these differences were medium to large effect sizes, ranging from 0.52 to 0.78.Symptoms of anxiety and depression are common in parents of infants with neonatal seizures, and several parent and infant characteristics are associated with poorer parental quality of life and family well-being. These findings are a call to action to improve mental health screening and services for parents of infants with neonatal seizures.

    View details for DOI 10.1016/j.jpeds.2020.02.024

    View details for PubMedID 32446494

  • Management of Multi Organ Dysfunction in Neonatal Encephalopathy. Frontiers in pediatrics O'Dea, M., Sweetman, D., Bonifacio, S. L., El-Dib, M., Austin, T., Molloy, E. J. 2020; 8: 239

    Abstract

    Neonatal Encephalopathy (NE) describes neonates with disturbed neurological function in the first post-natal days of life. NE is an overall term that does not specify the etiology of the encephalopathy although it often involves hypoxia-ischaemia. In NE, although neurological dysfunction is part of the injury and is most predictive of long-term outcome, these infants may also have multiorgan injury and compromise, which further contribute to neurological impairment and long-term morbidities. Therapeutic hypothermia (TH) is the standard of care for moderate to severe NE. Infants with NE may have co-existing immune, respiratory, endocrine, renal, hepatic, and cardiac dysfunction that require individualized management and can be impacted by TH. Non-neurological organ dysfunction not only has a negative effect on long term outcome but may also influence the efficacy of treatments in the acute phase. Post resuscitative care involves stabilization and decisions regarding TH and management of multi-organ dysfunction. This management includes detailed neurological assessment, cardio-respiratory stabilization, glycaemic and fluid control, sepsis evaluation and antibiotics, seizure identification, and monitoring and responding to biochemical and coagulation derangements. The emergence of new biomarkers of specific organ injury may have predictive value and improve the definition of organ injury and prognosis. Further evidence-based research is needed to optimize management of NE, prevent further organ dysfunction and reduce neurodevelopmental impairment.

    View details for DOI 10.3389/fped.2020.00239

    View details for PubMedID 32500050

  • Characterization of Death in Infants With Neonatal Seizures. Pediatric neurology Lemmon, M. E., Bonifacio, S. L., Shellhaas, R. A., Wusthoff, C. J., Greenberg, R. G., Soul, J. S., Chang, T. n., Chu, C. J., Bates, S. n., Massey, S. L., Abend, N. S., Cilio, M. R., Glass, H. C. 2020; 113: 21–25

    Abstract

    Neonatal seizures are associated with death and neurological morbidity; however, little is known about how neonates with seizures die.This was a prospective, observational cohort study of neonates with seizures treated at seven sites of the Neonatal Seizure Registry. We characterized the mode of death, evaluated the association between infant characteristics and mode of death, and evaluated predictors of death or transfer to hospice.We enrolled 611 consecutive neonates with seizures, and 90 neonates (15%) died before hospital discharge at a median age of 11 days (range: 1 to 163 days); 32 (36%) died in the first postnatal week. An additional 19 neonates (3%) were transferred to hospice. The most common mode of in-hospital death was death after extubation amidst concerns for poor neurological prognosis, in the absence of life-threatening physiologic instability (n = 43, 48%). Only one infant died while actively receiving cardiopulmonary resuscitation. In an adjusted analysis, premature birth (odds ratio: 3.06, 95% confidence interval 1.59 to 5.90) and high seizure burden (odds ratio: 4.33, 95% confidence interval 1.88 to 9.95) were associated with increased odds of death or transfer to hospice.In a cohort of neonates with seizures, death occurred predominantly after decisions to withdraw or withhold life-sustaining intervention(s). Future work should characterize how these decisions occur and develop optimized approaches to support families and clinicians caring for newborns with seizures.

