RESUMO
HYPOTHESIS: Premature infants with bronchopulmonary dysplasia (BPD) are at increased risk of secondary pulmonary hypertension (BPD-PH). Prior studies yielded mixed results on the utility of echocardiographic screening at 36 weeks post-menstrual age (PMA). We present our experience using echocardiographic screening at the time of BPD diagnosis to identify infants at highest risk of BPD-PH at discharge. MATERIALS AND METHODS: Retrospective cohort analysis of clinical/ demographic data and screening echocardiograms in patients with BPD. Discharge echocardiograms identified infants with or without BPD-PH at discharge. 36 weeks PMA screening echocardiograms and clinical data were then reviewed to identify which factors were associated with increased odds of BPD-PH at discharge. Associations between echocardiographic findings were evaluated with 2- and 3-variable models to predict increased risk of BPD-PH at discharge. RESULTS: In our cohort of 64 infants with severe BPD, BPD-PH was present in 22/64 (34%) infants at discharge. There were no clinical differences at time of 36 weeks PMA screening evaluation (mean PMA 36.6 ± 2.9 weeks). PH at screening was poorly predictive of PH at discharge as PH at screening resolved in 49% of patients. However, having an ASD, RV dilation, hypertrophy, or reduced function on screening, especially in combination, were associated with BPD-PH at discharge. CONCLUSION: In our cohort of premature infants with BPD, 36 weeks PMA screening echocardiogram identified patients at increased risk for BPD-PH at discharge when ASD, RVH, or impaired RV function were present. Larger prospective studies are indicated to validate these findings.
Assuntos
Displasia Broncopulmonar , Hipertensão Pulmonar , Doenças do Prematuro , Recém-Nascido , Lactente , Humanos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/epidemiologia , Estudos Prospectivos , Estudos Retrospectivos , Alta do Paciente , Recém-Nascido Prematuro , Ecocardiografia , Fatores de Risco , Idade GestacionalRESUMO
Hypoxemic events are common in sick preterm and term infants and represent the most common cause of seizures in the newborn period. Neonatal seizures often lack clinical correlates and are only recognized by electroencephalogram (EEG). The mechanisms leading from a hypoxic/ischemic insult to acute seizures in neonates remain poorly understood. Further, the effects of hypoxia on EEG at various developmental stages have not been fully characterized in neonatal animals, in part due to technical challenges. We evaluated the impact of hypoxia on neonatal mouse EEG to define periods of increased susceptibility to seizures during postnatal development. Hippocampal and cortical electrodes were implanted stereotaxically in C57BL/6 mice from postnatal age 3 (P3) to P15. Following recovery, EEG recordings were obtained during baseline, acute hypoxia (4% FiO2 for 4min) and reoxygenation. In baseline recordings, maturation of EEG was characterized by the appearance of a more continuous background pattern that replaced alternating high and low amplitude activity. Clinical seizures during hypoxia were observed more frequently in younger animals (100% P3-4, 87.5% P5-6, 93% P7-8, 83% P9-10, 33% P11-12, 17% P15, r(2)=0.81) and also occurred at higher FiO2 in younger animals (11.2±1.1% P3-P6 vs. 8.9±0.8% P7-12, p<0.05). Background attenuation followed the initial hypoxemic seizure; progressive return to baseline during reoxygenation was observed in survivors. Electrographic seizures without clinical manifestations were observed during reoxygenation, again more commonly in younger animals (83% P3-4, 86% P5-6, 75% P7-8, 71% P9-10, 20% P11-12, r(2)=0.82). All P15 animals died with this duration and degree of hypoxia. Post-ictal abnormalities included burst attenuation and post-anoxic myoclonus and were more commonly seen in older animals. In summary, neonatal mice exposed to brief and severe hypoxia followed by rapid reoxygenation reliably develop seizures and the response to hypoxia varies with postnatal age and maturation.
