RESUMO
OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.
Assuntos
Anticonvulsivantes , Eletroencefalografia , Hipóxia-Isquemia Encefálica , Convulsões , Humanos , Convulsões/tratamento farmacológico , Estudos Retrospectivos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Masculino , Anticonvulsivantes/uso terapêutico , Recém-Nascido , Feminino , Resultado do TratamentoRESUMO
OBJECTIVE: To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2. RESULTS: Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 [42%]) compared with the late TT group (n = 289 [58%]) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, -2.8 [95% CI, -6.1 to 0.5], language -3.3 [95% CI, -7.4 to 0.8], and motor -3.5 [95% CI, -7.3 to 0.3]). CONCLUSIONS: In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age. TRIAL REGISTRATION: High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta. CLINICALTRIALS: gov/study/NCT02811263.
Assuntos
Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Humanos , Recém-Nascido , Temperatura Baixa , Deficiências do Desenvolvimento/complicações , Hipóxia-Isquemia Encefálica/terapia , Hipóxia-Isquemia Encefálica/complicações , TemperaturaRESUMO
OBJECTIVE: To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs). STUDY DESIGN: Five hundred infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypothermia were randomized to Epo or placebo on days 1, 2, 3, 4, and 7. Pretreatment and posttreatment SAEs were compared with adjusted generalized linear models, with posttreatment models adjusted for the presence of a pretreatment SAE. Clinical risk factors and potential mechanisms for SAEs were also examined. RESULTS: The rate of experiencing at least one posttreatment SAE did not significantly differ between groups (adjusted relative risk [aRR], 95% CI: 1.17, 0.92-1.49); however, posttreatment thrombosis was identified more often in the Epo group (n = 6, 2.3%) than the placebo group (n = 1, 0.4%; aRR, 95% CI: 5.09, 1.32-19.64). The rate of posttreatment intracranial hemorrhage identified at the treatment sites by either ultrasound or magnetic resonance imaging was slightly elevated in the Epo group (n = 61, 24%) but not significantly different from the placebo group (n = 46, 19%; aRR, 95% CI: 1.21, 0.85, 1.72). CONCLUSIONS: A small increased risk of major thrombotic events was identified in the Epo treatment group. TRIAL REGISTRATION: NCT02811263.
Assuntos
Eritropoetina , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Recém-Nascido , Lactente , Humanos , Hipóxia-Isquemia Encefálica/complicações , Eritropoetina/efeitos adversos , Hipotermia Induzida/efeitos adversos , Hipotermia Induzida/métodos , Temperatura BaixaRESUMO
OBJECTIVES: To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN: In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS: The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002). CONCLUSIONS: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.
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Creatinina/urina , Eritropoetina/administração & dosagem , Hepcidinas/urina , Lactente Extremamente Prematuro/metabolismo , Ferro/metabolismo , Biomarcadores/sangue , Ferritinas/sangue , Heme , Humanos , Lactente , Recém-Nascido , Protoporfirinas/sangue , Estudos RetrospectivosRESUMO
OBJECTIVES: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. STUDY DESIGN: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. RESULTS: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. CONCLUSIONS: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.
Assuntos
Encéfalo/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Neuroproteção , Encéfalo/patologia , Pré-Escolar , Método Duplo-Cego , Eritropoetina , Feminino , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/patologiaRESUMO
OBJECTIVES: To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). STUDY DESIGN: This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. RESULTS: In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7 mg/kg/d (IQR 2.1-5.8 mg/kg/d) at day 60, with a mean of 3.6 mg/kg/d in infants treated with placebo and 4.8 mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90 days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater. CONCLUSIONS: A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01378273.
