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OBJECTIVE: To evaluate variations in management of therapeutic hypothermia (TH) for neonatal hypoxic-ischemic encephalopathy (HIE) among international clinical sites and to identify areas for harmonization. STUDY DESIGN: An electronic survey was sent to Children's Hospitals Neonatal Consortium site sponsors, Canadian Neonatal Network site investigators, members of the Newborn Brain Society, and American Academy of Pediatrics Neonatology chiefs. RESULTS: One hundred five sites responded, with most from high-income regions (n = 95). Groupings were adapted from the United Nations regional groups: US (n = 52 sites); Canada (n = 20); Western Europe and other states excluding Canada and US Group (WEOG, n = 18); and non-WEOG (central and eastern Europe, Asia, Africa, Latin America, and Caribbean, n = 15). Regional variations were seen in the eligibility criteria for TH, such as the minimum gestational age, grading of HIE severity, use of electroencephalography, and the frequency of providing TH for mild HIE. Active TH during transport varied among regions and was less likely in smaller volume sites. Amplitude-integrated electroencephalogram and/or continuous electroencephalogram to determine eligibility for TH was used by most sites in WEOG and non-WEOG but infrequently by the US and Canada Groups. For sedation during TH, morphine was most frequently used as first choice but there was relatively high (33%) use of dexmedetomidine in the US Group. Timing of brain magnetic resonance imaging and neurodevelopmental follow-up were variable. Neurodevelopmental follow occurred earlier and more frequently, although for a shorter duration, in the non-WEOG. CONCLUSIONS: We found significant variations in practices for TH for HIE across regions internationally. Future guidelines should incorporate resource availability in a global perspective.
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Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Humanos , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/terapia , Recién Nacido , Pautas de la Práctica en Medicina/estadística & datos numéricos , Electroencefalografía , Encuestas de Atención de la Salud , Canadá , InternacionalidadRESUMEN
OBJECTIVE: To compare the short- and long-term outcomes of infants with hypoxic-ischemic encephalopathy (HIE) treated with whole-body therapeutic hypothermia (TH), monitored by esophageal vs rectal temperature. STUDY DESIGN: We conducted a secondary analysis of the multicenter High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial. All infants had moderate or severe HIE and were treated with whole-body TH. The primary outcome was death or neurodevelopmental impairment (NDI) at 22-36 months of age. Secondary outcomes included seizures, evidence of brain injury on magnetic resonance imaging, and complications of hypothermia. Logistic regression was used with adjustment for disease severity and site as clustering variable because cooling modality differed by site. RESULTS: Of the 500 infants who underwent TH, 294 (59%) and 206 (41%) had esophageal and rectal temperature monitoring, respectively. There were no differences in death or NDI, seizures, or evidence of injury on magnetic resonance imaging between the 2 groups. Infants treated with TH and rectal temperature monitoring had lower odds of overcooling (OR 0.52, 95% CI 0.34-0.80) and lower odds of hypotension (OR 0.57, 95% CI 0.39-0.84) compared with those with esophageal temperature monitoring. CONCLUSIONS: Although infants undergoing TH with esophageal monitoring were more likely to experience overcooling and hypotension, the rate of death or NDI was similar whether esophageal monitoring or rectal temperature monitoring was used. Further studies are needed to investigate whether esophageal temperature monitoring during TH is associated with an increased risk of overcooling and hypotension.
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Temperatura Corporal , Esófago , Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Recto , Humanos , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/terapia , Masculino , Femenino , Recién Nacido , Lactante , Esófago/diagnóstico por imagen , Resultado del Tratamiento , Monitoreo Fisiológico/métodos , Imagen por Resonancia Magnética , PreescolarRESUMEN
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.
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Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Humanos , Recién Nacido , Frío , Discapacidades del Desarrollo/complicaciones , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/complicaciones , TemperaturaRESUMEN
OBJECTIVE: To determine cerebral glucose concentration and its relationship with glucose infusion rate (GIR) and blood glucose concentration in neonatal encephalopathy during therapeutic hypothermia (TH). METHODS: This was an observational study in which cerebral glucose during TH was quantified by magnetic resonance (MR) spectroscopy and compared with mean blood glucose at the time of scan. Clinical data (gestational age, birth weight, GIR, sedative use) that could affect glucose use were collected. The severity and pattern of brain injury on MR imaging were scored by a neuroradiologist. Student t test, Pearson correlation, repeated measures ANOVA, and multiple regression analysis were performed. RESULTS: Three-hundred-sixty blood glucose values and 402 MR spectra from 54 infants (30 female infants; mean gestational age 38.6 ± 1.9 weeks) were analyzed. In total, 41 infants had normal-mild and 13 had moderate-severe injury. Median GIR and blood glucose during TH were 6.0 mg/kg/min (IQR 5-7) and 90 mg/dL (IQR 80-102), respectively. GIR did not correlate with blood or cerebral glucose. Cerebral glucose was significantly greater during than after TH (65.9 ± 22.9 vs 60.0 ± 25.2 mg/dL, P < .01), and there was a significant correlation between blood glucose and cerebral glucose during TH (basal ganglia: r = 0.42, thalamus: r = 0.42, cortical gray matter: r = 0.39, white matter: r = 0.39, all P < .01). There was no significant difference in cerebral glucose concentration in relation to injury severity or pattern. CONCLUSIONS: During TH, cerebral glucose concentration is partly dependent on blood glucose concentration. Further studies to understand brain glucose use and optimal glucose concentrations during hypothermic neuroprotection are needed.