Assuntos
Envelhecimento , Ondas Encefálicas/fisiologia , Epilepsia/etiologia , Ataque Isquêmico Transitório/complicações , Animais , Animais Recém-Nascidos , Ondas Encefálicas/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/terapia , Feminino , Ataque Isquêmico Transitório/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/administração & dosagem , Gravidez , Fatores de TempoRESUMO
BACKGROUND: We aimed to describe our experience with gabapentin use in infants admitted to our neonatal intensive care unit (NICU), including neurodevelopmental follow-up after discharge. METHODS: We performed a retrospective medical record review of infants prescribed gabapentin during admission to the University of Virginia NICU from 01/01/2015 to 04/30/2021. We report clinical characteristics including gabapentin indication, dosing and side-effects while in the NICU, discharge data, and assessments in outpatient developmental follow-up clinic. RESULTS: Gabapentin was prescribed to 104 infants (median gestational age 29 weeks, median postmenstrual age at initiation 41 weeks). Sixty-one percent of infants were male. The primary indication was irritability in 86%, and 67% were receiving at least one other neurosedative medication. Median maximum dose was 25âmg/kg/day (IQR 15-35âmg/kg/day) and 84% were discharged home on gabapentin. The majority required equipment at discharge (64% gastrostomy or nasogastric tube feeds, 54% supplemental oxygen or mechanical ventilation, and 40% both). At the first neurodevelopmental follow-up appointment, at least one area of delay was identified in 93% of infants and by 2 years corrected age 66% had a diagnosis of global developmental delay. CONCLUSIONS: NICU patients treated with gabapentin often require complex post-discharge care and require close neurodevelopmental follow up.
Assuntos
Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Recém-Nascido , Lactente , Humanos , Masculino , Feminino , Gabapentina/uso terapêutico , Estudos Retrospectivos , Assistência ao Convalescente , Alta do PacienteRESUMO
BACKGROUND: Sedation is recommended to optimize neuroprotection in neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Dexmedetomidine is an alternative agent to opioids, which are commonly used but have adverse effects. Both TH and dexmedetomidine can cause bradycardia. In this study, we describe our experience with dexmedetomidine and fentanyl in neonates undergoing TH for HIE, with a focus on heart rate (HR). METHODS: We performed a retrospective chart review from 2011-2019 at a level IV NICU comparing sedation with dexmedetomidine (nâ=â14), fentanyl (nâ=â120), or both (nâ=â32) during TH for HIE. HR trends were compared based on sedation and gestational age. Neonates were included if they underwent TH and received sedation and were excluded if cooling was initiated past 24hours (h) from birth or if they required ECMO. RESULTS: Of the 166 neonates included, 46 received dexmedetomidine, 14 as monotherapy and 32 in combination with fentanyl. Mean hourly HR from 12-36âh after birth was significantly lower for infants on dexmedetomidine versus fentanyl monotherapy (91±9 vs. 103±11 bpm, pâ<â0.002). Dexmedetomidine was decreased or discontinued in 22 (47.8%) neonates, most commonly due to inadequate sedation with a low HR. Lower gestational age was associated with higher HR but no significant difference in dexmedetomidine-related HR trends. CONCLUSIONS: Despite an association with lower HR, dexmedetomidine may be successfully used in neonates with HIE undergoing TH. Implementation of a standardized protocol may facilitate dexmedetomidine titration in this population.
Assuntos
Dexmedetomidina , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Frequência Cardíaca , Humanos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Lactente , Recém-Nascido , Estudos RetrospectivosRESUMO
Hypothermia has been shown to be neuroprotective in some newborns with moderate-to-severe perinatal hypoxic-ischemic encephalopathy (HIE). In 2006, the American Academy of Pediatrics recommended that institutions that choose to use therapeutic hypothermia do so in the context of a rigorous protocol, with systematic collection of patient data including neurodevelopmental follow-up. In this report, we describe our experience with implementation of a 'Hypothermia for HIE' program in a single tertiary care Neonatal Intensive Care Unit (NICU). Important components of the program include detailed protocols, staff and outreach education, early initiation of cooling in both inborn and outborn patients, maintaining stable hypothermia during neonatal transport, and comprehensive neurologic evaluation including serial EEGs, brain MRI and neurodevelopmental follow-up. In the first 2 years of the program, we have used hypothermia therapy in 21 patients, 18 with perinatal and 3 with early postnatal events leading to HIE. Eleven of fifteen outborn patients were cooled prior to and during transport, resulting in initiation of therapy 3 h sooner than if therapy had been delayed until arrival at our center. While lowering the body temperature of encephalopathic newborns is not difficult, addressing the complex medical problems of this vulnerable group of patients requires an experienced multidisciplinary team in regional referral centers.
