Behavioral and neuroanatomical outcomes following altered serotonin expression in a hypoxic-ischemic injury neonate rodent model.

BACKGROUND: Children born prematurely (<37 gestational weeks) are at risk for a variety of adverse medical events. They may experience ischemic and/or hemorrhagic events leading to negative neural sequelae. They are also exposed to repeated stressful experiences as part of life-saving care within the neonatal intensive care unit (NICU). These experiences have been associated with methylation of SLC6A4, a gene which codes for serotonin transport proteins, and is associated with anxiety, depression, and increased incidence of autism spectrum disorders.The purpose of this study was to examine the effects of altered serotonin levels on behavioral and neuroanatomical outcomes in a neonatal rodent model with or without exposure to hypoxic-ischemic (HI) injury. METHODS: Wistar rat pups were randomly assigned to either HI injury or sham groups. Pups within each group were treated with a chronic SSRI (Citalopram HBr) to simulate the effects of SLC6A4 methylation, or saline (NS). Subjects were assessed on behavioral tasks and neuropathologic indices. RESULTS: HI injured subjects performed poorly on behavioral tasks. SSRI subjects did not display significantly greater anxiety. HI + SSRI subjects learned faster than HI+NS. Histologically, SSRI subjects had predominantly larger brain volumes than NS. CONCLUSION: SSRI treated subjects without injury showed patterns of increased anxiety, consistent with theories of SLC6A4 methylation. The paradoxical trend to improved cognition in HI+SSRI subjects relative to HI alone, may reflect an unexpected SSRI neuroprotective effect in the presence of injury, and may be related to serotonin-induced neurogenesis.

Behavioral and histological outcomes following neonatal HI injury in a preterm (P3) and term (P7) rodent model.

Hypoxia-ischemia (HI) occurs when blood and/or oxygen delivery to the brain is compromised. HI injuries can occur in infants born prematurely (<37 weeks gestational age) or at very low birth weight (<1500 g), as well as in term infants with birth complications. In both preterm and term HI populations, brain injury is associated with subsequent behavioral deficits. Neonatal HI injury can be modeled in rodents (e.g., the Rice-Vannucci method, via cautery of right carotid followed by hypoxia). When this injury is induced early in life (between postnatal day (P)1-5), neuropathologies typical of human preterm HI are modeled. When injury is induced later (P7-12), neuropathologies typical of those seen in HI term infants are modeled. The current study sought to characterize the similarities/differences between outcomes following early (P3) and late (P7) HI injury in rats. Male rats with HI injury on P3 or P7, as well as sham controls, were tested on a variety of behavioral tasks in both juvenile and adult periods. Results showed that P7 HI rats displayed deficits on motor learning, rapid auditory processing (RAP), and other learning/memory tasks, as well as a reduction in volume in various neuroanatomical structures. P3 HI animals showed only transient deficits on RAP tasks in the juvenile period (but not in adulthood), yet robust deficits on a visual attention task in adulthood. P3 HI animals did not show any significant reductions in brain volume that we could detect. These data suggest that: (1) behavioral deficits following neonatal HI are task-specific depending on timing of injury; (2) P3 HI rats showed transient deficits on RAP tasks; (3) the more pervasive behavioral deficits seen following P7 HI injury were associated with substantial global tissue loss; and (4) persistent deficits in attention in P3 HI subjects might be linked to neural connectivity disturbances rather than a global loss of brain volume, given that no such pathology was found. These combined findings can be applied to our understanding of differing long-term outcomes following neonatal HI injury in premature versus term infants.

Evaluation of the therapeutic benefit of delayed administration of erythropoietin following early hypoxic-ischemic injury in rodents.

