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.

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.

Effects of chronic fetal hyperglycemia upon oxygen consumption in the ovine uterus and conceptus.

Hyperglycemia has been shown to induce arterial hypoxemia in the chronically catheterized fetal sheep. To investigate the mechanism behind this glucose-induced hypoxemia, eight pregnant ewes and their fetuses were studied. Fetal glucose infusion (11.9 +/- 0.6 mg glucose/kg per min) was associated with a doubling of the fetal plasma glucose concentration with concomitant elevation of the umbilical vein-distal arterial O2 content difference by 24 h of infusion (P less than 0.01). Calculated fetal O2 consumption increased from 8.1 +/- 0.4 ml/kg per min in the control period to a maximum value of 10.6 +/- 0.3 ml/kg per min by third infusion day (P less than 0.01), which is an increase of approximately 30%. The degree of stimulation of fetal O2 consumption was related to the degree of fetal hyperglycemia but not to the degree of fetal hyperinsulinemia. The increase in fetal O2 consumption was accompanied by a significant increase in fetal O2 extraction with no change in either fetal O2 delivery or fetal blood O2 affinity. In addition, fetal hypercapnea with a mild fetal respiratory acidosis was induced by fetal hyperglycemia. The increase in fetal arterial PCO2 was linearly related (P less than 0.001) to the magnitude of increase in fetal O2 consumption. These studies suggest that chronic fetal hyperglycemia induces a state of accelerated fetal oxidative metabolism and may be important in explaining the etiology behind certain unusual findings in human infants of diabetic mothers.

Consequences of perturbations of fetal fuels in ovine pregnancy.

Maternal or fetal substrate infusions into chronically catheterized fetal lambs have recently been performed in order to examine the effects of excessive fetal substrate presentation on fetal metabolism and metabolic rate. The degree of maternal hyperglycemia in this animal model has been shown to relate to the degree of fetal hyperglycemia and to the magnitude of fetal glucose utilization. Series of direct fetal glucose infusions were performed designed to mimic the development of moderate maternal hyperglycemia. These studies suggest that fetal glucose excess stimulates fetal oxidative metabolism with increases in fetal glucose and lactate entry and stimulation of fetal oxygen consumption. If severe, fetal lamb hyperglycemia may result in fetal hypoxia with metabolic acidosis and fetal demise. The metabolic goal of the stimulation of fetal oxidation may relate to increases in fetal activity such as respiration, excessive fetal growth, and other factors, as yet unidentified. Insulin or catecholamines may be mediators of at least some of these events. Chronic infusion studies regarding other potential fetal fuels have not yet been performed. The chronically catheterized glucose-infused fetal lamb may offer insights into the metabolic derangements observed and suspected in infants born to women with gestational and insulin-requiring diabetes mellitus.

Effects of fetal insulin deficiency on growth in fetal lambs.

Insulin may be an important regulator of growth in late fetal life. To assess the importance of endogenous insulin release in regulation of normal fetal growth, eight fetal lamb pairs were given either an intravenous injection of streptozocin (STZ), a nitrosourea that selectively damages pancreatic beta-cells, or buffer infusion (controls). In six preparations, twins were used, and in two cases, triplets, thus allowing for comparison between treated and control fetuses residing in the same intrauterine environment. Fetal STZ injection was associated with relative fetal hyperglycemia, hypoinsulinemia, and a decrease in the fetal plasma insulin-glucose ratio. Fetal lambs exposed to STZ also developed a mild nonprogressive metabolic acidosis compared with controls. Fetal body weight was depressed by 21% overall, the magnitude of reduction related to length of time in utero after STZ injection. Similar reductions in organ weights (liver, heart, and kidney) were also observed in STZ-administered fetuses compared with controls. Protein accretion in carcass, liver, and kidney after STZ was also depressed, but no significant changes in fetal lipid accretion were observed. Skeletal growth, as measured by tail and tibial lengths, was also depressed after STZ but to a lesser extent than body weight or protein accretion. Thus, in a stable maternal environment, isolated fetal insulin deficiency is associated with significant retardation of somatic and skeletal growth and protein deposition.

