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Hypoxic-ischaemic encephalopathy (HIE) is a major cause of mortality and neurodevelopmental disability, especially in low-income countries. While therapeutic hypothermia has been shown to reduce morbidity and mortality in infants with HIE, some clinical trials in low-income countries have reported an increase in the risk of mortality. We conducted a systematic review and meta-analysis of all randomized and quasi-randomized controlled trials conducted in low-income and lower-middle-income countries that compared cooling therapy with standard care for HIE. Our primary outcome was composite of neonatal mortality and neurodevelopmental disability at 6 months or beyond. The review was registered with PROSPERO (CRD42022352728). Our review included 11 randomized controlled trials with 1324 infants with HIE. The composite of death or disability at 6 months or beyond was lower in therapeutic hypothermia group (RR 0.78, 95% CI 0.66-0.92, I2 = 85%). Neonatal mortality rate did not differ significantly between cooling therapy and standard care (RR 0.92, 95% CI 0.76-1.13, I2 = 61%). Additionally, the cooled group exhibited significantly lower rates of neurodevelopmental disability at or beyond 6 months (RR 0.34, 95%CI 0.22-0.52, I2 = 0%). Our analysis found that neonatal mortality rate did not differ between cooled and noncooled infants in low- and lower-middle-income countries. Cooling may have a beneficial effect on neurodevelopmental disability and the composite of death or disability at 6 months or beyond., (© The Author(s) [2024]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Caffeine and theophylline are methylxanthines and nonselective adenosine antagonists commonly used to treat apnea of prematurity. Both human and animal data suggest that xanthines also have clinically important long-term neuroprotective effects in the presence of inflammation in the perinatal period as seen following hypoxic-ischemic brain insults. Moreover, these protective effects appear to be more robust when administered shortly (<48 h) after preterm birth., Method: To evaluate the importance of the postdelivery therapeutic window, we collected and analyzed medical data from preterm infants meeting criteria (23-30 weeks' gestational age [GA]), born at the University of Connecticut Health Center (UCHC), and cared for at the UCHC/Connecticut Children's Medical Center (CCMC) NICU from 1991 to 2017 (n = 858). Eighteen-month follow-up data included cognitive and language scores from the Neonatal Neurodevelopmental Follow-Up Clinic records, with a retention of 81% of subjects (n = 696). Differences were analyzed via multivariate ANOVA and ANCOVA., Results: Analyses showed that infants who received xanthine treatment within the first 48 h after preterm birth showed significantly better 18-month behavioral outcomes than those treated later than 48 h, despite a lack of a priori differences in GA, birth, or length of stay. The positive effect of early xanthine therapy was particularly robust for infants exposed prenatally to the inflammatory conditions of chorioamnionitis and/or preeclampsia., Conclusions: Current findings are consistent with human and animal data, showing that caffeine exerts protective effects, at least in part via attenuation of inflammation. Results add to the evidence supporting routine immediate prophylactic neuroprotective xanthine therapy (i.e., caffeine) in preterm infants. Findings also add important new evidence of the augmented value of caffeine for infants with inflammatory exposure due to mothers with preeclampsia or chorioamnionitis., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Magnesium sulfate (MagSul) is used clinically to prevent eclamptic seizures during pregnancy and as a tocolytic for preterm labor. More recently, it has been implicated as offering neural protection in utero for at-risk infants. However, evidence is mixed. Some studies found that MagSul reduced the incidence of cerebral palsy (CP) but did not improve other measures of neurologic function. Others did not find any improvement in outcomes. Inconsistencies in the literature may reflect the fact that sex effects are largely ignored, despite evidence that MagSul shows sex effects in animal models of neonatal brain injury. The current study used retrospective infant data to assess differences in developmental outcomes as a function of sex and MagSul treatment. We found that on 18-month neurodevelopmental cognitive and language measures, preterm males treated with MagSul (n = 209) had significantly worse scores than their untreated counterparts (n = 135; p < 0.05). Female preterm infants treated with MagSul (n = 220), on the other hand, showed a cognitive benefit relative to untreated females (n = 123; p < 0.05). No significant effects of MagSul were seen among females on language ( p > 0.05). These results have tremendous implications for risk-benefit considerations in the ongoing use of MagSul and may explain why benefits have been hard to identify in clinical trials when sex is not considered.

