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The first objective was to identify factors associated with prolonged hospital stay (PHS: hospitalized42 weeks postmenstrual age) in extremely premature (EP: born less than or equal to 28 weeks gestation) infants. The second objective was to identify a PHS best-performing benchmark center.This study was a retrospective cohort analysis of infants bornor =28 weeks gestation and admitted to one of 12 tertiary centers between January 1998 and October 2001. Risk-adjusted odds of PHS, defined as hospitalization beyond 42 weeks postmenstrual age, and the competing outcome, mortality, were assessed using logistic regression models.Among 3892 EP survivors who had complete data for multivariable analysis, 685 (18%) had PHS. Variables contributing to PHS included chronic lung disease (oxygen use at discharge home or 36 week postmenstrual age) (OR 6.75; 95% CI: 5.04 to 9.03), necrotizing enterocolitis requiring surgery (OR 13.83; 95% CI: 8.05 to 23.76), andtwo episodes of late-onset sepsis (OR 2.39; 95% CI: 1.66 to 3.44). Centers' risk-adjusted PHS odds differed from the reference center, which had the lowest incidence of PHS and mortality (overall P-value0.0001). Mortality contributed to PHS, but in an opposite direction compared to other factors. Centers with lowest PHS odds were among those with highest mortality.These findings suggest that reduction of CLD, surgical NEC, and late onset sepsis could reduce PHS in EP infants. Risk adjusted odds of PHS and mortality are both crucial for selecting a PHS best-performing center.

(1) To determine the incidence and the time course of elevated temperature following delivery in term infants with clinical chorioamnionitis (CHORIO) and (2) to determine if the extent of temperature elevation at birth is associated with increased likelihood of NICU Admissions, birth depression, or with short-term neurological abnormalities.The infants were divided into two groups based on the median admission rectal temperature of 37.8 degrees C for the cohort. Depression at birth was defined as either the need of positive pressure ventilation for2 minutes, intubation, or Apgar score6 at 5 minutes. Neurological examination and assessment of encephalopathy (Sarnat staging) was performed at birth and daily thereafter, by one investigator blinded to temperature findings.Infants with higher rectal temperature at 30 minutes of life were more likely to be admitted to NICU: OR (2.8, 95% confidence interval (CI) [1.8 to 4.3]), and were more likely to have birth depression OR (3, 95% CI [1.4 to 6.5]). For infants in NICU, a rectal temperature above 37.8 degrees C was present in 87% in the delivery room, persisted in 47% at 30 minutes, and declined to a normal temperature at 60 minutes of life in the absence of medical interventions. There was no relationship between neurological scores and neonatal temperature.Term infants exposed to CHORIO who had a higher neonatal temperature at 30 minutes of life, were more likely to be admitted to the NICU and to have birth depression, than infants with lesser degree of temperature elevation after birth. Within the NICU group, the extent of temperature elevation was not associated with worse neurological outcomes.

Initiating therapeutic hypothermia during transport for encephalopathy: current state and future direction

This study examined 1) whether plasma total Mg (TMg) and ionized Mg (IMg) concentrations in children are reduced by traumatic brain injury (TBI) and 2) whether the extent of reduction correlates with severity of trauma assessed by the Glasgow Coma Scale (GSC) score. This was a prospective cohort study of 98 pediatric patients who had TBI and were admitted through the emergency department. A GCS score was assigned and blood was obtained upon presentation and 24 h later. Plasma was analyzed for TMg and IMg. Patients were grouped into three categories-GCS scores 13-15, 8-12, and