    View details for DOI 10.1016/j.pediatrneurol.2020.08.002

    View details for PubMedID 32980743

  • Neonatal Neurocritical Care: Providing Brain-Focused Care for All at Risk Neonates. Seminars in pediatric neurology Bonifacio, S. L., Van Meurs, K. 2019; 32: 100774

    Abstract

    Neonatal neurocritical care is an evolving subsubspecialty whose goal is to implement neuroprotective care strategies, continuous bedside monitoring of neurologic function, and therapies in order to reduce the risk of neurologic injury and improve long-term neurodevelopmental outcomes in neonates who require intensive care. The provision of neonatal neurocritical care requires a culture change across a Neonatal Intensive Care Unit (NICU) in which equal importance is placed on the neurologic care and the cardiorespiratory care of a given patient. It is a multidisciplinary framework of care in which neonatologist and pediatric neurologist come together to address the unique needs of NICU patients whose brains are still developing and are vulnerable to injury. Advances in bedside brain monitoring techniques and the use of therapeutic hypothermia for Hupoxic-Ischemic Encephalopathy have accelerated the development of NeuroNICUs across the United States and abroad. Neonatologists, neurologists, neurophysiologists, nurses, and other ancillary members of the team work together to develop guidelines for commonly encountered neurological conditions in the NICU. The use of these guidelines helps provide standardized care across a unit and can reduce morbidity and length of hospital stay.

    View details for DOI 10.1016/j.spen.2019.08.010

    View details for PubMedID 31813520

  • Differences in patient characteristics and care practices between two trials of therapeutic hypothermia PEDIATRIC RESEARCH Bonifacio, S. L., McDonald, S. A., Chock, V. Y., Wusthoff, C. J., Hintz, S. R., Laptook, A. R., Shankara, S., Van Meurs, K. P. 2019; 85 (7): 1008–15
  • Differences in patient characteristics and care practices between two trials of therapeutic hypothermia. Pediatric research Bonifacio, S. L., McDonald, S. A., Chock, V. Y., Wusthoff, C. J., Hintz, S. R., Laptook, A. R., Shankara, S., Van Meurs, K. P. 2019

    Abstract

    BACKGROUND: The Induced Hypothermia (IH) and Optimizing Cooling (OC) trials for hypoxic-ischemic encephalopathy (HIE) had similar inclusion criteria. The rate of death/moderate-severe disability differed for the subgroups treated with therapeutic hypothermia (TH) at 33.5°C for 72h (44% vs. 29%, unadjusted p=0.03). We aimed to evaluate differences in patient characteristics and care practices between the trials.METHODS: We compared pre/post-randomization characteristics and care practices between IH and OC.RESULTS: There were 208 patients in the IH trial, 102 cooled, and 364 in the OC trial, 95 cooled to 33.5°C for 72h. In OC, neonates were less ill, fewer had severe HIE, and the majority were cooled prior to randomization. Differences between IH and OC were observed in the adjusted difference in the lowest PCO2 (+3.08mmHg, p=0.005) and highest PO2 (-82.7mmHg, p<0.001). In OC, compared to IH, the adjusted relative risk (RR) of exposure to anticonvulsant prior to randomization was decreased (RR 0.58, (0.40-0.85), p=0.005) and there was increased risk of exposure during cooling to sedatives/analgesia (RR 1.86 (1.21-2.86), p=0.005).CONCLUSION: Despite similar inclusion criteria, there were differences in patient characteristics and care practices between trials. Change in care practices over time should be considered when planning future neuroprotective trials.

    View details for PubMedID 30862961

  • Response to antiseizure medications in neonates with acute symptomatic seizures EPILEPSIA Glass, H. C., Soul, J. S., Chu, C. J., Massey, S. L., Wusthoff, C. J., Chang, T., Cilio, M., Bonifacio, S. L., Abend, N. S., Thomas, C., Lemmon, M., McCulloch, C. E., Shellhaas, R. A., Neonatal Seizure Registry Study Gr 2019; 60 (3): E20–E24

    View details for DOI 10.1111/epi.14671

    View details for Web of Science ID 000460315700002

  • Response to antiseizure medications in neonates with acute symptomatic seizures. Epilepsia Glass, H. C., Soul, J. S., Chu, C. J., Massey, S. L., Wusthoff, C. J., Chang, T., Cilio, M. R., Bonifacio, S. L., Abend, N. S., Thomas, C., Lemmon, M., McCulloch, C. E., Shellhaas, R. A., Neonatal Seizure Registry study group 2019

    Abstract

    In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM.