Hypoxia-ischemia (HI) and associated brain injuries are seen in premature as well as term infants with birth complications. The resulting impairments involve deficits in many cognitive domains, including language development. Poor rapid auditory processing is hypothesized to be one possible underlying factor leading to subsequent language delays. Mild hypothermia treatment for HI injuries in term infants is widely used as an intervention but can be costly and time consuming. Data suggest that the effectiveness of hypothermia treatment following HI injury declines beyond 6 h following injury. Consequently, the availability of a therapeutic alternative without these limitations could allow doctors to treat HI-injured infants more effectively and thus reduce deleterious cognitive and language outcomes. Evidence from both human studies and animal models of neonatal HI suggests that erythropoietin (Epo), an endogenous cytokine hormone, may be a therapeutic agent that can ameliorate HI brain injury and preserve subsequent cognitive development and function. The current study sought to investigate the therapeutic effectiveness of Epo when administered immediately after HI injury, or delayed at intervals following the injury, in neonatal rodents. Rat pups received an induced HI injury on postnatal day 7, followed by an intraperitoneal injection of Epo (1,000 U/kg) immediately, 60 min, or 180 min following induction of injury. Subjects were tested on rapid auditory processing tasks in juvenile (P38-42) and adult periods (P80-85). Ventricular and cortical size was also measured from post mortem tissue. Results from the current study show a therapeutic benefit of Epo when given immediately following induction of HI injury, with diminished benefit from a 60-min-delayed injection of Epo and no protection following a 180-min-delayed injection. The current data thus show that the effectiveness of a single dose of Epo in ameliorating auditory processing deficits following HI injury decreases precipitously as treatment is delayed following injury. These data may have important implications for experimental human neonatal intervention with Epo.

Morbidity and mortality of preterm twins and higher-order multiple births.

OBJECTIVE: To determine if preterm infants of higher-order multiple (HOM) gestations have a significantly worse outcome during hospital stay when compared with preterm twins. STUDY DESIGN: Retrospective cohort analysis. METHODS: Perinatal outcome variables including gestational age (GA), birthweight, prenatal steroid use, cesarean section delivery rate, Apgar scores, and growth retardation were analyzed for 106 preterm HOM births (triplets and quadruplets) versus 328 preterm twins admitted to a single tertiary level neonatal intensive care unit. A comparison of the mortality and major neonatal morbidities such as respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity was made for these two groups. In addition, the duration of respiratory support including surfactant therapy, nasal continuous positive airway pressure, and mechanical ventilation, as well as the length of hospitalization, was analyzed. RESULTS: There were no significant differences in major morbidities between the infants of HOM and twin births of similar GA. There was no statistically significant difference in mortality, but the data showed a trend for lesser mortality in HOM. There was a highly significant increase in antenatal steroid use as well as the use of cesarean section for delivery in the HOM when compared with twin gestations. The infants of HOM gestations were of significantly lower birthweight than the twins and had a longer hospitalization. CONCLUSION: Although premature infants of HOM had lower birthweight and needed a longer hospital stay, their mortality and morbidity at hospital discharge were not worse than that for preterm twins.

Diagnosis and management of spinal epidural space extravasation complicating percutaneous central venous line placement in a premature infant: case report and review of literature.

Percutaneous central venous lines are commonly used to establish long-term venous access in the care of premature infants. Misplacement of these catheters can occur and may lead to significant morbidity and mortality. Here we report a very-low-birth-weight premature infant whose percutaneous central venous line was inadvertently placed into the spinal epidural space. The anatomical basis of this complication as well as a comprehensive review of literature are provided.

Pulmonary hemorrhage in neonates of early and late gestation.

Our objectives in this study of pulmonary hemorrhage (PH) were to define common characteristics of infants who develop PH, identify factors associated with PH and report the outcome. Neonates (42/2980 admissions) with PH and matched controls were identified. Early gestation (< or = 35 weeks) infants with PH [EGPH] (n = 34; 12 survived) had occurrence of PH at 3.6 +/- 1.1 (mean +/- sem) days and were significantly associated with multiple births (p = 0.03), RDS (p < 0.01) and use of Survanta (p < 0.02). Among EGPH, small for gestational age (SGA) infants (n = 7) had a 100% mortality rate. Late gestation (> or = 36 weeks) infants with PH [LGPH] (n = 8; 6 survived) had occurrence of PH at 0.7 +/- 0.3 days and were significantly associated with low 1 minute (p = 0.04) and 5 minutes (p = 0.01) Apgar scores. All infants were managed with increases in mean airway pressure (MAP) and/or use of cocaine/epinephrine through the endotracheal tube. We have identified 2 groups of neonates with distinct factors associated with PH; use of 1:10,000 epinephrine (0.1 ml/kg) and/or 4% cocaine (4 mg/kg) may be useful adjuncts to increases in MAP for management of PH.

Impact of the perception of viability on resource allocation in the neonatal intensive care unit.