Preterm infants are often treated with caffeine as a respiratory stimulant. However, follow-up data shows caffeine may also have neuroprotective potential. There are several theories as to how caffeine might protect the brain, but none have been proven. This study looked at caffeine effects on microglial activation in rodent brains post hypoxic ischemic (HI) injury. Rat pups underwent either sham or HI surgery on P6, followed by treatment with either caffeine or saline. Forty-eight hours post-injury, brains were collected and underwent paraffin embedding and sectioning followed by immunofluorescence staining. Ionized calcium binding adaptor molecule 1 (Iba-1) was used to label microglia, and 4',6-diamindino-2-phenylindole (DAPI) was used to label DNA. Cell size measurements of microglia were obtained to gauge microglia activation, and chromatin condensation (DAPI optical density) was used as an index of neuronal cell death. Results suggest that caffeine does offer protective effects, based on significantly increased levels of cell death in HI-saline animals not seen in caffeine-treated HI males and females. However, the mechanism of action may be different. Male HI animals showed marginally reduced microglial activation following caffeine treatment, whereas females did not. Results indicate that though caffeine may act protectively in both sexes by reducing cell death, the benefits may be mediated by different mechanisms.

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.

Differences in the development of the male and female brain are an evolving area of investigation. We are beginning to understand the underpinnings of male and female advantages due to differences in brain development as well as the consequences following hypoxic-ischemic brain injury in the newborn. The two main factors that appear to affect outcomes are gestation age at the time of injury and sex of the subject. This review starts with a summary of differences in the anatomy and physiology of the developing male and female brain. This is followed by a review of the major factors responsible for the observed differences in the face of normal development and hypoxic injury. The last section reviews the response of male and female subjects to various neuroprotective strategies that are currently being used and where there is a need for additional information for more precise therapy based on the sex of the infant.

Hypoxia ischemia (HI) is a recognized risk factor among late-preterm infants, with HI events leading to varied neuropathology and cognitive/behavioral deficits. Studies suggest a sex difference in the incidence of HI and in the severity of subsequent behavioral deficits (with better outcomes in females). Mechanisms of a female advantage remain unknown but could involve sex-specific patterns of compensation to injury. Neuroprotective hypothermia is also used to ameliorate HI damage and attenuate behavioral deficits. Though currently prescribed only for HI in term infants, cooling has potential intrainsult applications to high-risk late-preterm infants as well. To address this important clinical issue, we conducted a study using male and female rats with a postnatal (P) day 7 HI injury induced under normothermic and hypothermic conditions. The current study reports patterns of neuropathology evident in postmortem tissue. Results showed a potent benefit of intrainsult hypothermia that was comparable for both sexes. Findings also show surprisingly different patterns of compensation in the contralateral hemisphere, with increases in hippocampal thickness in HI females contrasting reduced thickness in HI males. Findings provide a framework for future research to compare and contrast mechanisms of neuroprotection and postinjury plasticity in both sexes following a late-preterm HI insult.

Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in premature infants. Data suggests that there is a sex difference in HI outcome, with males being more adversely affected relative to comparably injured females. Brain/body temperature may play a role in modulating the severity of an HI insult, with hypothermia during an insult yielding more favorable anatomical and behavioral outcomes. The current study utilized a postnatal day (P) 7 rodent model of HI injury to assess the effect of temperature modulation during injury in each sex. We hypothesized that female P7 rats would benefit more from lowered body temperatures as compared to male P7 rats. We assessed all subjects on rota-rod, auditory discrimination, and spatial/non-spatial maze tasks. Our results revealed a significant benefit of temperature reduction in HI females as measured by most of the employed behavioral tasks. However, HI males benefitted from temperature reduction as measured on auditory and non-spatial tasks. Our data suggest that temperature reduction protects both sexes from the deleterious effects of HI injury, but task and sex specific patterns of relative efficacy are seen.