    View details for PubMedID 30790268

  • Toward the elimination of bias in Pediatric Research. Pediatric research Bearer, C. n., Agostoni, C. n., Anand, K. J., Ambalavanan, N. n., Bhandari, V. n., Bliss, J. M., Bloomfield, F. n., Bonifacio, S. L., Buhimschi, I. n., Cilio, M. R., Coppes, M. n., Czinn, S. J., El-Khuffash, A. n., Embleton, N. n., Felderhoff-Müser, U. n., Ferriero, D. M., Florin, T. n., Fuentes-Afflick, E. n., Gardner, W. n., Gospe, S. M., Gunn, A. n., Gressens, P. n., Guissani, D. n., Haiden, N. n., Hauptman, M. n., Kim, K. S., Klebanoff, M. n., Lachman, P. n., Lanphear, B. n., Ozen, S. n., Roehr, C. n., Roland, D. n., Rosenblum, N. n., Schwarz, M. n., Staiano, A. n., Stroustrup, A. n., Valente, E. M., Wilson-Costello, D. n., Wynn, J. n., Molloy, E. n. 2019

    View details for DOI 10.1038/s41390-019-0583-5

    View details for PubMedID 31533126

  • Development of a NeuroNICU with a Broader Focus on All Newborns at Risk of Brain Injury: The First 2 Years AMERICAN JOURNAL OF PERINATOLOGY Van Meurs, K. P., Yan, E. S., Randall, K. S., Chock, V. Y., Davis, A. S., Glennon, C. S., Clark, C. L., Wusthoff, C. J., Bonifacio, S. L. 2018; 35 (12): 1197–1205
  • Pulmonary Hypertension Associated with Hypoxic-lschemic Encephalopathy-Antecedent Characteristics and Comorbidities JOURNAL OF PEDIATRICS Lakshminrusimha, S., Shankaran, S., Laptook, A., McDonald, S., Keszler, M., Van Meurs, K., Guillet, R., Chawla, S., Sood, B. G., Bonifacio, S., Das, A., Higgins, R. D. 2018; 196: 45-+

    Abstract

    To determine the characteristics of term infants with persistent pulmonary hypertension of the newborn (PPHN) associated with moderate or severe hypoxic ischemic encephalopathy (HIE).We compared infants with and without PPHN enrolled in 2 randomized trials of therapeutic hypothermia: the induced hypothermia trial of cooling to 33.5°C for 72 hours vs normothermia, and the "usual-care" arm (33.5°C for 72 hours) of the optimizing cooling trial.Among 303 infants with HIE from these 2 studies, 67 (22%) had PPHN and 236 (78%) did not. We compared infants with PPHN with those without PPHN. The proportion of patients treated with therapeutic hypothermia was similar in PPHN and no-PPHN groups (66% vs 65%). Medication use during resuscitation (58% vs 44%), acidosis after birth (pH: 7.0 ± 0.2 vs 7.1 ± 0.2), severe HIE (43% vs 28%), meconium aspiration syndrome (39% vs 7%), pulmonary hemorrhage (12% vs 3%), culture-positive sepsis (12% vs 3%), systemic hypotension (65% vs 28%), inhaled nitric oxide therapy (64% vs 3%), and extracorporeal membrane oxygenation (12% vs 0%) were more common in the PPHN group. Length of stay (26 ± 21 vs 16 ± 14 days) and mortality (27% vs 16%) were higher in the PPHN group.PPHN is common among infants with moderate/severe HIE and is associated with severe encephalopathy, lung disease, sepsis, systemic hypotension, and increased mortality. The prevalence of PPHN was not different between those infants receiving therapeutic hypothermia at 33.5°C in these 2 trials (44/197 = 22%) compared with infants receiving normothermia in the induced hypothermia trial (23/106 = 22%).