OBJECTIVE: To understand how neonatologists' perceptions of viability impact their willingness to recommend or provide medical interventions for infants born at 23 to 24 weeks' gestation. STUDY DESIGN: A 25-question survey mailed to 3056 neonatologists in the United States in 1992 yielded 1131 responses. Seven hundred seventy-five (775 of 1131, 69%) reported they believed that the lower limit of viability was 23 to 24 weeks' gestation. These respondents were asked if they were willing to recommend or provide a series of medical interventions for infants born at 23 and 24 weeks' gestation. RESULTS: Most respondents would provide ventilation (82% and 95%) and surfactant (62% and 78%) for infants born at 23 and 24 weeks' gestation, respectively. The respondent's prediction of <100% mortality, infant factors, and parental wishes were significant predictors of willingness to resuscitate infants born at 23 weeks' gestation. CONCLUSION: There is considerable variation among neonatologists in their willingness to recommend or provide medical interventions for infants born at 23 to 24 weeks' gestation.

Respiratory tract colonization with mycoplasma species increases the severity of bronchopulmonary dysplasia.

There is controversy regarding the role of mycoplasmas (MP) colonizing the neonatal respiratory tract in the development of bronchopulmonary dysplasia (BPD). To determine the association of respiratory MP colonization and BPD. Retrospective analysis of neonates (26-32 weeks of gestation) intubated for respiratory insufficiency. Tracheal aspirate cultures were obtained for MP if the lung disease was not improving by 7-10 days or there were radiographic changes suggestive of inflammation. Of 63 infants who had tracheal aspirates sent, 17 had positive MP cultures. We found no significant difference in the gestational ages (27.6 +/- 0.4 vs 27.8 +/- 0.2 weeks) or birth weights (1097 +/- 86 vs 997 +/- 42 grams) in MP positive vs negative infants. No differences were noted in antenatal or postnatal steroid use, gender, race, sepsis, RDS, PDA, air leaks, NEC, GER, days on positive pressure ventilation or days on oxygen. There were significantly (p = 0.04) more infants with severe BPD (defined as oxygen requirement at 36 weeks corrected post menstrual age) among MP positive (n = 14; 82%) versus MP negative (n = 25; 54%) infants. Presence of MP in the tracheal aspirates is associated with an increased likelihood of developing severe BPD.

Patterns of change in early neonatal nucleated erythrocyte counts in preterm deliveries.

OBJECTIVE: To examine whether changes in nucleated erythrocyte (nRBC) counts in the early neonatal period can distinguish between causes of nRBC release. METHODS: From a data set of 465 nonanomalous singleton live births delivered at 22-32 weeks, excluding maternal diabetes mellitus, Rh isoimmunization, and chronic hypertension, 125 cases had a complete blood count with an nRBC count within 3 hours of life and at least one other value obtained within 48 hours of the first. The change in nRBC count per deciliter was calculated (delta nRBC) and was correlated with antenatal fetal assessment, neonatal outcome variables, and placental histopathology in five categories: 1) histologic acute intrauterine inflammation, 2) uteroplacental vascular lesions, 3) intraplacental vasoocclusive lesions, 4) chronic inflammation, and 5) coagulation-related lesions. RESULTS: There were 92 cases (74%) of premature rupture of membranes (PROM) and preterm labor/intact membranes (PTL) and 33 cases (26%) of preeclampsia. In PROM/PTL, multivariate analyses demonstrated that a higher uteroplacental vascular lesion score was related to more stable nRBC counts (P = .009), whereas a higher nonmyeloid count in the initial neonatal white blood cell count was related to a more rapid decrease in delta nRBC (combined r = 0.54, P < .0001). No features were related to delta nRBC in preeclampsia. CONCLUSION: In PROM/PTL, but not in preeclampsia, patterns of change in the nRBC count in the early newborn period vary with uteroplacental vascular lesions and acute inflammation. This may reflect differences in the mediators of nRBC release (erythropoietin versus cytokines) and in disease acuity.

Early neonatal nucleated erythrocyte counts in preterm deliveries: clinical and pathologic correlations.