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Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Recién Nacido , Lactante , Humanos , Femenino , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/patología , Glucemia , Hipotermia Inducida/efectos adversos , Hipotermia Inducida/métodos , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia MagnéticaRESUMEN
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.
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Hipoxia-Isquemia Encefálica/patología , Enfermedades Placentarias/diagnóstico , Enfermedades Placentarias/epidemiología , Enfermedad Aguda , Enfermedad Crónica , Estudios de Cohortes , Método Doble Ciego , Eritropoyetina/uso terapéutico , Femenino , Edad Gestacional , Humanos , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/terapia , Recién Nacido , Masculino , Embarazo , Factores de RiesgoRESUMEN
OBJECTIVE: To assess differences in regional brain temperatures during whole-body hypothermia and test the hypothesis that brain temperature profile is nonhomogenous in infants with hypoxic-ischemic encephalopathy. STUDY DESIGN: Infants with hypoxic-ischemic encephalopathy were enrolled prospectively in this observational study. Magnetic resonance (MR) spectra of basal ganglia, thalamus, cortical gray matter, and white matter (WM) were acquired during therapeutic hypothermia. Regional brain tissue temperatures were calculated from the chemical shift difference between water signal and metabolites in the MR spectra after performing calibration measurements. Overall difference in regional temperature was analyzed by mixed-effects model; temperature among different patterns and severity of injury on MR imaging also was analyzed. Correlation between temperature and depth of brain structure was analyzed using repeated-measures correlation. RESULTS: In total, 53 infants were enrolled (31 girls, mean gestational age: 38.6 ± 2 weeks; mean birth weight: 3243 ± 613 g). MR spectroscopy was acquired at mean age of 2.2 ± 0.6 days. A total of 201 MR spectra were included in the analysis. The thalamus, the deepest structure (36.4 ± 2.3 mm from skull surface), was lowest in temperature (33.2 ± 0.8°C, compared with basal ganglia: 33.5 ± 0.9°C; gray matter: 33.6 ± 0.7°C; WM: 33.8 ± 0.9°C, all P < .001). Temperatures in more superficial gray matter and WM regions (depth: 21.9 ± 2.4 and 21.5 ± 2.2 mm) were greater than the rectal temperatures (33.4 ± 0.4°C, P < .03). There was a negative correlation between temperature and depth of brain structure (rrm = -0.36, P < .001). CONCLUSIONS: Whole-body hypothermia was effective in cooling deep brain structures, whereas superficial structures were warmer, with temperatures significantly greater than rectal temperatures.
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Temperatura Corporal/fisiología , Encéfalo/diagnóstico por imagen , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/terapia , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Encéfalo/fisiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Prospectivos , Recto/fisiología , TermometríaRESUMEN
OBJECTIVE: To delineate the systemic and cerebral hemodynamic response to incremental increases in core temperature during the rewarming phase of therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Continuous hemodynamic data, including heart rate (HR), mean arterial blood pressure (MBP), cardiac output by electrical velocimetry (COEV), arterial oxygen saturation, and renal (RrSO2) and cerebral (CrSO2) regional tissue oxygen saturation, were collected from 4 hours before the start of rewarming to 1 hour after the completion of rewarming. Serial echocardiography and transcranial Doppler were performed at 3 hours and 1 hour before the start of rewarming (T-3 and T-1; "baseline") and at 2, 4, and 7 hours after the start of rewarming (T+2, T+4, and T+7; "rewarming") to determine Cardiac output by echocardiography (COecho), stroke volume, fractional shortening, and middle cerebral artery (MCA) flow velocity indices. Repeated-measures analysis of variance was used for statistical analysis. RESULTS: Twenty infants with HIE were enrolled (mean gestational age, 38.8 ± 2 weeks; mean birth weight, 3346 ± 695 g). During rewarming, HR, COecho, and COEV increased from baseline to T+7, and MBP decreased. Despite an increase in fractional shortening, stroke volume remained unchanged. RrSO2 increased, and renal fractional oxygen extraction (FOE) decreased. MCA peak systolic flow velocity increased. There were no changes in CrSO2 or cerebral FOE. CONCLUSIONS: In neonates with HIE, CO significantly increases throughout rewarming. This is due to an increase in HR rather than stroke volume and is associated with an increase in renal blood flow. The lack of change in cerebral tissue oxygen saturation and extraction, in conjunction with an increase in MCA peak systolic velocity, suggests that cerebral flow metabolism coupling remained intact during rewarming.