Infants born prematurely are at risk for cardiovascular events causing hypoxia-ischemia (HI; reduced blood and oxygen to the brain). HI in turn can cause neuropathology, though patterns of damage are sometimes diffuse and often highly variable (with clinical heterogeneity further magnified by rapid development). As a result, though HI injury is associated with long-term behavioral and cognitive impairments in general, pathology indices for specific infants can provide only limited insight into individual prognosis. The current paper addresses this important clinical issue using a rat model that simulates unilateral HI in a late preterm infant coupled with long-term behavioral evaluation in two processing domains - auditory discrimination and spatial learning/memory. We examined the following: (1) whether deficits on one task would predict deficits on the other (suggesting that subjects with more severe injury perform worse across all cognitive domains) or (2) whether domain-specific outcomes among HI-injured subjects would be uncorrelated (suggesting differential damage to orthogonal neural systems). All animals (sham and HI) received initial auditory testing and were assigned to additional auditory testing (group A) or spatial maze testing (group B). This allowed within-task (group A) and between-task (group B) correlation. Anatomic measures of cortical, hippocampal and ventricular volume (indexing HI damage) were also obtained and correlated against behavioral measures. Results showed that auditory discrimination in the juvenile period was not correlated with spatial working memory in adulthood (group B) in either sham or HI rats. Conversely, early auditory processing performance for group A HI animals significantly predicted auditory deficits in adulthood (p = 0.05; no correlation in shams). Anatomic data also revealed significant relationships between the volumes of different brain areas within both HI and shams, but anatomic measures did not correlate with any behavioral measure in the HI group (though we saw a hippocampal/spatial correlation in shams, in the expected direction). Overall, current data provide an impetus to enhance tools for characterizing individual HI-related pathology in neonates, which could provide more accurate individual prognoses within specific cognitive/behavioral domains and thus improved patient-specific early interventions., (© 2015 S. Karger AG, Basel.)

Objective: Blood pressure monitoring is an essential vital sign when caring for critically ill children. Invasive monitoring is considered the gold standard, but is not always feasible. The following study compared the CAS model 740 noninvasive blood pressure monitor with the Orion/MaxIQ NIBP module with the reference (invasive arterial measurement). We evaluated the validity of the system using the criteria provided by the Association for the Advancement of Medical Instrumentation., Results: We performed paired measurements of 29 critically ill neonates and children. For individual paired comparisons, the mean difference in the systolic blood pressure was 2.42 mmHg (SD ± 6.3). The mean difference in the diastolic blood pressure was -1.29 mmHg (SD ± 5.45). The percentage of readings within 5, 10, and 15 mmHg for systolic blood pressure was 65.6, 86.0, and 96.8%, respectively. The percentage of readings within 5, 10, and 15 mmHg for diastolic blood pressure was 77.7, 93, and 95.5%, respectively., Conclusion: The CAS model 740 noninvasive blood pressure monitor with the Orion/MaxIQ NIBP module fulfills the accuracy performance criteria of the Association for the Advancement of Medical Instrumentation. This model may allow for rapid and accurate noninvasive blood pressure monitoring in neonates and children.

Hypoxia-ischemia (HI; reduction in blood/oxygen supply) is common in infants with serious birth complications, such as prolonged labor and cord prolapse, as well as in infants born prematurely (<37 weeks gestational age; GA). Most often, HI can lead to brain injury in the form of cortical and subcortical damage, as well as later cognitive/behavioral deficits. A common domain of impairment is working memory, which can be associated with heightened incidence of developmental disorders. To further characterize these clinical issues, the current investigation describes data from a rodent model of HI induced on postnatal (P)7, an age comparable to a term (GA 36-38) human. Specifically, we sought to assess working memory using an eight-arm radial water maze paradigm. Study 1 used a modified version of the paradigm, which requires a step-wise change in spatial memory via progressively more difficult tasks, as well as multiple daily trials for extra learning opportunity. Results were surprising and revealed a small HI deficit only for the final and most difficult condition, when a delay before test trial was introduced. Study 2 again used the modified radial arm maze, but presented the most difficult condition from the start, and only one daily test trial. Here, results were expected and revealed a robust and consistent HI deficit across all weeks. Combined results indicate that male HI rats can learn a difficult spatial working memory task if it is presented in a graded multi-trial format, but performance is poor and does not appear to remediate if the task is presented with high initial memory demand. Male HI rats in both studies displayed impulsive characteristics throughout testing evidenced as reduced choice latencies despite more errors. This aspect of behavioral results is consistent with impulsiveness as a core symptom of ADHD-a diagnosis common in children with HI insult. Overall findings suggest that task specific behavioral modifications are crucial to accommodating memory deficits in children suffering from cognitive impairments following neonatal HI.

Hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) is one of the most common injuries among preterm infants and term infants with birth complications. Both populations show cognitive/behavioral deficits, including impairments in sensory, learning/memory, and attention domains. Clinical data suggests a sex difference in HI outcomes, with males exhibiting more severe cognitive/behavioral deficits relative to matched females. Our laboratory has also reported more severe behavioral deficits among male rats with induced HI relative to females with comparable injury (Hill et al., 2011a,b). The current study initially examined published clinical studies from the past 20years where long-term IQ outcome scores for matched groups of male and female premature infants were reported separately (IQ being the most common outcome measure). A meta-analysis revealed a female "advantage," as indicated by significantly better scores on performance and full scale IQ (but not verbal IQ) for premature females. We then utilized a rodent model of neonatal HI injury to assess sham and postnatal day 7 (P7) HI male and female rats on a battery of behavioral tasks. Results showed expected deficits in HI male rats, but also showed task-dependent sex differences, with HI males having significantly larger deficits than HI females on some tasks but equivalent deficits on other tasks. In contrast to behavioral results, post mortem neuropathology associated with HI was comparable across sex. These findings suggest: 1) neonatal female "protection" in some behavioral domains, as indexed by superior outcome following early injury relative to males; and 2) female protection may entail sex-specific plasticity or compensation, rather than a reduction in gross neuropathology. Further exploration of the mechanisms underlying this sex effect could aid in neuroprotection efforts for at-risk neonates in general, and males in particular. Moreover, our current report of comparable anatomical damage coupled with differences in cognitive outcomes (by sex) provides a framework for future studies to examine neural mechanisms underlying sex differences in cognition and behavior in general., (Copyright © 2014. Published by Elsevier Inc.)

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., (Published by Elsevier B.V.)

Hypoxia Ischemia (HI) refers to the disruption of blood and/or oxygen delivery to the brain. Term infants suffering perinatal complications that result in decreased blood flow and/or oxygen delivery to the brain are at risk for HI. Among a variety of developmental delays in this population, HI injured infants demonstrate subsequent memory deficits. The Rice-Vannucci rodent HI model can be used to explore behavioral deficits following early HI events, as well as possible therapeutic agents to help reduce deleterious outcomes. Caffeine is an adenosine receptor antagonist that has recently shown promising results as a therapeutic agent following HI injury. The current study sought to investigate the therapeutic benefit of caffeine following early HI injury in male rats. On post-natal day (P) 7, HI injury was induced (cauterization of the right common carotid artery, followed by two hours of 8% oxygen). Male sham animals received only a midline incision with no manipulation of the artery followed by room air exposure for two hours. Subsets of HI and sham animals then received either an intraperitoneal (i.p.) injection of caffeine (10 mg/kg), or vehicle (sterile saline) immediately following hypoxia. All animals later underwent testing on the Morris Water Maze (MWM) from P90 to P95. Results show that HI injured animals (with no caffeine treatment) displayed significant deficits on the MWM task relative to shams. These deficits were attenuated by caffeine treatment when given immediately following the induction of HI. We also found a reduction in right cortical volume (ipsilateral to injury) in HI saline animals as compared to shams, while right cortical volume in the HI caffeine treated animals was intermediate. These findings suggest that caffeine is a potential therapeutic agent that could be used in HI injured infants to reduce brain injury and preserve subsequent cognitive function.