Assuntos
Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/terapia , Terapia Intensiva Neonatal/métodos , Lesão Encefálica Crônica/etiologia , Eletroencefalografia , Seguimentos , Hospitais Universitários , Humanos , Hipotermia Induzida/efeitos adversos , Hipóxia-Isquemia Encefálica/complicações , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Transtornos das Habilidades Motoras/etiologiaRESUMO
Nuclear Ca2+ signals are thought to play a critical role in the initiation and progression of programmed cell death. The present study tests the hypothesis that hypoxia alters nuclear Ca2+ transport pathways and leads to an increase in nuclear Ca(2+)-influx in cerebral cortical neuronal nuclei. To test this hypothesis the effect of tissue hypoxia on high affinity Ca(2+)-ATPase activity and the binding characteristics of inositol 1,4,5-triphosphate (IP3) and inositol 1,3,4,5-tetrakisphosphate (IP4) receptors were studied in neuronal nuclei from the cerebral cortex of guinea-pig fetuses. Results show increased high-affinity Ca(2+)-ATPase activity (nmol/mg protein/h) in the hypoxic group 969.7+/-79 as compared with 602.4+/-90.9 in the normoxic group, P<0.05. The number of IP3 receptors (Bmax, fmol/mg protein) increased from 61+/-21 in the normoxic group to 164+/-49 in the hypoxic group, P<0.05. K(d) values did not change following hypoxia. In contrast, IP4 receptor Bmax (fmol/mg protein) and K(d) (nM) values increased from 360+/-32 in the normoxic group to 626+/-136 in the hypoxic group (P<0.001) and, from 26+/-1 in the normoxic group to 61+/-9 in the hypoxic group (P<0.001), respectively. 45Ca(2+)-influx (pmol/mg protein) significantly increased from 6.3+/-1.9 in the normoxic group to 10.9+/-1.1 the hypoxic group (P<0.001). The data show that hypoxia modifies nuclear Ca2+ transport pathways and results in increased nuclear Ca(2+)-influx. We speculate that hypoxia increases nuclear Ca2+ uptake from the cytoplasm to the nucleoplasm, resulting in increased transcription of proapoptotic genes and subsequent activation of programmed cell death pathways.
Assuntos
Cálcio/metabolismo , Núcleo Celular/metabolismo , Córtex Cerebral/metabolismo , Hipóxia Fetal/metabolismo , Hipóxia Encefálica/metabolismo , Degeneração Neural/metabolismo , Animais , Canais de Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , ATPases Transportadoras de Cálcio/metabolismo , Morte Celular/fisiologia , Córtex Cerebral/embriologia , Córtex Cerebral/fisiopatologia , Citoplasma/metabolismo , Modelos Animais de Doenças , Hipóxia Fetal/fisiopatologia , Cobaias , Hipóxia Encefálica/fisiopatologia , Receptores de Inositol 1,4,5-Trifosfato , Degeneração Neural/fisiopatologia , Neurônios/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologiaRESUMO
OBJECTIVE: The present study tested the hypothesis that exposure to in vitro hypoxia-ischemia alters membrane properties and excitability as well as excitatory synaptic transmission of CA1 pyramidal neurons in the neonatal mouse. METHODS: Experiments were conducted in hippocampal slices in P7-P9 C57Bl/6 mice using whole-cell patch clamp in current- and voltage-clamp mode. Passive membrane potential (Vm), input resistance (Rin) and active (action potential (AP) threshold and amplitude) membrane properties of CA1 pyramidal neurons were assessed at baseline, during 10 min in vitro ischemia (oxygen-glucose deprivation (OGD)) and during reoxygenation. Spontaneous and miniature excitatory post-synaptic currents (s and mEPSCs) were studied under similar conditions. RESULTS: OGD caused significant depolarization of CA1 pyramidal neurons as well as decrease in AP threshold and increase in AP amplitude. These changes were blocked by the application of tetrodotoxin (TTX), indicating Na(+) channels' involvement. Following 10 min of reoxygenation, significant membrane hyperpolarization was noted and it was associated with a decrease in Rin. AP threshold and amplitude returned to baseline during that stage. sEPSC and mEPSC frequency increased during both OGD and reoxygenation but their amplitude remained unchanged. Additionally, we found that OGD decreases Ih (hyperpolarization activated current) in CA1 neurons from neonatal mice and this effect persists during reoxygenation. SIGNIFICANCE: These results indicate that in vitro ischemia leads to changes in membrane excitability mediated by sodium and potassium channels. Further, it results in enhanced neurotransmitter release from presynaptic terminals. These changes are likely to represent one of the mechanisms of hypoxia/ischemia-mediated seizures in the neonatal period.