OBJECTIVE: To determine the relation between the initial neonatal nucleated erythrocyte (nRBC) count and acute infection or ischemia in cases delivered before 32 weeks' gestation. METHODS: A set of 465 nonanomalous singleton live births delivered at 22-32 weeks' gestational age (GA) contained 386 cases with a complete blood count obtained by 3 hours of life, including 173 cases of premature rupture of the membranes (PROM) before labor, 143 cases of preterm labor with intact membranes (PTL), and 70 cases of preeclampsia. Maternal and neonatal charts were reviewed. Placental histopathology was scored in the following five categories: acute intrauterine inflammation, uteroplacental vascular lesions, intraplacental vaso-occlusive lesions, chronic inflammation, and coagulation-related lesions. The initial nRBC count (nRBCs/100 white blood cells [WBC] x WBC count/dL) was analyzed. RESULTS: In PROM and PTL (controlling for GA), the nRBC count was directly related to the maternal WBC count (PTLP = .018), maternal temperature within 24 hours of delivery (PROM P = .014), initial neonatal WBC count (PROM P < .0001; PTL P = .0004), total myeloid elements (PROM P = .005, PTL P = .009), total nonmyeloid elements (PROM P < .0004, PTL P < .0001), and total placental acute inflammatory score (PROM P = .04, PTL P = .02). In preeclampsia, cytotrophoblast proliferation (P = .02), villous edema (P = .008), "hemorrhagic endovasculitis" (P = .04), and histologic abruption (P = .0006) were directly related to the nRBC count. In well-grown, nonacidotic, nondepressed preterm infants, the nRBC count was independent of gestational age, with the 90th percentile at 5229 nRBC/dL. CONCLUSION: When preterm PROM and PTL are accompanied by acute ascending infection, nRBC release may be a fetal response to the inflamed environment. In preterm preeclampsia, nRBC elevation marks uteroplacental hypoperfusion.

Brain cell membrane Na+,K(+)-ATPase activity following severe hypoxic injury in the newborn piglet.

This study tests the hypothesis that severe brain hypoxia causes decreased Na+,K(+)-ATPase activity, resulting in permanent alterations in the neuronal cell membranes. Seventeen anesthetized piglets (normoxic control (NC), no recovery after hypoxia (Group 1), 6 h normoxic recovery (Group 2), and 48 h normoxic recovery (Group 3)) were studied. Hypoxia was induced by lowering the FiO2 to maintain PCr/Pi ratio at 25% of baseline for 1 h as monitored by 31P-NMR spectroscopy. PCr/Pi returned to 57% of baseline by 6 h and was normal by 48 h. At termination, cortical tissue Na+,K(+)-ATPase activity was determined. Na+,K(+)-ATPase activity was measured in cortical membrane preparations by determining the rate of ATP hydrolysis. NC membranes had Na+,K(+)-ATPase activity of 58.3 +/- 1.3 microM Pi/mg protein/h (mean +/- S.E.M.). Na+,K(+)-ATPase activity was reduced in Groups 1, 2, and 3 (45.8 +/- 1.3, 47.4 +/- 3.6, 48.7 +/- 2.9 microM Pi/mg protein/h) (P < 0.05 compared to NC). There was no difference in enzyme activity among Groups 1, 2, or 3. The data show that in spite of recovery of neuronal oxidative phosphorylation (PCr/Pi) by 48 h, there is a permanent decrease in Na+,K(+)-ATPase activity in cells that have undergone severe hypoxic injury. The persistent decrease in Na+,K(+)-ATPase activity indicates ongoing cell injury following severe cerebral hypoxia, and that recovery of oxidative phosphorylation as indicated by PCr/Pi values cannot be used as an index of recovery of cell function.

Perceptions of the limit of viability: neonatologists' attitudes toward extremely preterm infants.

Although recent technologic advances have dramatically improved the survival of preterm infants, little information exists regarding the attitudes of neonatologists toward their smallest patients, infants born at the "limit of viability." In this pilot study we sent a single mailing of a 25-question survey designed to provide information about the medical treatment of extremely preterm infants (< 22 to 27 weeks' gestational age) to 3056 neonatologists practicing in the United States in September 1992. The 1131 (37%) respondents were well distributed geographically and by nature of practice (i.e., academic, academic affiliate, and community hospitals). Most of the respondents counseled parents that all infants < or = 22 weeks' gestational age die and that at least 75% of infants born at 23 weeks' gestation die. Only for infants born at > or = 26 weeks' gestational age did most of the neonatologists counsel parents that mortality is < or = 50%. Nonintervention or compassionate care in the delivery room was believed to be appropriate for infants less than 23 weeks' gestational age by virtually all neonatologists, by 52% of respondents for infants 23 weeks' gestational age, and by only 1% of respondents for infants 25 weeks' gestational age. Approximately two thirds of neonatologists considered parental wishes regarding resuscitation, and one quarter considered parental parity/fertility history in their medical decision making for infants born at 23 to 24 weeks' gestation. If an infant who had been previously resuscitated decompensated in spite of maximal medical treatment, most of the neonatologists were not willing to provide full resuscitation for infants born at any gestation less than 27 weeks. However, the number of neonatologists who would actively encourage withdrawal of support in a decompensating infant decreased markedly for infants born at > or equal 25 weeks' gestation. Neonatologists who responded to this survey in 1992 considered 23 to 24 weeks of gestation the limit of viability and had great concerns regarding medical decision making for these infants.