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., (Copyright © 2013 S. Karger AG, Basel.)

Neonatal polycythemia and hyperviscosity are defined as a hematocrit > or =65% and a viscosity value >2 standard deviations greater than the norm. Although polycythemia can reflect normal fetal adaptation, it has been thought to be responsible for abnormalities in the neonate. Polycythemia and hyperviscosity are associated with blood-flow changes in some organs, which alter their function. Partial exchange transfusion (PET) has been used to treat both symptomatic and asymptomatic patients. At present, no data support the use of PET in asymptomatic infants; the potential benefit in symptomatic infants depends on the symptoms. Studies of long-term neurodevelopmental status do not show any clear long-term benefits for PET. Crystalloids are as effective as colloids in PET and have the advantage of being cheaper and more readily available; also, they do not confer any risk of infection or anaphylaxis.

Background: There are differences in the literature regarding outcomes of premature small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants, possibly due to failure to take into account gestational age at birth., Objective: To compare mortality and respiratory morbidity of SGA and AGA premature newborn infants., Design/methods: A retrospective study was done of the 2,487 infants born without congenital anomalies at 32 wk (OR = 0.41, 95% CI 0.27 - 0.63; p < 0.01). After controlling for GA, SGA infants were observed to be at a significantly higher risk for developing chronic lung disease as compared to AGA infants (OR = 2.2, 95% CI = 1.2 - 3.9, P = 0.01). There was no significant difference between SGA and AGA infants in total days on ventilator. Among infants who survived, mean length of hospital stay was significantly higher in SGA infants born between 26-36 wks GA than AGA infants., Conclusions: Premature SGA infants have significantly higher mortality, significantly higher risk of developing chronic lung disease and longer hospital stay as compared to premature AGA infants. Even the reduced risk of RDS in infants born at >/=32 wk GA, (conferred possibly by intra-uterine stress leading to accelerated lung maturation) appears to be of transient effect and is counterbalanced by adverse effects of poor intrauterine growth on long term pulmonary outcomes such as chronic lung disease.

The objective of this study was to determine the incidence of gastroesophageal reflux (GER) as documented by extended esophageal pH monitoring in symptomatic premature infants and to identify its relationship with chronic lung disease (CLD). This was a retrospective study of 629 infants born < 32 weeks gestational age and admitted to the neonatal intensive care unit during the study period. Univariate analyses were done on the 137 infants undergoing the test for the association of the following risk factors with acid reflux: birth weight, gestational age, race, sex, length of stay, bronchopulmonary dysplasia (BPD; O2 requirement at 28 days), and severe CLD (O2 requirement at 36 weeks postmenstrual age). Eighty-seven of 137 infants were positive for GER. There was no association of GER with the risk factors studied, nor were there correlations with BPD or severe CLD. GER is common (63%) in premature infants < 32 weeks gestational age but clinical symptoms and CLD are poorly correlated with this diagnosis.

With ongoing improvements in technology and the understanding of neonatal physiology, there has been increasing debate regarding the gestational age and birth weight limits of an infants' capability of sustaining life outside the womb and how this is to be determined. The objective of this review was to address this issue with an analysis of current data (following the introduction of surfactant therapy in 1990) from published studies of survival in extremely low gestational age infants. We found that survival was possible at 22 completed weeks of gestation but only in < 4% of live births reported. Survival increased from 21% at 23 weeks gestational age to 46% at 24 weeks gestational age. Historically, despite continual advances in neonatology, the mortality at 22 weeks has not improved over the past three decades. Combining the data from studies on survival with evidence from developmental biology, we believe that it is not worthwhile to pursue aggressive support of infants born at < 23 weeks gestational age. Given the complicated issues related to morbidity and mortality in infants born at 22 to 25 weeks gestational age and the ethical implications of the available evidence, we propose the need for a consensus derived framework to help in decision-making.