Assuntos
Região CA1 Hipocampal/fisiopatologia , Potenciais Pós-Sinápticos Excitadores , Hipóxia-Isquemia Encefálica/fisiopatologia , Potenciais Pós-Sinápticos em Miniatura , Células Piramidais/fisiologia , Potenciais de Ação , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Purkinje cells (PCs) are vulnerable to hypoxic/ischemic insults and rich in calcium and calcium-buffering/sequestering systems, including calcium-binding proteins (CaBPs). Calbindin-D28k is an EF-hand CaBP, which is highly expressed in PCs where it acts primarily as a cellular Ca++ buffer. Elevation of [Ca++] in the cytosol and nuclei of PCs is pivotal in hypoxic/ischemic cell death. We hypothesize that hypoxia results in decreased concentration, or availability of calbindin-D28k in PCs, thereby decreasing their buffering capacity and resulting in increase of intracellular and intranuclear [Ca++]. Cerebellar tissues from normoxic fetuses were compared to fetuses obtained from term pregnant guinea pigs exposed to hypoxia [7% FiO2] for 60 min. The pregnant guinea pigs were either killed upon delivery immediately following hypoxia (Hx0h) or were subsequently allowed to recover for 24 h (Hx24h) or 72 h (Hx72h). Fetal brain hypoxia was documented biochemically by a decrease in brain tissue levels of ATP and phosphocreatine. Compared to normoxic fetuses, there is a predominantly somatodendritic loss or decrease of calbindin-D28k immunohistochemical staining in PCs of Hx0h (p < 0.005), Hx24h (p < 0.05), and Hx72h (p < 0.005) fetuses. Hypoxia-induced alterations of calbindin-D28k immunoreactivity are qualitatively similar at all time points and include a distinctive intranuclear localization in subpopulations of PCs. A similar trend is demonstrated by immunoblotting. Subpopulations of TUNEL+/calbindin-D28k- PCs lacking morphologic features of apoptosis or necrosis are demonstrated in Hx24h and Hx72h fetuses. The present study demonstrates an abrogating effect of perinatal hypoxia on calbindin-D28k immunoreactivity in cerebellar PCs. The perturbation of this Ca++ buffer protein in hypoxia-induced neuronal injury may herald delayed cell death or degeneration.
Assuntos
Cerebelo/embriologia , Hipóxia Fetal/metabolismo , Células de Purkinje/metabolismo , Proteína G de Ligação ao Cálcio S100/metabolismo , Doença Aguda , Trifosfato de Adenosina/metabolismo , Animais , Calbindinas , Cerebelo/patologia , Feto/metabolismo , Cobaias , Immunoblotting , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Valores de Referência , Distribuição Tecidual , Tubulina (Proteína)/metabolismoRESUMO
The present study tested the hypothesis that nitration is a mechanism of hypoxia-induced modification of the N-methyl-D-aspartate (NMDA) receptor. To test this hypothesis the effect of hypoxia on the nitration of the NR1, NR2A and NR2B subunits of the NMDA receptor was determined. Furthermore, the effect of administration of a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine (NNLA) on the hypoxia-induced nitration of the NMDA receptor subunits as well as the NMDA receptor-mediated Ca2+ influx, an index of NMDA receptor-ion channel function, were determined in cortical synaptosomes. Studies were performed in newborn piglets divided into normoxic, hypoxic and hypoxic-NNLA groups. Hypoxia was induced by decreasing the FiO(2) to 0.07-0.09 for 60 min. Cerebral tissue hypoxia was confirmed by determining the levels of high energy phosphates ATP and phosphocreatine. Nitration of the NMDA receptor subunits was determined by immunoprecipitation using specific antibodies and western blot analysis. NMDA receptor-ion channel-mediated Ca2+ influx was determined using 45Ca2+. There was a significant increase in the nitrated NR1, NR2A and NR2B subunits following hypoxia: 104+/-11 vs. 275+/-18 optical density (OD)xmm(2) for NR1 (P<0.05), 212+/-36 vs. 421+/-16 ODxmm(2) for NR2A (P<0.05) and 246+/-44 vs. 360+/-26 ODxmm(2) for NR2B (P<0.05). This increase in nitrated NR1, NR2A and NR2B subunits of the NMDA receptor was prevented by the administration of NNLA prior to hypoxia (NR1 160+/-19, P=NS, NNLA vs. normoxic; NR2A 304+/-49, P=NS, NNLA vs. normoxic, and NR2B 274+/-19, P=NS, NNLA vs. normoxic). The increase in nitration of the NR1, NR2A and NR2B subunits of the NMDA receptor increased as a function of decreased cerebral high-energy phosphates, ATP and phosphocreatine, during hypoxia. Furthermore, NOS blockade prior to hypoxia resulted in prevention of the hypoxia-induced increase in NMDA receptor-mediated Ca2+ influx. Our results demonstrate that hypoxia results in increased nitration of the NMDA receptor subunits and that administration of an NOS inhibitor prior to hypoxia prevents the hypoxia-induced nitration of the NMDA receptor subunits as well as the hypoxia-induced increase in NMDA receptor-mediated Ca2+ influx. We conclude that nitration is a mechanism of modification of the NMDA receptor function during hypoxia in the newborn piglet brain.