Neonatal lethal skeletal dysplasias are rare and typically involve thoracic malformations and severe limb shortening. We report on a newborn boy manifesting an osteochondrodysplasia associated with fatal respiratory insufficiency who had normal lung volumes and extremity lengths. His disorder featured aberrant skeletal patterning and defective ossification including a severely osteopenic skull, apparent absence of clavicles, and clefting of the mandible and vertebrae. Serum alkaline phosphatase and osteocalcin levels were markedly low. Biochemical studies suggested parathyroid insufficiency probably from critical illness. Histopathology at autopsy excluded impaired mineralization of skeletal matrix, but endochondral bone formation appeared disorganized with growth plate clustering of chondrocytes in hypertrophic zones and in zones of provisional calcification. Parathyroid glands were not found. Despite features of two distinctive heritable entities, hypophosphatasia and cleidocranial dysplasia, the cumulative findings did not match either condition, and no mutations were found in either the tissue nonspecific ALP isoenzyme or core-binding factor genes, respectively, or in the genes encoding osteocalcin or the osteoblast transcription factor osterix. This patient could represent the extreme of cleidocranial dysplasia (a disorder not always associated with structural mutation in core-binding factor A1), but more likely he defines a unique osteochondrodysplasia disrupting both intramembranous and endochondral bone formation.

Objective. To determine the potential contribution of initial hypoglycemia to the development of neonatal brain injury in term infants with severe fetal acidemia.Methods. A retrospective chart review was conducted of 185 term infants who were admitted to the neonatal intensive care unit between January 1993 and December 2002 with an umbilical arterial pH Results. Forty-one (22%) infants developed an abnormal neurologic outcome, including 14 (34%) with severe hypoxic ischemic encephalopathy who died, 24 (59%) with moderate to severe hypoxic ischemic encephalopathy, and 3 (7%) with seizures. Twenty-seven (14.5%) of the 185 infants had an initial blood sugar ≤40 mg/dL. Fifteen (56%) of 27 infants with a blood sugar ≤40 mg/dL versus 26 (16%) of 158 infants with a blood sugar >40 mg/dL had an abnormal neurologic outcome (odds ratio [OR]: 6.3; 95% confidence interval [CI]: 2.6–15.3). Infants with abnormal outcomes and a blood sugar ≤40 mg/dL versus >40 mg/dL had a higher pH (6.86 ± 0.07 vs 6.75 ± 0.09), a lesser base deficit (−19 ± 4 vs −23.8 ± 4 mEq/L), and lower mean arterial blood pressure (34 ± 10 vs 45 ± 14 mm Hg), respectively. There was no difference between groups in the proportion of infants who required cardiopulmonary resuscitation (7 [46%] vs 15 [57%]) and those with a 5-minute Apgar score 40 mg/dL (OR: 18.5; 95% CI: 3.1–111.9), cord arterial pH ≤6.90 versus >6.90 (OR: 9.8; 95% CI: 2.1–44.7), a 5-minute Apgar score ≤5 versus >5 (OR: 6.4; 95% CI: 1.7–24.5), and the requirement for intubation with or without cardiopulmonary resuscitation versus neither (OR: 4.7; 95% CI: 1.2–17.9).Conclusion. Initial hypoglycemia is an important risk factor for perinatal brain injury, particularly in depressed term infants who require resuscitation and have severe fetal acidemia. It remains unclear, however, whether earlier detection of hypoglycemia, such as in the delivery room, in this population could modify subsequent neurologic outcome.

Background. Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known. Methods. We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis. Results. Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97–1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation. Conclusions. Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population.