Maternal, placental, and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks' gestation.

This study tests the hypothesis that histologic placental lesions were significantly related to incidence of early or late germinal matrix/intraventricular hemorrhage (GM/IVH) in infants of less than 32 weeks' gestation independent of maternal or neonatal factors. Maternal and neonatal charts of 406 singleton liveborn nonanomalous infants born at less than 32 weeks' gestation were studied retrospectively for principal indication for delivery, delivery mode, timing of antenatal steroid treatment, diagnosis of labor and augmentation, tocolysis, fetal presentation, and umbilical arterial and venous blood gas values. Extracted from neonatal charts were gestational age, growth measurements, initial hematocrit and white blood cell count, administration of surfactant, and in the first 3 days of life, the use of pressor agents and volume expansion, lowest blood pressure, and data pertinent to respiratory function. Placental histologic examination was reviewed for various lesions, including histologic acute inflammation (graded on a scale of 0 to 4). GM/IVH (grades 1 to 4) diagnosed ultrasonographically less than 72 hours after birth was "early." GM/IVH diagnosed after 72 hours of life was defined as "late." Of the 406 patients, 44 (10.8%) had early GM/IVH; 21 (4.9%) had late GM/IVH. Stepwise logistic regression selected five factors independently related to increased early GM/IVH risk: Histologic acute inflammation (p < 0.002); gestational age in days (p = 0.053); antenatal steroid treatment less than 48 hours before birth (p < 0.035); volume expansion in the neonate (p < 0.30), and magnesium sulfate tocolysis (p < 0.025). Stepwise regression analysis considering the grade of GM/IVH changed the order of variables, with gestational age and use of pressor therapy being more strongly related to higher grade of GM/IVH than amnion inflammation. Delivery mode, presentation, principal indication for delivery, presence/augmentation of labor, mean biophysical profile scores, mean umbilical arterial and venous blood gas values, and surfactant therapy were not related to early GM/IVH in univariate or multivariate analyses. Neonatal factors associated (p < 0.05) with amnion inflammation were volume expansion at delivery and in the first 3 days of life, low mean systolic pressure, low mean oxygen pressure, low initial hematocrit and cord pH, and increased initial WBC and toxic granulations of neutrophils. Only gestational age, and no maternal or placental factors, was significantly related to late GM/IVH. Infants who have placentas with acute amnion inflammation and receive volume expansion, born to mothers who receive less than 48 hour's exposure to antenatal steroids and are selected to receive magnesium sulfate tocolysis, have increased incidence of early but not late GM/IVH. Amnion inflammation is significantly related to early GM/IVH and with early neonatal abnormalities in oxygenation, perfusion, and effective blood volume. Intra-amniotic infection leads to advanced preterm labor, which is unresponsive to tocolysis because of the inflammation. Intra-amniotic inflammation may sensitize the fetus to postpartum stresses or initiate early GM/IVH in utero via cytokine effects on cardiovascular instability.

Intrauterine growth restriction in infants of less than thirty-two weeks' gestation: associated placental pathologic features.