Assuntos
Córtex Cerebral/metabolismo , Inibidores Enzimáticos/farmacologia , Hipóxia/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Cálcio/metabolismo , Córtex Cerebral/enzimologia , Hipóxia/enzimologia , Óxido Nítrico Sintase Tipo I , Testes de Precipitina , Suínos , Sinaptossomos/metabolismoRESUMO
Previous studies have shown that the N-methyl-D-aspartate (NMDA) receptor is modified during hypoxia in the cerebral cortex of newborn piglets. The present study tests the hypothesis that the NMDA receptor 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) high-affinity binding site is modified during hypoxia and that the degree of modification correlates with the progressive decrease in cerebral cellular energy metabolism and increase in lipid peroxidation induced by hypoxia. Studies were conducted in twelve anesthetized, ventilated newborn piglets, five normoxic and seven hypoxic which were exposed to decreased fraction of inspired oxygen (FiO2) to achieve varying phosphocreatine (PCr) levels. 3[H]-CPP binding was performed with CPP concentrations ranging from 0.5 to 1500 nM at 23 degrees C for 40 min in P2 membrane fractions. Brain tissue PCr levels were determined biochemically. Conjugated dienes (CDs) were measured as an index of lipid peroxidation. In the normoxic group, B(max) (receptor number) for the CPP binding site was 329+/-93 fmol/mg protein and Kd (dissociation constant) 137+/-44 nM, the mean PCr value was 2.5+/-0.4 micromol/g brain and the CD level was 0.0 nmol/g brain. As tissue hypoxia worsened, there was a gradual decline in tissue PCr as well as receptor B(max) and K(d) values, and there was an increase in conjugated dienes. Both the receptor B(max) (r=0.90) and Kd (r=0.72) decreased in a linear relationship as PCr decreased. As the levels of CDs increased both the receptor B(max) (r=0.88) and Kd (r=0.68) decreased in a linear fashion. The data show that there is not a critical hypoxic threshold for modification of the CPP binding site of the NMDA receptor, but that modification is coupled to a gradual decrease in brain cell energy metabolism and increase in lipid peroxidation. We speculate that hypoxia-induced modification of the NMDA receptor is mediated not only by changes in the receptor recognition site but also by an alteration of brain cell membrane structure secondary to conjugated diene formation.