    View details for PubMedID 29502880

  • Development of a NeuroNICU with a Broader Focus on All Newborns at Risk of Brain Injury: The First 2 Years. American journal of perinatology Van Meurs, K. P., Yan, E. S., Randall, K. S., Chock, V. Y., Davis, A. S., Glennon, C. S., Clark, C. L., Wusthoff, C. J., Bonifacio, S. L. 2018

    Abstract

    OBJECTIVE: Many critically ill neonates have an existing brain injury or are at risk of neurologic injury. We developed a "NeuroNICU" (neurologic neonatal intensive care unit) to better provide neurologically focused intensive care.STUDY DESIGN: Demographic and clinical variables, services delivered, and patient outcomes were recorded in a prospective database for all neonates admitted to the NeuroNICU between April 23, 2013, and June 25, 2015.RESULTS: In total, 546 neonates were admitted to the NeuroNICU representing 32% of all NICU admissions. The most common admission diagnoses were congenital heart disease (30%), extreme prematurity (18%), seizures (10%), and hypoxic-ischemic encephalopathy (9%). Neuromonitoring was common, with near-infrared spectroscopy used in 69%, amplitude-integrated electroencephalography (EEG) in 45%, and continuous video EEG in 35%. Overall, 43% received neurology or neurosurgery consultation. Death prior to hospital discharge occurred in 11%. Among survivors, 87% were referred for developmental follow-up, and among those with a primary neurologic diagnosis 57% were referred for neurology or neurosurgical follow-up.CONCLUSION: The NeuroNICU-admitted newborns with or at risk of brain injury comprise a high percentage of NICU volume; 38% had primary neurologic diagnoses, whereas 62% had medical diagnoses. We found many opportunities to provide brain focused intensive care, impacting a substantial proportion of newborns in our NICU.

    View details for PubMedID 29702712

  • Seizures in Preterm Neonates: A Multicenter Observational Cohort Study. Pediatric neurology Glass, H. C., Shellhaas, R. A., Tsuchida, T. N., Chang, T., Wusthoff, C. J., Chu, C. J., Cilio, M. R., Bonifacio, S. L., Massey, S. L., Abend, N. S., Soul, J. S. 2017

    Abstract

    The purpose of this study was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society's neonatal electroencephalography monitoring guideline.Of 611 enrolled neonates with seizures, 92 (15%) were born preterm. Seizure characteristics were evaluated by gestational age at birth for extremely preterm (<28 weeks, N = 18), very preterm (28 to <32 weeks, N = 18), and moderate to late preterm (32 to <37 weeks, N = 56) and compared with term neonates.Hypoxic-ischemic encephalopathy (33%) and intracranial hemorrhage (27%) accounted for the etiology in more than half of preterm neonates. Hypothermia therapy was utilized in 15 moderate to late preterm subjects with encephalopathy. The presence of subclinical seizures, monotherapy treatment failure, and distribution of seizure burden (including status epilepticus) was similar in preterm and term neonates. However, exclusively subclinical seizures occurred more often in preterm than term neonates (24% vs 14%). Phenobarbital was the most common initial medication for all gestational age groups, and failure to respond to an initial loading dose was 63% in both preterm and term neonates. Mortality was similar among the three preterm gestational age groups; however, preterm mortality was more than twice that of term infants (35% vs 15%).Subclinical seizures were more common and mortality was higher for preterm than term neonates. These data underscore the importance of electroencephalographic monitoring and the potential for improved management in preterm neonates.

    View details for DOI 10.1016/j.pediatrneurol.2017.04.016

    View details for PubMedID 28558955

  • Brain-focused care in the neonatal intensive care unit: the time has come. Jornal de pediatria Van Meurs, K. P., Bonifacio, S. L. 2017

    View details for DOI 10.1016/j.jped.2017.03.002

    View details for PubMedID 28359015

  • Characterization of Death in Neonatal Encephalopathy in the Hypothermia Era. Journal of child neurology Lemmon, M. E., Boss, R. D., Bonifacio, S. L., Foster-Barber, A., Barkovich, A. J., Glass, H. C. 2017; 32 (4): 360-365

    Abstract

    This study aimed to characterize the circumstances of death in encephalopathic neonates treated with therapeutic hypothermia. Patients who died after or during treatment with therapeutic hypothermia between 2007-2014 were identified. Patient circumstance of death was characterized using an established paradigm. Thirty-one of 229 patients died (14%) at a median of 3 days of life. Most who died were severely encephalopathic on examination (90%) and had severely abnormal electroencephalographic (EEG) findings (87%). All those who had magnetic resonance images (n = 13) had evidence of moderate-severe brain injury; 6 had near-total brain injury. Cooling was discontinued prematurely in 61% of patients. Most patients (90%) were physiologically stable at the time of death; 81% died following elective extubation for quality of life considerations. Three patients (10%) died following withholding or removal of artificial hydration and nutrition. Characterization of death in additional cohorts is needed to identify differences in decision making practices over time and between centers.