Effects of fetal insulin secretory deficiency on metabolism in fetal lamb.

Fetal insulin secretion may be of importance in determining both fetal metabolic rate and glucose homeostasis in the resting state. To investigate this question, streptozocin (STZ) was injected into 10 late-gestation fetal lambs, and the effects of STZ on fetal pancreatic insulin storage and secretion, fetal metabolic rate, and umbilical glucose uptake were then studied. Fetal STZ injection caused a relative fetal hyperglycemia by 24 h after injection. Fetal hyperglycemia reached a maximum by 72 h and persisted for at least 10 days after injection. Neonates delivered after fetal injection were frankly diabetic. Fetal STZ injection was associated with complete suppression of both glucose- and tolbutamide-stimulated insulin release, although no changes in peripheral insulin concentration were observed when compared with controls. Fetal pancreatic insulin content was only 13% of that expected on the basis of gestational age. In a subgroup of 7 STZ-treated fetal lambs, fetal hyperglycemia was related to decrements in umbilical venoarterial difference of glucose, umbilical glucose uptake, and glucose-O2 quotient. No changes in maternal glucose homeostasis or in fetal O2 consumption were noted. The data suggest that deficient fetal insulin storage and secretion are associated with a decrement in exogenous fetal glucose entry but not in fetal metabolic rate. Whether the observed fetal changes relate to enhanced endogenous fetal glucose production with a passive decrease in maternofetal glucose transfer or are simply due to a decrease in overall fetal glucose utilization is not known. It is speculated that a quantitative decrease in pancreatic insulin secretion is responsible for the observed changes.

Regulation of cerebral glucose metabolism in normal and polycythemic newborn lambs.

In contrast to previous investigations, a recent study of polycythemic lambs suggested that cerebral glucose delivery (concentration x blood flow), not arterial glucose concentration, determined cerebral glucose uptake. In the present study, the independent effects of arterial glucose concentration and delivery on cerebral glucose uptake were examined in two groups of chronically catheterized newborn lambs (control and polycythemic). Arterial glucose concentration was varied by an infusion of insulin. CBF was reduced in one group of lambs (polycythemic) by increasing the hematocrit. At all arterial glucose concentrations, the cerebral glucose delivery of the polycythemic group was 59.6% of the control group. At arterial glucose concentrations of greater than 1.6 mmol/L, cerebral glucose uptake was constant and similar in both groups. At arterial glucose concentrations of less than or equal to 1.6 mmol/L, cerebral glucose uptake was unchanged in the control group, but was significantly decreased in the polycythemic group. In contrast, the cerebral glucose uptake was similar in both groups over a broad range of cerebral glucose delivery values. At cerebral glucose delivery values less than or equal to 83 mumols/min/100 g, there was a significant decrease in cerebral glucose uptake in both groups. During periods of low cerebral glucose delivery and uptake, cerebral oxygen uptake fell in the control group but remained unchanged in the polycythemic group. Maintenance of cerebral oxygen uptake in the polycythemic group was associated with an increased extraction and uptake of lactate and beta-hydroxybutyrate. We conclude that cerebral glucose delivery, not arterial glucose concentration alone, determines cerebral glucose uptake.

Validity of Doppler measurements of anterior cerebral artery blood flow velocity: correlation with brain blood flow in piglets.

Continuous wave Doppler ultrasonography through the anterior fontanel has recently been used to assess changes in cerebral blood flow in human neonates. There has been controversy concerning whether measurements of Doppler blood flow velocity indeed correlate with brain blood flow. An in vivo correlation was performed between brain blood flow as measured by the microsphere method and Doppler flow velocity measurements of the cerebral arteries via an artificial fontanel in young piglets. The peak systolic velocity (r = .76, P less than .001), end diastolic velocity (r = .72, P less than .001) and area under the velocity curve (r = .86, P less than .001) all showed significant positive correlations with brain blood flow. The pulsatility index did not correlate with brain blood flow. Although continuous wave Doppler flow velocity measurements of the anterior cerebral artery cannot quantitatively assess cerebral blood flow, this methodology can be used to correlate changes in cerebral blood flow and provide a meaningful trend analysis following physiologic or pharmacologic perturbation of the cerebral circulation.