OBJECTIVE: Our purpose was to describe placental lesions associated with normal and abnormal fetal growth in infants delivered for obstetric indications at < 32 weeks' gestation. STUDY DESIGN: Maternal and neonatal charts and placental tissues from 420 consecutive nonanomalous live-born singleton infants delivered at < 32 weeks' gestation with accurate gestational dates were retrospectively studied. Excluded were cases with maternal diabetes, chronic hypertension, hydrops fetalis, diagnosed congenital viral infection, and placenta previa, leaving four primary indications for delivery: preeclampsia, preterm labor, premature rupture of membranes, and nonhypertensive abruptio placentae. The presence and severity of placental lesions was scored by a pathologist blinded to clinical data. Birth weight and length percentiles were calculated from published nomograms. Asymmetric intrauterine growth retardation (n = 32) was defined as birth weight < 10th percentile with length > 10th percentile and symmetric intrauterine growth retardation (n = 48) as both weight and length < 10th percentile for gestational age. A "growth restriction index" was developed to express a continuum of growth in both length and weight. Contingency tables, analyses of variance, and multiple regression analysis defined significance as p < 0.05 (with corrections for multiple comparisons). RESULTS: A greater proportion of cases with intrauterine growth retardation had lesions of uteroplacental insufficiency (p < 0.001) or chronic villitis (p < 0.02) than did appropriately grown preterm infants. Cases with asymmetric intrauterine growth retardation tended to have more lesions than did cases with appropriate-for-gestational-age infants. Four multiple regression analyses used the growth restriction index as outcome and the histologic lesion that had significant relationships to fetal growth as independent predictors in univariate analyses. Overall, uteroplacental fibrinoid necrosis, circulating nucleated erythrocytes, avascular terminal villi, and villous infarct were significant independent predictors of fetal growth (adjusted R2 = 0.312). With addition of preeclampsia as a variable, villous fibrosis, avascular villi, infarct, and preeclampsia were independent predictors of fetal growth (adjusted R2 = 0.341). In the 65 preeclampsia cases no histologic lesion was an independent predictor of fetal growth, whereas in the nonpreeclampsia cases, villous fibrosis and avascular villi were independent predictors of fetal growth (adjusted R2 = 0.075). CONCLUSIONS: In nonanomalous preterm infants intrauterine growth retardation is most commonly symmetric and is primarily related to the cumulative number and severity of lesions reflecting abnormal uteroplacental or fetoplacental blood flow. The growth restriction index may contribute to the study of the biologic range of fetal growth. The statistical relationship of most placental lesions to intrauterine growth retardation depends on the presence or absence of preeclampsia.

The very low birthweight infant: maternal complications leading to preterm birth, placental lesions, and intrauterine growth.

The placental lesions of the very low birthweight (VLBW) infant were investigated in relation to clinical complications leading to preterm birth and evidence of growth impairment. The 249 singleton gestations yielding infants less than 1500 g were grouped according to the clinical complications leading to preterm birth as premature membrane rupture (116/249, 47%) preterm labor (55/249, 22%), pregnancy-induced hypertension (PIH, 54/249, 22%), and normotensive abruption (ABR, 24/249, 10%). Specifically excluded from this data set were cases with greater than 2 weeks discordance, fetal congenital anomalies, placenta previa, and maternal medical or gestational diseases such as chronic hypertension and diabetes mellitus, and intrauterine growth retardation (IUGR) as a primary indication for delivery. Placental weight and lesions including decidual vasculopathy and related villous lesions, chronic villitis/intervillositis, and decidual plasmacytosis were considered as variables in analyses in which raw birthweight was the dependent variable and gestational age a confounder. Of the 195 VLBW, 79 (41%) infants from normotensive mothers had lesions of decidual vasculopathy or chronic inflammation. In the VLBW infants from hypertensive mothers, growth restriction was related to markers of decidual vasculopathy. In the absence of maternal hypertension the growth restriction was independently associated with chronic villitis. Decidual vasculopathy (characteristic of PIH) and chronic intrauterine inflammation underlie the complications of many normotensive VLBW infants. The placental lesions in VLBW-IUGR depend on the presence or absence of maternal hypertension. In the absence of maternal hypertension, VLBW-IUGR is associated with chronic inflammation and is independent of decidual vasculopathy. In the presence of maternal hypertension, VLBW-IUGR is directly related to decidual vasculopathy.

Cerebral blood flow and EEG changes in preterm infants with patent ductus arteriosus.

It is unknown whether the decreased cerebral blood flow seen in infants with a large patent ductus arteriosus is associated with cerebral dysfunction. Decreased cerebral blood flow in adult human and animal models has been associated with altered electroencephalography (EEG), spectral-analyzed EEG, and EEG response to photic stimulation. Cerebral blood flow velocity, EEG, spectral analysis of EEG, and photic alteration of EEG spectra were evaluated in 8 infants before and after closure of a significant patent ductus arteriosus and in 10 control infants without a patent ductus arteriosus. All infants with patent ductus arteriosus had moderate or large shunts associated with a 25% mean reduction in cerebral blood flow velocity. There were no differences, however, in EEG, spectral analysis of EEG, or photic alteration of the spectral analysis for these infants before and after patent ductus arteriosus closure as compared to controls. It is concluded that the degree of decreased cerebral blood flow in infants with a significant patent ductus arteriosus is not sufficient to cause measurable alteration in electrocortical activity.