Research from the past 15 to 20 years has led to a comprehensive understanding of the etiology and effects of polycythemia and hyperviscosity in the newborn. Polycythemia and hyperviscosity are generally a result of a poor intrauterine environment or hypoxic complications during labor and delivery. Changes in blood viscosity are a direct result of changes in hematocrit because the plasma viscosity in the newborn is virtually always normal. Polycythemia and hyperviscosity are associated with decreases in blood flow to the brain, heart, lung, intestines, and carcass. Renal blood flow is not affected, but renal plasma flow is diminished, resulting in a lower glomerular filtration rate (GFR). The elevated hemoglobin and hematocrit are associated with an increase in the arterial oxygen content. It is the increase in arterial oxygen content, not the hyperviscosity, that is directly responsible for the decreased blood flow in the brain and heart as well as cardiac output. As a result, brain and cardiac oxygenation is normal. Decreased pulmonary blood flow appears to be the result of hyperviscosity and can result in system hypoxia. This can be corrected by a partial exchange transfusion to lower the hematocrit and viscosity. This will also improve renal function by increasing plasma flow. Because the abnormalities in brain function are due to a primary hypoxia event and not reduced cerebral blood flow, a partial exchange transfusion will not improve short-term or long-term abnormalities in neurological functioning.

The current incidence of inguinal hernia (IH) in premature infants is not well-established. It is also unclear whether common co-morbidities in this population, i.e., chronic lung disease (CLD) or nutritional status or both contribute to the development of IH. The purpose of this study was to establish the epidemiologic profile of preterm infants of 32 weeks gestational age (GA) or less at birth with IH and determine whether the severity of CLD or poor nutritional status predisposes to the development of IH. Perioperative profiles of infants undergoing surgery were also reviewed. A retrospective study of 1,057 infants born at 23-32 weeks GA from January 1990 to December 1995 was done. Specific risk and demographic factors were identified. Factors used to determine severity of CLD were: days on intermittent mandatory ventilation (IMV); days on positive pressure (IMV + continuous positive airway pressure); and total number of days on supplemental oxygen. Overall nutritional status was determined by weight gain in g/kg per day. The incidence of IH in preterm infants of 32 weeks GA or less who were admitted for 28 days or more was 9.34% (65/696) prior to discharge. The incidence in infants weighing 1,500 g or less was 11.11% (63/567) and in infants 1,000 g or less 17.39% (48/276). All parameters that determined the severity of CLD were statistically significant in infants with IH by univariate analysis. In a multivariate regression model, male gender was the most important variable that was significantly associated with IH (odds ratio OR=9.6; 95% confidence interval CI=3.90-23.59), followed by total days on supplemental oxygen (adjusted OR=1.00; 95% CI= 1.01-1.02). Weight gain (g/kg per day) was not significantly different between the two groups. Surgical correction before discharge was well tolerated. We conclude that the incidence of IH is GA-dependent. Factors related to severity of CLD play a more important role than weight gain in predisposing to IH.

Objective: There has been a major increase in the incidence of hypospadias in infants in the 1990s, but the risk factors are not known. Although there are scattered reports in the literature regarding the association of low birth weight and hypospadias, this has not been systematically studied. The objective of this study was to determine the association between early gestation intrauterine growth and hypospadias., Methods: A retrospective review of 13 years of admissions to 2 tertiary care neonatal intensive care units (NICUs) in Connecticut (1987--2000) showed that 112 (1.66%) of 6746 male infants had any degree of hypospadias. Of these, 8 were part of a genetic syndrome and were excluded. A retrospective cohort analysis of these 6738 infants was performed. Infant growth parameters at birth (weight, head circumference, and length) were analyzed along with maternal risk factors known to be associated with changes in fetal growth, including maternal age, race, diagnosis of preeclampsia, gestational diabetes, and maternal use of alcohol or tobacco or substance abuse during pregnancy., Results: The incidence of hypospadias in the NICU population increased 10-fold from 0.4% in 1987 to 4% in the first quarter of 2000. Hypospadias was significantly more common in infants who had uniformly poor intrauterine growth (<10th percentiles) in the various parameters measured: birth weight, length, or head circumference. There were no significant differences in maternal age or race, nor were there differences in the use of alcohol, tobacco, or street drugs by the mother. There were no differences between singletons and multiple-gestation births. However, the frequency of occurrence was significantly higher among first-born infants (1.9%) compared with all other infants (0.9%)., Conclusions: The incidence of hypospadias in our NICU population has increased 10-fold during the 13-year period of study. There was a significant association of hypospadias with poor intrauterine growth. The growth restriction was probably of early gestational cause as there was proportionate involvement of somatic (weight and length) and brain growth (head circumference). The increasing frequency of hypospadias and its association with poor intrauterine growth originating in early gestation suggests that common environmental factor(s) that have an impact on both conditions may be involved.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