Assuntos
Córtex Cerebral/metabolismo , Antagonistas de Aminoácidos Excitatórios/metabolismo , Hipóxia Encefálica/metabolismo , Neurônios/metabolismo , Piperazinas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Animais Recém-Nascidos/metabolismo , Asfixia Neonatal/metabolismo , Asfixia Neonatal/fisiopatologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Membrana Celular/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Humanos , Hipóxia Encefálica/fisiopatologia , Recém-Nascido , Peroxidação de Lipídeos/fisiologia , Neurônios/efeitos dos fármacos , Piperazinas/farmacocinética , Ensaio Radioligante , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Suínos , TrítioRESUMO
Previous studies have shown that during hypoxia, neuronal nuclear high affinity Ca(2+)-ATPase activity is increased in the cerebral cortex of newborn piglets. The present study tests the hypothesis that pretreatment with N-nitro-L-arginine (NNLA) will prevent the hypoxia-induced increase in high affinity Ca(2+)-ATPase activity in cortical neuronal nuclear membrane of newborn piglets. We also tested the hypothesis that nitration is a mechanism of elevation of the high affinity Ca(2+)-ATPase activity during hypoxia. Studies were performed in five normoxic, five hypoxic, and six NNLA-pretreated (40 mg/kg) hypoxic newborn piglets. Cerebral cortical neuronal nuclei were isolated and the high affinity Ca(2+)-ATPase activity was determined. Further, normoxic samples were aliquoted into two sub-groups for in vitro nitration with 0.5 mM peroxynitrite and subsequent determination of the high affinity Ca(2+)-ATPase activity. The activity increased from 309+/-40 nmol Pi/mg protein/h in the normoxic group to 520+/-108 nmol Pi/mg protein/h in the hypoxic group (P<0.05). In the NNLA-pretreated group, the activity was 442+/-53 nmol Pi/mg protein/h (P<0.05), which is 25% lower than in the hypoxic group. In the nitrated group the enzyme activity increased to 554+/-59 nmol Pi/mg protein/h (P<0. 05). Thus peroxynitrite-induced nitration in vitro increased the high affinity Ca(2+)-ATPase activity and NNLA administration in vivo partially prevented the hypoxia-induced increase in neuronal nuclear high affinity Ca(2+)-ATPase activity. We conclude that the hypoxia-induced increase in nuclear membrane high affinity Ca(2+)-ATPase activity is NO-mediated and that nitration of the enzyme is a mechanism of its modification.
Assuntos
ATPases Transportadoras de Cálcio/metabolismo , Córtex Cerebral/enzimologia , Hipóxia Encefálica/enzimologia , Neurônios/enzimologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Membrana Nuclear/enzimologia , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Fosfocreatina/metabolismo , SuínosRESUMO
Previous studies have shown, employing direct measurements with electron spin resonance (ESR) spectroscopy, that hypoxia induces an increased production of oxygen free radicals (OFR) in the brain of the guinea pig fetus. The present study using the same approach, investigated the effects of maturity and Mg2+-pretreatment on hypoxia-induced OFR formation in the guinea pig fetal brain. The normoxic and the hypoxic groups were exposed for 60 min to 21% or 7% oxygen, respectively. The control group consisted of term fetuses exposed to normoxia (n=7) and hypoxia (n=7). The experimental groups consisted of the following: (a) for the investigation on maturity effect, preterm fetuses (40 days) exposed to normoxia (n=6) or hypoxia (n=6); and (b) for the Mg2+-pretreatment investigation, term fetuses (60 days) exposed to normoxia (n=6) or hypoxia (n=6) following maternal pretreatment with Mg2+ which consisted of an initial bolus of MgSO4 (600 mg/kg, i.p.) 1 h prior to hypoxia followed by a second dose (300 mg/kg, i.p.). Oxygen free radicals were measured by ESR spectroscopy in the fetal cerebral cortical tissue utilizing phenyl-N-tert-butylnitrone (PBN) spin trapping. Fetal brain tissue hypoxia was documented biochemically by decreased tissue levels of ATP and phosphocreatine. In the control group of term fetuses, the cortical tissue from hypoxic fetuses showed a significant increase in spin adducts (71% increase, p<0.01). In the preterm group, the cortical tissue from hypoxic fetuses showed a 33% increase in spin adducts (p<0.001). The baseline free radical generation during normoxia was 22.5% higher at preterm than at term (41.4+/-3.5 units/g issue vs. 33.8+/-9.3 units/g tissue, p<0.05). In Mg2+-treated groups, spin adduct levels in cortical tissue from hypoxic fetuses did not significantly differ from those of the normoxic group (30.2+/-9.9 units/g tissue, normoxic-Mg2+ vs. 30. 6+/-8.1 units/g tissue, hypoxic-Mg2+). The results indicate that the fetal brain at term may be more susceptible to hypoxia-induced free radical damage than at preterm and that Mg2+ administration significantly decreased the hypoxia-induced increase in oxygen free radical generation in the term fetal guinea pig brain in comparison with non-treated hypoxic group.
Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia Encefálica/tratamento farmacológico , Sulfato de Magnésio/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal , Espécies Reativas de Oxigênio/metabolismo , Análise de Variância , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Feminino , Radicais Livres , Cobaias , Hipóxia Encefálica/metabolismo , GravidezRESUMO
The present study tests the hypothesis that nitration is a potential mechanism of N-methyl-D-aspartate (NMDA) receptor modification, by assessing the effect of peroxynitrite in vitro on the glutamate and ion-channel sites of the NMDA receptor in the fetal guinea pig. Nitration of NMDA receptor subunits was confirmed by Western blot. Following peroxynitrite exposure, (3)H-MK-801 bindings show an increase in the B(max) and a decrease in the K(d), while (3)H-glutamate bindings show a decrease in the K(d) with no change in the B(max). We conclude that peroxynitrite regulates the NMDA receptor function by increasing the affinity of the ion-channel and glutamate sites, and by exposing additional ion-channel sites. We propose that nitration of the NMDA receptor is a potential mechanism for the regulation of the receptor during hypoxia.
Assuntos
Córtex Cerebral/fisiologia , Nitratos/farmacologia , Receptores de Glutamato/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Córtex Cerebral/efeitos dos fármacos , Maleato de Dizocilpina/farmacocinética , Feto , Ácido Glutâmico/farmacocinética , Cobaias , Hipóxia , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/fisiologia , Cinética , Receptores de Glutamato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the role of uterine artery Doppler investigation in predicting perinatal outcome of patients with chronic hypertension. STUDY DESIGN: Uterine artery velocimetry was investigated at 24 weeks gestation in 78 chronic hypertensive pregnant women by means of color Doppler. The resistance index (RI) and the presence of a diastolic notch were recorded and related to the development of superimposed preeclampsia (SPE), pregnancy aggravated hypertension (PAH). and intrauterine growth retardation (IUGR). RESULTS: There were more pregnancy complications in the 25 patients with abnormal RI, compared with the 53 women with normal RI (SPE 12% vs. 0%, PAH 36% vs. 7% and IUGR 52% vs. 2%; P<0.01), and more in women with a bilateral diastolic notch compared with those without (SPE 23% vs. 0, PAH 54% vs. 4%, IUGR 85% vs. 2%; P<0.0001), while no differences were detected in those with only a unilateral notch, except for PAH (27% vs. 4%; P<0.01). CONCLUSION: Uterine artery Doppler velocimetry identifies a subgroup of chronic hypertensive patients with a high frequency of pregnancy complications.
Assuntos
Hipertensão/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Útero/irrigação sanguínea , Doença Crônica , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico por imagem , Pré-Eclâmpsia/epidemiologia , Valor Preditivo dos Testes , Gravidez , Prevalência , Sensibilidade e EspecificidadeRESUMO
Article 2 of Directive 96/82/EC on the control of major accident hazards caused by dangerous substances requires to consider also the hazards due to the dangerous substances "which it is believed may be generated during loss of control of an industrial chemical process", although no generally accepted guidelines are available for the identification of these substances. In the present study, the accidents involving the unwanted formation of dangerous substances as a consequence of the loss of control of chemical systems were investigated. A specifically developed database was used, containing data on more than 400 of these accidents and on the substances involved. The hazardous substances formed in the accidents and the precursors of these substances were identified. The influence of accident characteristics on the substances formed was investigated. In the context of the application of Directive 96/82/EC, an accident severity index and a hazard rating of the precursors of dangerous substances formed in the accidents were proposed. A lumping approach was used in order to develop schemes for the preliminary identification of substances that may be formed in the loss of control of chemical system. The results of accident analysis were used to test the schemes developed.
Assuntos
Acidentes de Trabalho/estatística & dados numéricos , Bases de Dados Factuais , Substâncias Perigosas/análise , Substâncias Perigosas/metabolismo , Resíduos Perigosos/estatística & dados numéricos , Acidentes de Trabalho/prevenção & controle , Análise por Conglomerados , Planejamento em Desastres , Guias como Assunto , Resíduos Perigosos/prevenção & controle , Humanos , Reprodutibilidade dos TestesRESUMO
An accident in a plant for solvent recovery from solvent-contaminated wastes was examined. An experimental investigation of the accident was carried out using calorimetric and thermogravimetric techniques. The immediate cause of the accident was an unforeseen exothermic decomposition reaction. The main underlying cause of the accident was the absence of safety culture in the plant management, that resulted in the lack of a testing procedure to evaluate the thermal stability of the process feed. A simplified screening procedure based on differential scanning calorimetry was used in order to test the thermal stability of the nonvolatile fraction of the solvent-contaminated wastes present on the plant in order to be processed. More than 75% of the samples examined showed exothermal decomposition phenomena starting at temperatures higher than 100 degrees C. These phenomena were common to solvent wastes that originated from a number of different industrial activities. Thus, the thermal instability of the process feed is one of the main problems in solvent recovery operations. Our analysis of the accident suggested that the safe operation of waste solvent recovery processes requires an accurate characterization of the thermal stability of the process feed. Process safety is also increased by an adequate emergency vent and an accurate control of operating temperature, that may be reduced operating under vacuum. Safety devices may also include a water supply for emergency quench.
