Sonia Bonifacio, MD

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

View details for PubMedID 37573378

View details for PubMedCentralID 6477286

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

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

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

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, 21.0min/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, 21.0min/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

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

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

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

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

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

View details for PubMedID 35681096

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

View details for Web of Science ID 000737459400295

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

View details for Web of Science ID 000737459401175

View details for DOI 10.1016/j.pediatrneurol.2021.11.014

View details for PubMedID 34991933

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

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

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

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

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 33.5C0.5C. 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

View details for DOI 10.1016/j.siny.2021.101260

View details for PubMedID 34154944

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

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

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

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

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

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

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 11days (range: 1 to 163days); 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

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

View details for DOI 10.1038/s41390-019-0371-2

View details for Web of Science ID 000468524800020

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 33.5C 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 33.5C 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

View details for DOI 10.1111/epi.14671

View details for Web of Science ID 000460315700002

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

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

View details for PubMedID 31533126

View details for DOI 10.1055/s-0038-1646954

View details for Web of Science ID 000445491700012

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 33.5C for 72 hours vs normothermia, and the "usual-care" arm (33.5C 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: 7.00.2 vs 7.10.2), 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 (2621 vs 1614 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 33.5C 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

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

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 (<28weeks, N=18), very preterm (28 to <32weeks, N=18), and moderate to late preterm (32 to <37weeks, 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

View details for DOI 10.1016/j.jped.2017.03.002

View details for PubMedID 28359015

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

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

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 g/kg followed by a continuous infusion of 5 g/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

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) 44weeks' 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

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

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

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

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

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

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 (Q36h 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 Q36h 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 Q36h period (P<0.001). Peak concentrations were minimally impacted (Q24 h 11.4 2.3 mg l(-1) vs Q36h 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

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 (>6mg/L) and trough (<2mg/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 3.3kg, serum creatinine 0.9mg/dl), clearance was 0.034L/hour/kg and volume was 0.52L/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 4-5mg/kg is predicted to achieve target gentamicin peak and trough concentrations in more than90% 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