Context. Neonatal meningitis is associated with significant morbidity and mortality. We speculated that meningitis may be underdiagnosed among very low birth weight (VLBW) infants because of the failure to perform lumbar punctures (LPs) in infants with suspected sepsis.Objective. This study was undertaken to review the epidemiology of late-onset meningitis in VLBW (401–1500 g) infants and to evaluate the concordance of cerebrospinal fluid (CSF) and blood culture (BC) results.Methods. VLBW infants (excluding those with intraventricular shunts) born at centers of the National Institute of Child Health and Human Development Neonatal Research Network from September 1, 1998, through December 31, 2001, were studied. Late-onset meningitis was defined by culture-based criteria and classified as meningitis with or without associated sepsis. Unadjusted comparisons were made using χ2 tests and adjusted comparisons using regression models.Results. Of 9641 VLBW infants who survived >3 days, 2877 (30%) had ≥1 LPs, and 6056 (63%) had ≥1 BC performed after day 3. One hundred thirty-four infants had late-onset meningitis (1.4% of all patients; 5% of those with an LP). Pathogens associated with meningitis were similar to those associated with sepsis. One third (45 of 134) of the infants with meningitis had negative BCs. Lower gestational age and prior sepsis increased risk for meningitis. Compared with uninfected infants, those with meningitis had a longer time on mechanical ventilation (28 vs 18 days), had longer hospitalizations (91 vs 79 days), were more likely to have seizures (25% vs 2%), and were more likely to die (23% vs 2%).Conclusions. Meningitis is a serious complication among VLBW infants, associated with increased severity of illness and risk of death. Of note, one third of the infants with meningitis had meningitis in the absence of sepsis. Because CSF cultures were performed only half as often as BCs, this discordance in blood and CSF culture results suggests that meningitis may be underdiagnosed among VLBW infants.

The mechanism of neuroprotection associated with systemically administered magnesium remains unclear. This investigation examined the acute effects of systemically administered MgSO4 on brain extracellular ([Mg]ecf) and intracellular ([Mg]i) fluid Mg concentrations, specific brain phosphorylated metabolites, and brain intracellular pH. Miniswine were studied with P-31 magnetic resonance spectra, to derive [Mg]i, and brain microdialysis probes, to measure [Mg]ecf. Animals were infused with MgSO4 (n = 5, 275 mg/kg over 30 min followed by 100 mg/kg over 30 min, designated MgHI) or Na2SO4 (n = 5, designated NaHI), and both groups underwent hypoxia-ischemia (HI) over the last 15 min of the infusions. Groups differed in plasma [Mg] at the completion of HI (9.1 +/- 1.5 versus 1.1 +/- 0.6 mM for MgHI and NaHI, respectively, p < 0.05). MgHI had elevations of [Mg]ecf (0.23 +/- 0.11 and 0.40 +/- 0.14 mM at control and completion of HI, respectively), and [Mg]ecf was unchanged for NaHI (p < 0.05 versus MgHI). At the completion of HI, MgHI had greater decreases in nucleoside triphosphate (NTP) (48 +/- 6% of control), and more brain acidosis after HI (6.01 +/- 0.07) compared with NaHI (NTP, 70 +/- 3% of control; brain pH, 6.51 +/- 0.14, both p < 0.05 versus MgHI). [Mg]i increased to elevated values during HI in both MgHI and NaHI (p < 0.05 versus control of each group) and remained higher in MgHI over the next 25 min (p < 0.05 versus NaHI). There were inverse correlations during HI between [Mg]i and brain NTP (r2 = 0.73 and 0.59 for MgHI and NaHI, respectively), and brain acidosis (r2 = 0.85 and 0.85 for MgHI and NaHI, respectively) in each group. These findings indicate complex effects of Mg on the brain. Elevation of [Mg]ecf may be beneficial with regards to excitatory neurotransmitters. However, greater disturbance of brain NTP concentration, more acidosis, and the increase in [Mg]i may offset any benefit. The results warrant further investigation using indicators of neuronal injury to determine whether Mg supplementation provides neuroprotection.