Assuntos
Acidentes de Trabalho/estatística & dados numéricos , Poluentes Ocupacionais do Ar/efeitos adversos , Poluentes Ocupacionais do Ar/análise , Monitoramento Ambiental/métodos , Incêndios/estatística & dados numéricos , Resíduos Perigosos/efeitos adversos , Resíduos Perigosos/análise , Temperatura Alta/efeitos adversos , Solventes/efeitos adversos , Solventes/análise , Calorimetria , Humanos , Saúde Ocupacional , Cultura Organizacional , Medição de Risco , Fatores de Risco , Solventes/química , TermogravimetriaRESUMO
Bacterial meningitis in the newborn and infant remains a serious problem, with a mortality rate of 24% and a morbidity rate ranging from 30 to 50%. This retrospective study conducted between January 1982 and December 1997, aims to characterize the epidemiology of bacterial meningitis in infants less than 60 days of age. Thirty-five infants between 6 and 60 days of age, hospitalized for bacterial meningitis in the pediatric units of Edouard-Herriot Hospital in Lyon, France, were included. The clinical presentation was not specific for most cases, hyperthermia being the most common symptom (97%). Neurological symptoms such as bulging fontanelle or nuchal rigidity were present in 30% and 8% of the cases, respectively. The four predominant meningeal pathogens were: group B streptococcus (36%), Escherichia coli (28%), meningogoccus (8.6%) and Staphylococcus aureus (8.6%). This study emphasizes the importance of prompt diagnosis, including CSF evaluation, and antimicrobial therapy in infants less than 2 months of age presenting an isolated fever.
Assuntos
Febre/etiologia , Meningites Bacterianas/epidemiologia , Antibacterianos/uso terapêutico , Líquido Cefalorraquidiano/microbiologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Meningites Bacterianas/diagnóstico , Meningites Bacterianas/patologia , Estudos RetrospectivosRESUMO
We report the case of a 37-week male infant born via spontaneous vaginal delivery who developed Salmonella berta sepsis and meningitis. The infant was born to a mother with active diarrhea and stool cultures growing S. berta. On day 3, the infant developed poor feeding, lethargy, apnea and bradycardia prompting a sepsis evaluation. Blood, stool and cerebrospinal fluid cultures were positive for S. berta. An electroencephalogram performed for posturing revealed neonatal status epilepticus. Extensive bilateral periventricular venous hemorrhagic infarctions with multiple herniations were seen on brain magnetic resonance imaging. The infant's condition continued to deteriorate despite maximal support and care was redirected towards comfort measures.
Assuntos
Bacteriemia/diagnóstico , Meningites Bacterianas/microbiologia , Infecções por Salmonella/diagnóstico , Salmonella/classificação , Bacteriemia/terapia , Terapia Combinada , Progressão da Doença , Eletroencefalografia/métodos , Evolução Fatal , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Imageamento por Ressonância Magnética/métodos , Masculino , Meningites Bacterianas/diagnóstico , Meningites Bacterianas/terapia , Infecções por Salmonella/terapia , Índice de Gravidade de Doença , Nascimento a TermoRESUMO
With mounting evidence that hypothermia is neuroprotective in newborns with hypoxic-ischemic encephalopathy (HIE), an increasing number of centers are offering this therapy. Hypothermia is associated with a wide range of physiologic changes affecting every organ system, and awareness of these effects is essential for optimum patient management. Lowering the core temperature also alters pharmacokinetic and pharmacodynamic properties of medications commonly used in asphyxiated neonates, necessitating close attention to drug efficacy and side effects. Rewarming introduces additional risks and challenges as the hypothermia-associated physiologic and pharmacologic changes are reversed. In this review we provide an organ system-based assessment of physiologic changes associated with hypothermia. We also summarize evidence from randomized controlled trials showing lack of serious adverse effects of moderate hypothermia therapy in term and near-term newborns with moderate-to-severe HIE. Finally, we review the effects of hypothermia on drug metabolism and clearance based on studies in animal models and human adults, and limited data from neonates.