Objective: This retrospective study was conducted to determine whether predischarge survival and morbidity of very-low-birth weight infants varied according to the principal pregnancy complication that led to preterm delivery., Study Design: The hospital records of 535 consecutive live-born singleton infants who weighed between 500 and 1499 gm were reviewed, and five primary complications that resulted in preterm delivery were identified: (1) premature rupture of membranes (n = 244, 46%), (2) idiopathic preterm labor (n = 97, 18%), (3) antepartum hemorrhage (n = 58, 11%), (4) pregnancy-induced hypertension (n = 98, 18%), and (5) "other" complications (n = 38, 7%). Neonatal records were studied to identify the presence of respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, and infant death before hospital discharge. Logistic regression analysis was used to analyze the association of each pregnancy complication with the various forms of neonatal morbidity., Results: There were no statistically significant differences in discharge survival rates (range 71% to 88%) among infants born to women who experienced one of the five types of primary complications. Independent of all confounders, premature rupture of membranes was associated with a decreased risk of respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary interstitial emphysema, patent ductus arteriosus, and intraventricular hemorrhage. Preterm labor was associated with an increased risk of pulmonary interstitial emphysema, patent ductus arteriosus, and intraventricular hemorrhage. Pregnancy-induced hypertension was associated with an increased risk of respiratory distress syndrome, pulmonary interstitial emphysema, and patent ductus arteriosus. Antepartum hemorrhage was associated with an increased risk of patent ductus arteriosus., Conclusion: The principal pregnancy complication that led to preterm delivery significantly influenced predischarge morbidity but not the predischarge survival of live-born infants.

The effects of a continuous infusion of tris(hydroxymethyl)aminomethane (THAM) on pH, base excess, p50, serum osmolality, and plasma drug concentration during respiratory acidosis were studied in newborn piglets. Measurements were made during three experimental periods: (1) control period with normal blood gases; (2) hypercapnia period, and (3) hypercapnia plus THAM period (THAM infusion: 1.65 mmol/kg/h). pH decreased and paCO2 increased between control period (7.40 +/- 0.05 and 45 +/- 3 mm Hg) and hypercapnia period (7.24 +/- 0.06 and 59 +/- 2 mm Hg; p < 0.001; mean +/- SD). pH returned to baseline (7.37 +/- 0.04) during the hypercapnia plus THAM period, while paCO2 remained elevated (63 +/- 4 mm Hg). p50 increased from 30.7 +/- 5.9 to 38.3 +/- 4.7 (p < 0.05) during hypercapnia and decreased with hypercapnia plus THAM. THAM concentration and base excess increased with time and were linearly related. Serum osmolality was unchanged during the THAM infusion. We conclude that continuous infusion of THAM is effective in normalizing pH during respiratory acidosis in the piglet.

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)

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.

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.

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.