Objectives. The objectives of this study were to determine, first, whether an early neurologic examination could predict a persistent abnormal neonatal neurologic state comparable to the amplitude-integrated electroencephalography (a-EEG) and, second, whether a combination of the 2 methods would further enhance early identification of high-risk infants.Methods. Fifty term infants were enrolled prospectively when they had evidence of intrapartum distress, Apgar score ≤5 at 5 minutes, or cord arterial pH ≤7.00 and were admitted to intensive care. Each enrolled infant underwent an early neurologic examination using a modified Sarnat staging system (stages 2 and 3 were regarded as abnormal) and a blinded simultaneous a-EEG measurement. Predictive values were calculated for a short-term abnormal outcome defined as persistent moderate to severe encephalopathy beyond 5 days.Results. An abnormal short-term outcome was present in 14 (28%) of 50 infants. The neurologic examination was performed at 5 ± 3 hours after delivery. A short-term abnormal outcome occurred in 9 (53%) of 17 infants with initial stage 2 and in both infants with initial stage 3 encephalopathy. In addition, 13 infants manifested features of both stage 1s and 2 and post hoc were classified (S1–2). Three of the latter infants (23%) developed an abnormal short-term outcome. The a-EEG was abnormal in 15 (30%) infants, 11 (73%) of whom developed an abnormal outcome. An abnormal a-EEG was more specific (89% vs 78%), had a greater positive predictive value (73% vs 58%), and had similar sensitivity (79% vs 78%) and negative predictive value (90% vs 91%) when compared with an abnormal early neurologic examination. A combination of abnormalities had the highest specificity (94%) and positive predictive value (85%).Conclusion. The combination of the a-EEG and the neurologic examination shortly after birth enhances the ability to identify high-risk infants and limits the number of infants who would be falsely identified compared with either evaluation alone.

Over the past 15 years it has been recognized that the temperature of the brain has an important influence on the extent of brain injury that follows intervals of hypoxia-ischemia. Available data in animals and humans show that brain injury is worsened when fever is superimposed on an ischemic event. Furthermore, data in neonates and adults strongly suggest a neuroprotective role for modest hypothermia (temperature reductions of 1 to 6 degrees C) applied during or following ischemia or hypoxia-ischemia. This article provides an overview of the effects of brain temperature, including its role in the development of brain injury, mechanisms of brain injury which may be temperature sensitive, the regulation of brain temperature, thermal characteristics during brain cooling, and current clinical investigations that use temperature as a therapeutic modality.

Objective. Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth. Methods. In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5°C for 72 hours followed by slow rewarming. Results. In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 ± 0.2°C (mean ± standard deviation) around the set point of 33.5°C were reduced to 0.7 ± 0.2°C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 ± 0.3°C). In the human investigation, the infants were randomized at 4.1 ± 1.3 hours (mean ± standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5°C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 ± 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups. Conclusions. Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at

To determine whether early pulmonary hypertension (PH) at 10-14 days of life in preterm infants is associated with bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA).This was a prospective observational cohort study of infants28 weeks' gestation. Exclusion criteria were any major anomaly, genetic syndrome, or death before the initial echocardiogram. Echocardiograms were performed between 10 and 14 days of life and at 36 weeks' PMA to assess PH. BPD and its severity were determined at 36 weeks PMA by the National Institutes of Health workshop definition.From March 2011 to April 2013, of 146 consecutively admitted infants28 weeks, 120 were enrolled. One infant was excluded, 17 did not consent, and 8 died before undergoing a study echocardiogram. At 10-14 days of life, 10 infants had early PH (8%). Male sex (56% vs 40%), gestational age (26(+2) ± 1(+2) vs 25(+6) ± 1(+4) weeks), birth weight (837 ± 205 g vs 763 ± 182 g), and small for gestational age (14% vs 20%) were not significantly different among infants with no PH and early PH, respectively. Infants with early PH required0.3 fraction of inspired oxygen by day 10 of life (70% vs 27%, P.01). Moderate/severe BPD or death was greater among infants with early PH (90%) compared with no PH (47%, relative risk 1.9, 95% CI 1.43-2.53).In this prospective, single-center cohort, early PH was associated with moderate/severe BPD or death at 36 weeks' PMA.

Phosphorus-31 magnetic resonance spectroscopy was used in 2-day (n = 4) and 40-day (n = 4) miniswine to determine whether plasma hypermagnesemia alters brain intracellular magnesium concentration and if the plasma-brain intracellular magnesium relationship changes with age. At control, brain intracellular magnesium concentration was similar in the 2-day (0.24 ± 0.04 mM) and 40-day groups (0.21 ± 0.01 mM). Intravenous infusions of magnesium sulfate (MgSO 4 , 60 minute) raised plasma magnesium concentration to 4-6 mM in both groups. During and for 3 hours after MgSO 4 infusions, there were no changes in brain intracellular magnesium concentration in either group and no correlation between plasma and brain intracellular magnesium ( r = 0.11 and 0.08 for 2- and 40-day groups, respectively). Brain intracellular magnesium concentration appears to be tightly regulated.