    View details for DOI 10.1177/0883073816681904

    View details for PubMedID 28193115

    View details for PubMedCentralID PMC5359080

  • Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study. journal of pediatrics Shellhaas, R., Chang, T., Wusthoff, C., Soul, J., Massey, S., Chu, C., Cilio, M. R., Bonifacio, S., Abend, N., Tsuchida, T., Glass, H. 2017; 181: 298-301 e1

    Abstract

    We aimed to define determinants of duration of treatment for acute symptomatic neonatal seizures in a contemporary multicenter observational cohort study. After adjustment for potential confounders, only study site and seizure etiology remained significantly associated with the chance of continuing antiseizure medication after discharge to home.

    View details for DOI 10.1016/j.jpeds.2016.10.039

    View details for PubMedID 27829512

    View details for PubMedCentralID PMC5322461

  • Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia JOURNAL OF CLINICAL PHARMACOLOGY Frymoyer, A., Bonifacio, S. L., Drover, D. R., Su, F., Wustoff, C. J., Van Meurs, K. P. 2017; 57 (1): 64-76

    Abstract

    Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweight. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jcph.775

    View details for PubMedID 27225747

  • Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study JOURNAL OF PEDIATRICS Glass, H. C., Shellhaas, R. A., Wusthoff, C. J., Chang, T., Abend, N. S., Chu, C. J., Cilio, M. R., Glidden, D. V., Bonifacio, S. L., Massey, S., Tsuchida, T. N., Silverstein, F. S., Soul, J. S. 2016; 174: 98-?

    Abstract

    To determine the contemporary etiology, burden, and short-term outcomes of seizures in neonates monitored with continuous video-electroencephalogram (cEEG).We prospectively collected data from 426 consecutive neonates (56% male, 88% term) ≤44 weeks' postmenstrual age with clinically suspected seizures and/or electrographic seizures. Subjects were assessed between January 2013 and April 2015 at 7 US tertiary care pediatric centers following the guidelines of the American Clinical Neurophysiology Society for cEEG for at-risk neonates. Seizure etiology, burden, management, and outcome were determined by chart review by the use of a case report form designed at study onset.The most common seizure etiologies were hypoxic-ischemic encephalopathy (38%), ischemic stroke (18%), and intracranial hemorrhage (11%). Seizure burden was high, with 59% having ≥7 electrographic seizures and 16% having status epilepticus; 52% received ≥2 antiseizure medications. During the neonatal admission, 17% died; 49% of survivors had abnormal neurologic examination at hospital discharge. In an adjusted analysis, high seizure burden was a significant risk factor for mortality, length of hospital stay, and abnormal neurological examination at discharge.In this large contemporary profile of consecutively enrolled newborns with seizures treated at centers that use cEEG per the guidelines of the American Clinical Neurophysiology Society, about one-half had high seizure burden, received ≥2 antiseizure medications, and/or died or had abnormal examination at discharge. Greater seizure burden was associated with increased morbidity and mortality. These findings underscore the importance of accurate determination of neonatal seizure frequency and etiology and a potential for improved outcome if seizure burden is reduced.

