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Sonia Bonifacio, MD

  • Sonia Lomeli Bonifacio

Specialties

Neonatal-Perinatal Medicine

Work and Education

Professional Education

University of California at San Francisco School of Medicine, San Francisco, CA, 6/15/2003

Internship

Univ of California San Francisco, School of Medicine, San Francisco, CA, United States of America, 6/30/2004

Residency

Univ of California San Francisco, School of Medicine, San Francisco, CA, United States of America, 6/30/2006

Fellowship

Univ of California San Francisco, School of Medicine, San Francisco, CA, United States of America, 5/30/2009

Board Certifications

Neonatal-Perinatal Medicine, American Board of Pediatrics

Pediatrics, American Board of Pediatrics

All Publications

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): 100815
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 33.5C 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

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): E20E24

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

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): 11971205
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 33.5C 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

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 (<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

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 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

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) 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

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): 8794

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 (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

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 (>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