Objective. To compare brain temperature and cerebral blood flow (CBF) during head and body cooling, with and without systemic hypoxemia. Methods. Seventeen newborn swine were studied for either measurement of brain temperature alone (n = 9) or measurement of brain temperature and CBF (n = 8). All animals were ventilated and instrumented, and temperature probes were inserted into the rectum, into the brain at depths of 2 and 1 cm from the cortical surface, and on the dural surface. Blood flow was measured with microspheres. The protocol consisted of a control period, an interval of either head or body cooling, and cooling with 15 minutes of superimposed hypoxia. After a 1-hour recovery period, animals were exposed to the same sequence except that the alternate mode of cooling was evaluated. Results. Head cooling with a constant rectal temperature resulted in an increase in the temperature gradient across the brain from the warmer central structures to the cooler periphery (brain 2 cm − dura temperature: 1.3 ± 1.1°C at control to 7.5 ± 3.5°C during cooling). Hypoxia superimposed on head cooling decreased the temperature gradient by at least 50%. In contrast, body cooling was associated with an unchanged temperature gradient across the brain (brain 2 cm − dura temperature: 1.5 ± 1.2°C at control to 1.1 ± 0.9°C during cooling). Hypoxia superimposed on body cooling did not change brain temperature. Both modes of brain cooling resulted in similar reductions of global CBF (∼40%) and O2 uptake. Conclusion. Brain hypothermia achieved through head or body cooling results in different brain temperature gradients. Alterations in systemic variables (ie, hypoxemia) alters brain temperature differently in these 2 modes of brain cooling. The mode of brain cooling may affect the efficacy of modest hypothermia as a neuroprotective therapy.

In this issue of Pediatrics , Simbruner et al1 report results of the neo.nEURO.network study of hypothermia for infants with hypoxic-ischemic encephalopathy (HIE). They enrolled infants of ≥36 weeks' gestational age with clinical and electrophysiological evidence of HIE and randomly assigned them to targeted temperature reduction (33.5°C rectal temperature [range: 33°C–34°C]) or a control group (37°C rectal temperature [range: 36.5°C–37.5°C]). The study design shared features with previously published trials of this intervention; entry criteria were those of the CoolCap trial,2 target temperature was identical to that of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)3 and Total Body Hypothermia (TOBY)4 trials, and a manually controlled-cooling blanket (Tecotherm TS 200 [Tec-Com, Munich, Germany]) was used as it was in the TOBY trial. All the trials, including the neo.nEURO.network trial, maintained targeted temperature for 72 hours followed by rewarming at a rate of ≤0.5°C/hour. The neo.nEURO.network used morphine in both study arms; the TOBY trial used sedation for distressed infants, but the percentage of infants so treated was not reported.4 The primary outcome of death or … Address correspondence to Abbot R. Laptook, MD, Department of Pediatrics, Women & Infants Hospital of Rhode Island, 101 Dudley St, Suite 1100, Providence, RI 02905. E-mail: alaptook{at}wihri.org

BACKGROUND Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. METHODS We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. RESULTS The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P