Effect of corticosteroids on the maturation of neutrophil motility in very low birthweight neonates.

Neutrophil (PMN) chemotaxis and chemokinesis were longitudinally studied in a group of 17 neonates with birthweights between 750 and 1250 g. Five of the 17 neonates were treated with prenatal betamethasone to attempt to prevent hyaline membrane disease, six received postnatal dexamethasone in an effort to reduce bronchopulmonary dysplasia, three received both, and three were not treated with corticosteroids. The group of 17 neonates were tested on four separate occasions: (1-2, 3-4, 7-8, and 10-14 postnatal days). PMN chemotaxis and chemokinesis were determined using a standard micropore filter assay. A group of 36 adults was used as additional controls. There were no significant differences noted in PMN chemotaxis or chemokinesis for the corticosteroid vs the noncorticosteroid-treated groups. In the total group of 17 neonates, there was depression in PMN chemotaxis compared with adult values, which lasted at least through postnatal day 8. By day 13 to 14, PMN chemotactic values were similar to those of adults. In contrast, chemokinesis, was depressed during the initial 14 days (except for the first 2 postnatal days). These data suggest that perinatal corticosteroid administration does not affect PMN motility in newborn infants.

(S)-emopamil attenuates acute reduction in regional cerebral blood flow following experimental brain injury.

We examined the effects of (S)-emopamil, a phenylalkylamine calcium channel blocker with serotonin receptor antagonist properties, on regional cerebral blood flow (rCBF) following experimental brain injury in the rat. Animals were subjected to fluid percussion brain injury of moderate severity (2.1 atm), and received (S)-emopamil (20 mg/kg, i.p., n = 10) or saline (n = 10) at 20 minutes postinjury and 2.5 hours after the first injection of the drug. Consecutive rCBF measurements were performed: (1) prior to injury, (2) 15 minutes, (3) 90 minutes, and (4) 4 hours postinjury, using the radiolabeled microsphere technique. Brain injury produced an acute and significant reduction of rCBF at 15 minutes postinjury in all the regions examined (p < 0.05). At 90 minutes postinjury, rCBF remained significantly depressed in the forebrain regions. All brain regions showed a recovery of rCBF to normal by 4 hours following injury in saline-treated animals, with the exception of injured left parietal cortex and bilateral hippocampi, where rCBF remained significantly depressed. A significant attenuation of the trauma-induced reduction in rCBF was observed at 70 minutes after the first administration of (S)-emopamil in the forebrain regions and cerebellum (p < 0.05). Following the second (S)-emopamil injection, the significant improvement in rCBF observed in left injured cortex was maintained. These results suggest that (S)-emopamil may be efficacious in reversing post-traumatic alterations in rCBF, which may contribute to the post-traumatic pathophysiologic sequelae.

Cerebral metabolism and electrocortical activity in the chronically hyperglycemic fetal lamb.

Previous studies in the fetal lamb have demonstrated that hyperglycemia stimulates the fetal metabolic rate. The present study examined the effects of chronic fetal hyperglycemia on fetal cerebral metabolic rate and electrocortical activity. Nine chronically instrumented fetal lambs had measurements of cerebral blood flow and cerebral uptake/excretion of oxygen, glucose, lactate, and beta-hydroxybutyrate taken before and during a 48-h fetal glucose infusion. Electrocortical activity was also recorded. The fetal arterial glucose concentration was 19.8 +/- 2.0 mg/dl before glucose infusion and 48 +/- 4.5 to 54.6 +/- 6.6 mg/dl during the infusion period. Cerebral blood flow and cerebral glucose and oxygen uptake increased by 219, 209, and 171%, respectively, by the end of the infusion period. There was a linear relationship between the fetal arterial glucose concentration and cerebral blood flow and cerebral glucose and oxygen uptakes. The electroencephalogram showed significant slowing with increases in the cerebral metabolic rate. These findings suggest that fetal hyperglycemia is associated with significant metabolic stimulation of the brain.