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Ferro/administração & dosagem , Transtornos do Neurodesenvolvimento/prevenção & controle , Neuroproteção/efeitos dos fármacos , Adulto , Nutrição Enteral , Eritropoetina/administração & dosagem , Eritropoetina/farmacologia , Feminino , Humanos , Lactente , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Recém-Nascido , Ferro/efeitos adversos , Ferro/farmacologia , Masculino , Gravidez , Estudos ProspectivosRESUMO
OBJECTIVES: To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 240/7 to 276/7 weeks of gestational age and to characterize the association between ICH and death or neurodevelopmental impairment (NDI) at 2 years of corrected age. STUDY DESIGN: Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial had serial cranial ultrasound scans performed on day 1, day 7-9, and 36 weeks of postmenstrual age to evaluate ICH. Potential risk factors for development of ICH were examined. Outcomes included death or severe NDI as well as Bayley Scales of Infant and Toddler Development, 3rd Edition, at 2 years of corrected age. RESULTS: ICH was identified in 38% (n = 339) of 883 enrolled infants. Multiple gestation and cesarean delivery reduced the risk of any ICH on day 1. Risk factors for development of bilateral Grade 2, Grade 3, or Grade 4 ICH at day 7-9 included any ICH at day 1; 2 or more doses of prenatal steroids decreased risk. Bilateral Grade 2, Grade 3, or Grade 4 ICH at 36 weeks were associated with previous ICH at day 7-9. Bilateral Grade 2, any Grade 3, and any Grade 4 ICH at 7-9 days or 36 weeks of postmenstrual age were associated with increased risk of death or severe NDI and lower Bayley Scales of Infant and Toddler Development, 3rd Edition, scores. CONCLUSIONS: Risk factors for ICH varied by timing of bleed. Bilateral and increasing grade of ICH were associated with death or NDI in infants born extremely preterm.
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Hemorragias Intracranianas/mortalidade , Transtornos do Neurodesenvolvimento/epidemiologia , Pré-Escolar , Feminino , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido , Doenças do Prematuro , Hemorragias Intracranianas/diagnóstico por imagem , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , UltrassonografiaRESUMO
OBJECTIVE: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. STUDY DESIGN: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. RESULTS: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. CONCLUSIONS: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02811263.
Assuntos
Hipóxia-Isquemia Encefálica/patologia , Doenças Placentárias/diagnóstico , Doenças Placentárias/epidemiologia , Doença Aguda , Doença Crônica , Estudos de Coortes , Método Duplo-Cego , Eritropoetina/uso terapêutico , Feminino , Idade Gestacional , Humanos , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/terapia , Recém-Nascido , Masculino , Gravidez , Fatores de RiscoRESUMO
BACKGROUND: Robotic-assisted gynecologic surgery is common, but requires unique training. A validated assessment tool for evaluating trainees' robotic surgery skills is Robotic-Objective Structured Assessments of Technical Skills. OBJECTIVE: We sought to assess whether crowdsourcing can be used as an alternative to expert surgical evaluators in scoring Robotic-Objective Structured Assessments of Technical Skills. STUDY DESIGN: The Robotic Training Network produced the Robotic-Objective Structured Assessments of Technical Skills, which evaluate trainees across 5 dry lab robotic surgical drills. Robotic-Objective Structured Assessments of Technical Skills were previously validated in a study of 105 participants, where dry lab surgical drills were recorded, de-identified, and scored by 3 expert surgeons using the Robotic-Objective Structured Assessments of Technical Skills checklist. Our methods-comparison study uses these previously obtained recordings and expert surgeon scores. Mean scores per participant from each drill were separated into quartiles. Crowdworkers were trained and calibrated on Robotic-Objective Structured Assessments of Technical Skills scoring using a representative recording of a skilled and novice surgeon. Following this, 3 recordings from each scoring quartile for each drill were randomly selected. Crowdworkers evaluated the randomly selected recordings using Robotic-Objective Structured Assessments of Technical Skills. Linear mixed effects models were used to derive mean crowdsourced ratings for each drill. Pearson correlation coefficients were calculated to assess the correlation between crowdsourced and expert surgeons' ratings. RESULTS: In all, 448 crowdworkers reviewed videos from 60 dry lab drills, and completed a total of 2517 Robotic-Objective Structured Assessments of Technical Skills assessments within 16 hours. Crowdsourced Robotic-Objective Structured Assessments of Technical Skills ratings were highly correlated with expert surgeon ratings across each of the 5 dry lab drills (r ranging from 0.75-0.91). CONCLUSION: Crowdsourced assessments of recorded dry lab surgical drills using a validated assessment tool are a rapid and suitable alternative to expert surgeon evaluation.