OBJECTIVE: The objective of this study was to determine whether Apgar scores at 10 minutes are associated with death or disability in early childhood after perinatal hypoxic-ischemic encephalopathy.METHODS: This was a secondary analysis of infants who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hypothermia trial. Infants who were born at ≥36 weeks’ gestation and had clinical and/or biochemical abnormalities at birth and encephalopathy at RESULTS: Twenty of 208 infants were excluded (missing data). More than 90% of the infants had Apgar scores of 0 to 2 at 1 minute, and Apgar scores at 5 and 10 minutes shifted to progressively higher values; at 10 minutes, 27% of infants had Apgar scores of 0 to 2. After adjustment, each point decrease in Apgar score at 10 minutes was associated with a 45% increase in the odds of death or disability. Death or disability occurred in 76%, 82%, and 80% of infants with 10-minute Apgar scores of 0, 1, and 2, respectively. Classification and regression-tree analysis indicated that Apgar scores at 10 minutes were discriminators of outcome.CONCLUSIONS: Apgar scores at 10 minutes provide useful prognostic data before other evaluations are available for infants with hypoxic-ischemic encephalopathy. Death or moderate/severe disability is common but not uniform with Apgar scores of

The frequency, time of identification, and type of problems of newborns in an urban indigent population were prospectively studied during their hospital stay to evaluate feasibility of early hospital discharge. Eight percent (563) of 7,021 term and near-term low-risk infants developed one or more predefined problems. Of those with problems, 42.1% received therapy and/or a higher level of care. Tachypnea, temperature instability, and cyanotic episodes were the most frequently treated problems. Nearly 69% of all problems were detected after the initial examination, and 31% developed problems after 24 hours of age; 5% were transferred to the NICU. Problems occurring after 24 hours of age emphasize the need for follow-up within days after hospital discharge in this population.

BACKGROUND AND PURPOSE: Brain temperature may be an important factor governing the extent of neuronal injury associated with stroke. The goal of this study was to develop a noninvasive method for measuring brain temperature, both to characterize the extent to which temperature changes after stroke and to test protocols designed to reduce brain temperature. We used an animal model to test the ability of (1)H MR spectroscopy to measure temperature from infarcted brain tissue at 24 hours after insult. METHODS: Unilateral permanent focal ischemia in the middle cerebral artery territory was induced in adult dogs by intravascular delivery of microfibrillar collagen. MR imaging performed at 24 hours after insult was used to guide the implantation of temperature probes into the basal ganglia infarct and into the same anatomic location on the contralateral side. Serial non-water-suppressed (1)H MR spectra were obtained from 1.3-cm(3) voxels using an echo time of 136 and 272 ms, alternately, from the infarcted and contralateral non-infarcted tissue during a period when brain temperature was raised and lowered by whole-body heating and cooling. RESULTS: The chemical shift difference between the (1)H MR spectroscopy signal of water and N-acetylaspartate or water and trimethylamines was plotted against brain temperature for two voxel locations. The slope and intercept of the plots obtained for infarcted and non-infarcted brain were not significantly different (P < .05, t test), and there was no difference between the slope and intercept of plots made from data collected with an echo time of 136 or 272 ms. CONCLUSION: The results of this study indicate that brain temperature can be measured from regions of brain containing infarcted tissue, at least up to 24 hours after ischemia. It should be possible to apply the (1)H MR spectroscopy method used in the present study to measure brain temperature after stroke.