    View details for DOI 10.1016/j.jpeds.2016.03.035

    View details for PubMedID 27106855

  • High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial PEDIATRICS Wu, Y. W., Mathur, A. M., Chang, T., McKinstry, R. C., Mulkey, S. B., Mayock, D. E., Van Meurs, K. P., Rogers, E. E., Gonzalez, F. F., Comstock, B. A., Juul, S. E., Msall, M. E., Bonifacio, S. L., Glass, H. C., Massaro, A. N., Dong, L., Tan, K. W., Heagerty, P. J., Ballard, R. A. 2016; 137 (6)

    Abstract

    To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy.In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit ≥15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system.The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05).High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

    View details for DOI 10.1542/peds.2016-0191

    View details for Web of Science ID 000378520100042

    View details for PubMedID 27244862

  • The Neurointensive Care Nursery and Evolving Roles for Nursing NEONATAL NETWORK Peloquin, S., Carley, A., Bonifacio, S. L., Glass, H. C. 2016; 35 (2): 87–94

    Abstract

    Neonatal neurocritical care is an emerging subspecialty that combines the expertise of critical care medicine and neurology with that of nursing and other providers in an interprofessional team approach to care. Neurocritical care of the neonate has roots in adult and pediatric practice. It has been demonstrated that adults with acute neurologic conditions who are treated in a specialized neurocritical care unit have reduced morbidity and mortality, as well as decreased length of stay, lower costs, and reduced need for neurosurgical procedures. In pediatrics, neurocritical care has focused on various primary and secondary neurologic conditions complicating critical care that also contribute to mortality, morbidity, and duration of hospitalization. However, the concept of neurocritical care as a subspecialty in pediatric practice is still evolving, and evidence demonstrating improved outcomes is lacking. In the neonatal intensive care nursery, neurocritical care is also evolving as a subspecialty concept to address both supportive and preventive care and optimize neurologic outcomes for an at-risk neonatal patient population. To enhance effectiveness of this care approach, nurses must be prepared to appropriately recognize acute changes in neurologic status, implement protocols that specifically address neurologic conditions, and carefully monitor neurologic status to help prevent secondary injury. The complexity of this team approach to brain-focused care has led to the development of a specialized role: the neurocritical care nurse (neonatal intensive care nursery [NICN] nurse). This article will review key concepts related to neonatal neurocritical care and the essential role of nursing. It will also explore the emerging role of the NICN nurse in supporting early recognition and management of at-risk infants in this neonatal subspecialty practice.

    View details for DOI 10.1891/0730-0832.35.2.87

    View details for Web of Science ID 000410863500006

    View details for PubMedID 27052983

  • Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia THERAPEUTIC DRUG MONITORING Sampson, M. R., Frymoyer, A., Rattray, B., Cotten, C. M., Smith, P. B., Capparelli, E., Bonifacio, S. L., Cohen-Wolkowiez, M. 2014; 36 (5): 584-589

    Abstract

    Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated.A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions.Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05).The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.

    View details for Web of Science ID 000342493500005

    View details for PubMedCentralID PMC4166612

  • Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia. Therapeutic drug monitoring Sampson, M. R., Frymoyer, A., Rattray, B., Cotten, C. M., Smith, P. B., Capparelli, E., Bonifacio, S. L., Cohen-Wolkowiez, M. 2014; 36 (5): 584-589

    Abstract

    Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated.A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions.Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05).The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.

    View details for DOI 10.1097/FTD.0000000000000056

    View details for PubMedID 25225917

  • Risk factors for EEG seizures in neonates treated with hypothermia: A multicenter cohort study. Neurology Glass, H. C., Wusthoff, C. J., Shellhaas, R. A., Tsuchida, T. N., Bonifacio, S. L., Cordeiro, M., Sullivan, J., Abend, N. S., Chang, T. 2014; 82 (14): 1239-1244

    Abstract

    To assess the risk factors for electrographic seizures among neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE).Three-center observational cohort study of 90 term neonates treated with hypothermia, monitored with continuous video-EEG (cEEG) within the first day of life (median age at onset of recording 9.5 hours, interquartile range 6.3-14.5), and continued for >24 hours (total recording 93.3 hours, interquartile range 80.1-112.8 among survivors). A pediatric electroencephalographer at each site reviewed cEEGs for electrographic seizures and initial EEG background category.A total of 43 (48%) had electrographic seizures, including 9 (10%) with electrographic status epilepticus. Abnormal initial EEG background classification (excessively discontinuous, depressed and undifferentiated, burst suppression, or extremely low voltage), but not clinical variables (including pH <6.8, base excess ≤-20, or 10-minute Apgar ≤3), was strongly associated with seizures.Electrographic seizures are common among neonates with HIE undergoing hypothermia and are difficult to predict based on clinical features. These results justify the recommendation for cEEG monitoring in neonates treated with hypothermia.