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Hemodinámica/fisiología , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/terapia , Recalentamiento/métodos , Circulación Cerebrovascular/fisiología , Ecocardiografía , Femenino , Humanos , Hipoxia-Isquemia Encefálica/fisiopatología , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Estudios Prospectivos , Ultrasonografía Doppler TranscranealRESUMEN
OBJECTIVE: To noninvasively determine brain temperature of neonates with hypoxic-ischemic encephalopathy (HIE) during and after therapeutic hypothermia. STUDY DESIGN: Using a phantom, we derived a calibration curve to calculate brain temperature based on chemical shift differences in magnetic resonance spectroscopy. We enrolled infants admitted for therapeutic hypothermia and assigned them to a moderate HIE (M-HIE) or severe HIE (S-HIE) group based on Sarnat staging. Rectal (core) temperature and magnetic resonance spectroscopy data used to derive regional brain temperatures (basal ganglia, thalamus, and cortical gray matter) were acquired concomitantly during and after therapeutic hypothermia. We compared brain and rectal temperature in the M-HIE and S-HIE groups during and after therapeutic hypothermia using 2-tailed t-tests. RESULTS: Eighteen patients (14 with M-HIE and 4 with S-HIE) were enrolled. As expected, both brain and rectal temperatures were lower during therapeutic hypothermia than after therapeutic hypothermia. Brain temperature in patients with S-HIE was higher than in those with M-HIE both during (35.1 ± 1.3°C vs 33.7 ± 1.2°C; P < .01) and after therapeutic hypothermia (38.1 ± 1.5°C vs 36.8 ± 1.3°C; P < .01). The brain-rectal temperature gradient was also greater in the S-HIE group both during and after therapeutic hypothermia. CONCLUSION: For this analysis of a small number of patients, brain temperature and brain-rectal temperature gradient were higher in neonates with S-HIE than in those with M-HIE during and after therapeutic hypothermia. Further studies are needed to determine whether further decreasing brain temperature in neonates with S-HIE is safe and effective in improving outcome.
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Temperatura Corporal , Encéfalo/fisiología , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/fisiopatología , Hipoxia-Isquemia Encefálica/terapia , Femenino , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Recto/fisiopatología , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To assess the utility of hepcidin, a potent regulator of host defense and inflammation, in the diagnosis of late-onset sepsis in very low birth weight infants. STUDY DESIGN: We compared the diagnostic performance of hepcidin with C-reactive protein from the serum concentrations in acute and convalescent blood specimens obtained from 44 infants suspected of late-onset sepsis. The predictive accuracies were assessed from the areas under receiver operating characteristic curves and the cutoffs that differentiated infants with and without sepsis were identified using classification and regression tree analysis. RESULTS: Seventeen of the enrolled infants in this study were bacteremic and/or received antibiotics for neonatal sepsis for ≥ 5 days (infants with sepsis). The concentrations of hepcidin were increased 4-fold in infants with compared with infants without sepsis (P < .0001) and returned to similar levels following therapy. The areas under receiver operating characteristic curves of hepcidin was 0.93 compared with 0.83 for C-reactive protein, P = .06. Hepcidin concentration >92.2 ng/mL correctly classified 91% of all infants (positive predictive value: 100%, negative predictive value: 87%, specificity: 100%, and sensitivity: 76%). CONCLUSION: Serum hepcidin concentration may be a useful adjunct test, in addition to blood culture and other markers of infection, in the evaluation of late-onset sepsis in very low birth weight infants.
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Péptidos Catiónicos Antimicrobianos/sangre , Sepsis/sangre , Sepsis/diagnóstico , Edad de Inicio , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Femenino , Hepcidinas , Humanos , Recién Nacido , Recién Nacido de muy Bajo Peso , Masculino , Valor Predictivo de las PruebasRESUMEN
OBJECTIVE: To investigate the effect of pH on cardiac function and systemic vascular resistance (SVR) in preterm infants. STUDY DESIGN: In this prospective observational study, we evaluated hemodynamically stable, ≤ 30 weeks' gestation preterm infants during the first 2 postnatal weeks. Cardiac function was assessed by echocardiography at the time of arterial blood draw for clinically indicated blood gas analysis. Data were separately analyzed for the transitional (days 1-3) and post-transitional (days 4-14) periods. RESULTS: We evaluated 147 pairs of arterial blood gases and echocardiograms in 29 preterm neonates (gestational age = 26.2 ± 1.5 weeks). Arterial pH ranged from 7.02-7.46. There was no linear relationship between pH and shortening fraction or stress-velocity index in transitional or post-transitional periods. We found a weak negative linear relationship between pH and left ventricular output and a positive linear relationship between pH and SVR only during the post-transitional period. These relationships were maintained after adjustment for the degree of base deficit. Arterial CO2 had effects similar to pH on myocardial function. CONCLUSIONS: Unlike adults, myocardial contractility remains relatively unaffected by acidosis even at pH values close to 7.00 in hemodynamically stable preterm neonates during the first 2 postnatal weeks. However, as in adults, worsening acidosis in preterm neonates after the immediate transitional period is associated with a decrease in SVR along with an increase in left ventricular output. Thus, although myocardial contractility remains unaffected in preterm neonates during the first 2 postnatal weeks, the vascular response to acidosis undergoes a relatively rapid postnatal maturational process.