(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.

A comparison of pre-discharge survival and morbidity in singleton and twin very low birth weight infants.

The perinatal mortality rate of twins is four to 11 times higher than that of singletons, and twins are widely reported to have more morbidity than singletons, mainly because of a higher preterm birth rate. However, it is not clear that live-born preterm birth rate. However, it is not clear that live-born preterm twins suffer greater morbidity than comparable singletons. In fact, twins have been reported to develop pulmonary maturity earlier than singletons, which might result in decreased morbidity relative to comparable preterm singletons. We conducted this retrospective review of 496 consecutive singleton and 104 twin infants weighing 500-1499 g and born alive at 24-31 weeks' gestation to determine whether pre-discharge survival and morbidity in very low birth weight (VLBW) twin infants were greater than those of comparable singletons. The mean (+/- standard deviation) gestational age of the singletons was 27.5 +/- 2.0 weeks and of the twins 27.6 +/- 2.0 weeks. There were no differences in mean gestational age, gestational age distribution, mean birth weight, birth weight distribution, gender, or maternal race between the two groups. The pre-discharge survival rate for twins (77%) was not significantly different than that of singletons (82%). There were no differences between twins and singletons in the incidences of neonatal respiratory distress syndrome (63 versus 71%), pulmonary interstitial emphysema (14 versus 16%), patent ductus arteriosus (28 versus 29%), necrotizing enterocolitis (3 versus 5%), intraventricular hemorrhage (11 versus 16%), and retinopathy of prematurity (11 versus 18%). The incidence of bronchopulmonary dysplasia was significantly less in twins (27 versus 46%; P = .001).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Prediction of survival in severely asphyxiated infants.

There is currently no set of evaluations that allows for the accurate prediction of survival or death following severe perinatal asphyxia and the development of hypoxic-ischemic encephalopathy. We hypothesized that low cerebral blood flow velocity, as determined by Doppler ultrasonography, may predict neurologic nonviability in a group of severely asphyxiated infants who exhibited signs of severe encephalopathy. Using the staging system of Sarnat and Sarnat, 11 infants who had had severe perinatal asphyxia were studied at the time that their neurologic examinations met the criteria for stage 3 encephalopathy. Apgar scores, cord or initial blood gases and pH, blood pressure, heart rate, and electroencephalographic findings were similar between those infants who survived (N = 8) and those who died due to cerebral injury (N = 3). Cerebral blood flow velocity, however, was significantly lower in those infants who died (3,288 +/- 884 vs 1,051 +/- 789 planimeter units/min; P less than .005). All infants who died had retrograde diastolic blood flow in the common carotid artery. In the study group the combination of low cerebral blood flow velocity and retrograde diastolic blood flow in the common carotid artery allowed prediction of survival and death with sensitivity and specificity of 100% (P less than .006). Following perinatal asphyxia and the development of severe encephalopathy, the finding of low cerebral blood flow velocity appears to be predictive of neurologic nonviability.

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.

Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease.

Previous studies of cerebral blood flow (CBF) and blood flow velocity regulation in stressed neonates, both term and preterm, have suggested that CBF is pressure passive. These studies are in conflict with data obtained from fetal and newborn animals. To determine if autoregulation of CBF is present in preterm infants, we studied eight very low birth weight infants (gestational age, 29.1 +/- 1.5 weeks; birth weight, 1117 +/- 278 g), all of whom had hyaline membrane disease that necessitated mechanical ventilation. None of the infants suffered from perinatal asphyxia, intraventricular hemorrhage, or patent ductus arteriosus. All infants demonstrated appropriate changes in cerebral blood flow velocity (CBFV) in response to changes in arterial oxygen content and pCO2. CBFV was not affected by changes in systemic mean arterial blood pressure. The data indicate that nonasphyxiated very low birth weight infants regulate their CBF in a manner similar to that observed in adults.

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.

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.

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.

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.