    View details for DOI 10.1212/WNL.0000000000000282

    View details for PubMedID 24610326

  • Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. Journal of perinatology Frymoyer, A., Lee, S., Bonifacio, S. L., Meng, L., LUCAS, S. S., Guglielmo, B. J., Sun, Y., Verotta, D. 2013; 33 (10): 778-782

    Abstract

    To examine the impact of a change in the empiric gentamicin dose from 5 mg kg(-1) every 24 h (Q24 h period) to 5 mg kg every 36 h (Q36 h period) on target drug concentration achievement in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia.Gentamicin drug concentrations in neonates with HIE receiving therapeutic hypothermia were examined during two time periods in a retrospective chart review. During the initial treatment period (November 2007 to March 2010; n=29), neonates received Q24 h period. During the second treatment period (January 2011 to May 2012; n=23), the dose was changed to Q36 h period. Cooling criteria and protocol remained the same between treatment periods. Gentamicin drug concentrations including achievement of target trough concentrations (<2 mg l(-1)) were compared between treatment periods. Individual Bayesian estimates of gentamicin clearance were also compared.Neonates with an elevated trough concentration >2 mg l(-1) decreased from 38 to 4% with implementation of a Q36-h dosing interval (P<0.007). The mean gentamicin trough concentration was 2.0 ± 0.8 mg l(-1) during the Q24 h period and 0.9 ± 0.4 mg l(-1) during the Q36 h period (P<0.001). Peak concentrations were minimally impacted (Q24 h 11.4 ± 2.3 mg l(-1) vs Q36 h 10.0 ± 1.9 mg l(-1); P=0.05). The change in gentamicin trough concentration could not be accounted for by differences in gentamicin clearance between treatment periods (P=0.9).A 5 mg kg(-1) every 36-h gentamicin dosing strategy in neonates with HIE receiving therapeutic hypothermia improved achievement of target trough concentration <2 mg l(-1), while still providing high peak concentration exposure.

    View details for DOI 10.1038/jp.2013.59

    View details for PubMedID 23702622

    View details for PubMedCentralID PMC3762884

  • Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia. Pharmacotherapy Frymoyer, A., Meng, L., Bonifacio, S. L., Verotta, D., Guglielmo, B. J. 2013; 33 (7): 718-726

    Abstract

    STUDY OBJECTIVE: To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations. DESIGN: Population pharmacokinetic study using retrospective medical record data. SETTING: Tertiary neonatal intensive care unit. PATIENTS: A total of 29 full-term neonates diagnosed with HIE treated with hypothermia who received gentamicin and underwent therapeutic drug monitoring MEASUREMENT AND MAIN RESULTS: Patient demographics and gentamicin concentration data were retrospectively collected over a 2-year period. A population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). Using the developed model, Monte Carlo simulations were performed to evaluate the probability of achieving target peak (> 6 mg/L) and trough (< 2 mg/L) gentamicin concentrations for various potential dosing regimens. A one-compartment model best described the available gentamicin concentration data. Birthweight and serum creatinine significantly influenced gentamicin clearance. For the typical study neonate (birthweight 3.3 kg, serum creatinine 0.9 mg/dl), clearance was 0.034 L/hour/kg and volume was 0.52 L/kg. At a 24-hour dosing interval, Monte Carlo simulations predicted target gentamicin peak and trough concentrations could not be reliably achieved at any dose. At a 36-hour dosing interval, a dose of 4-5 mg/kg is predicted to achieve target gentamicin peak and trough concentrations in more than 90% of neonates. CONCLUSIONS: Gentamicin clearance is decreased in neonates with HIE treated with hypothermia compared with previous reports in nonasphyxiated normothermic full-term neonates. A prolonged 36-hour dosing interval will be needed to achieve target gentamicin trough concentrations in this population. Further prospective evaluation of this dosing recommendation is needed.

    View details for DOI 10.1002/phar.1263

    View details for PubMedID 23553582