Furosemide was administered as either an i.v. bolus (6 mg/kg) or primed continuous infusion (4 mg/kg/hr) with quantitative fluid replacement to 10 3-day-old and 9 18-day old piglets. Total and unbound plasma as well as urinary furosemide concentrations were measured for up to 6 hr and drug disposition and renal sodium excretory dynamics were compared at the two ages. The plasma clearance of furosemide was concentration-independent over the range studied (0.1-10 mg/l). Steady-state volume of distribution and unbound fraction of furosemide in plasma were both considerably higher in the younger piglets (618 +/- 320 vs. 201 +/- 71 ml/kg, p less than .01 and 0.22 +/- 0.08 vs. 0.06 +/- 0.02 ml/kg, p less than .001, respectively) while unbound secretory clearance was several-fold lower in this age group (49.2 +/- 23 vs. 107 +/- 55 ml/min/kg, P less than .01). A log-logistic equation was fitted to sigmoidal plots of sodium excretion rate vs. log furosemide excretion rate. While basal response and slope parameters did not differ significantly, maximal response and stimulus required for half-maximal response were both reduced in the younger piglets (0.70 +/- 0.24 vs. 1.18 +/- 0.30 mmol/min and 0.06 +/- 0.04 vs. 0.14 +/- 0.06 mumol/min, respectively, P less than 0.05). Thus, younger piglets were more sensitive to the natriuretic effects of the drug. While term piglets were useful for studying the maturation of protein binding and renal drug excretory processes for furosemide, drug disposition was not comparable to that in human premature infants because of the higher secretory capability of the piglet.

To investigate the role of insulin in modulation of fetal amino acid metabolism, insulin infusions were performed in 10 chronically-catheterized fetal lambs. Fetal insulin infusion caused a dose related fall in the arterial blood concentrations of 13 of 15 amino acids studied as well as a 15-25% decrease in total amino acid concentration. Fetal lambs exhibited a biphasic response of umbilical total amino acid uptake when compared to fetal blood insulin concentration, i.e., at achieved fetal insulin concentrations less than 100 microU/ml, umbilical uptake of 9 specific amino acids as well as summed amino acid uptake from the umbilical circulation were depressed, but at insulin concentrations of 100-350 microU/ml, amino acid uptakes were similar to or above control values. Insulin infusion also caused a drastic diminution in the rate of fetal urea excretion. These findings suggest that insulin acts in the fetus to depress amino acid catabolism, thus altering amino acid extraction and uptake. Depressed protein catabolism with or without enhanced amino acid uptake would have the theoretical effect of stimulation of net protein synthesis with a shift toward use of nonprotein substrates for energy purposes.

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.

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.

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.

We measured hematocrit, whole blood viscosity, arterial oxygen content, and cerebral blood flow in seven newborn lambs in which polycythemia and hyperviscosity were induced by partial exchange transfusion with packed red blood cells from a donor lamb. After the exchange transfusion, the hematocrit, whole blood viscosity, and arterial oxygen content were significantly elevated, whereas cerebral blood flow was reduced from baseline measurements. Sodium nitrite was then infused to reduce the arterial oxygen content to baseline values while the hematocrit and viscosity remained elevated. Under this condition, cerebral blood flow returned to baseline values. Oxygen delivery to the brain remained constant throughout the study. These results indicate that the reduction of cerebral blood flow in neonatal polycythemia and hyperviscosity is a physiologic response to increased arterial oxygen content and not a result of hyperviscosity.

Infants with polycythemia and hyperviscosity are known to have a reduced cerebral blood flow. Eight newborn lambs were studied to determine what effect the reduction in cerebral blood flow might have on the cerebral delivery and uptake of oxygen, glucose, lactate, pyruvate, beta-hydroxybutyrate, and acetoacetate. Measurements of cerebral blood flow, hematocrit, blood viscosity as well as delivery and uptake of the forementioned substrates were made during a control period and at 60, 180, and 300 min after an exchange transfusion with packed newborn red blood cells was performed to increase the hematocrit. Sixty min after the exchange transfusion, cerebral blood flow fell while cerebral oxygen delivery and uptake were stable. Although arterial glucose concentration remained unchanged, there was a significant fall in cerebral glucose delivery. At 180 min after the exchange transfusion, the arterial glucose concentration fell from 90 to 70 mg/100 ml causing the cerebral glucose delivery to further decrease. This resulted in a significant fall in the cerebral glucose uptake and glucose:oxygen quotient. At 300 min arterial glucose concentration remained low but a rise in cerebral blood flow resulted in a small increase in the cerebral glucose delivery and consequently the cerebral glucose uptake and glucose:oxygen quotient returned to normal. We conclude that polycythemia results in a decrease in cerebral glucose delivery and uptake during normoglycemia.