Marked acute changes in arterial carbon dioxide tension (PaCO2) and acid-base status occur in the immediate postnatal period in infants delivered in the presence,of pathologic fetal acidemia (FA) in whom the risk for hypoxic-ischemic cerebral injury is high. The cerebral vasculature is extremely sensitive to changes in PaCO2. However, the relationship between the acute changes in PaCO2 and subsequent neonatal neurologic characteristics remains unclear.(1) To determine the extent of the acute changes in PaCO2 and acid-base status following birth in infants delivered in the presence of pathologic FA and (2) to determine the potential relationship of the initial changes in PaCO2 and neonatal neurologic characteristics.PaCO2 and acid base status of cord umbilical arterial blood and initial postnatal arterial blood were studied in 73 term infants admitted to the Neonatal Intensive Care Unit. Infants were categorized in three groups: I, no FA, no respiratory support and normal neonatal neurologic examination (n = 49); II, pathologic FA (umbilical artery pHor = 7.00, base deficitor = 12 mEq/l), no respiratory support and normal neonatal neurologic examination (n = 17); III, FA, intubated and with evidence of hypoxic ischemic encephalopathy (HIE) including seizures (n = 7).Demographic characteristics were similar among the three groups, although 5-min Apgar scoreor = 5 was more common in group II (47%) and group III (100%) than in group I (4%). Umbilical arterial pH was lower in group III (6.75 +/- 0.18) vs. group II (6.90 +/- 0.09) and in group II vs. group I (6.90 +/- 0.09 vs. 7.19 +/- 0.09) (P0.005) and the PaCO2 was higher in group III (141 +/- 37 mmHg) vs. group II (94 +/- 22 mmHg) and in group II vs. group I (94 +/- 22 vs. 60 +/- 13 mmHg) (P0.05). The mean base deficit was large but comparable between groups III and II, i.e. 18 +/- 6 vs. 18 +/- 5 mEq/l, respectively, and higher than in group I infants (6 +/- 4 mEq/l) (P0.00). At 1 h postnatal age, the mean arterial pH had increased in all groups, i.e. 7.06 +/- 0.15 (group III), 7.25 +/- 0.09 (group II), and 7.31 +/- 0.06 (group I); however, the differences amongst the groups remained significant (P0.005). The mean PaCO2 decreased from 94 +/- 22 mmHg (12.5 +/- 2.9 kPa) to 30 +/- 6 mmHg (4.0 +/- 0.8 kPa) for the spontaneously ventilating group II infants and from 141 +/- 37 mmHg (18.8 +/- 4.9 kPa) to 45 +/- 14 mmHg (6.0 +/- 1.9 kPa) in the intubated group III infants (P0.005). A repeat PaCO2 at 2 h of age in group III infants had decreased to 29 + 2 mmHg (3.9 +/- 0.3 kPa),which was not different from the PaCO2 at 2 h in group II infants (30 +/- 8 mmHg; 4.0 +/- 1.1 kPa). No significant differences were observed for pH or base deficit at this time.Marked and rapid changes in PaCO2 and pH were observed in term infants delivered in the presence of pathologic FA. Initial postnatal PaCO2 values varied significantly with the lowest values noted in those infants breathing spontaneously and who exhibited an uneventful neonatal course; higher initial postnatal values, despite mechanical ventilation, were noted in infants with HIE including seizures. Further investigation in this area is imperative in order to better define the optimal respiratory management of the neurologically at-risk infant.

This investigation determined if a short interval of modest hypothermia (1 h) initiated 30 min after brain ischemia provided neuroprotection. The rationale for the time and duration of brain cooling reflects the likelihood that the implementation of neuroprotective strategies will occur at an interval shortly after ischemia, and that long-term maintenance of normothermia is a cornerstone of neonatal stabilization. Studies were performed in 22 ventilated neonatal mini-swine in a superconducting magnet to obtain 31P magnetic resonance spectra. After a control period all animals underwent 15 min of global brain ischemia and were maintained normothermic for the first 30 min post-ischemia. In one group of 11 swine normothermia was continued. In the other group of 11 swine, modest hypothermia was initiated at 30 min post-ischemia, continued for 1 h and followed by resumption of normothermia. Animals were subsequently weaned from ventiltor support, removed from the magnet, and underwent neurobehavioral and histologic assessment at 72 h post-ischemia. Both groups had similar severity of ischemia, as indicated by identical changes in arterial blood pressure and pH, alterations in brain beta-nucleotide triphosphate (% of control where control = 100%, 32 +/- 28 vs 27 +/- 26% for normothermic and hypothermic groups, respectively), and the extent of intraischemic brain acidosis (6.13 +/- 0.19 vs 6.14 +/- 0.14 for normothermic and hypothermic groups, respectively). In both groups the distribution of stages of encephalopathy were the same: 1 normal and 10 abnormal (4 mild, 2 moderate, and 4 severe) normothermic, and, 3 normal and 8 abnormal (4 mild, 2 moderate, and 2 severe) hypothermic animals. There was no difference in the extent of neuronal injury between groups. We conclude that a 1-h interval of modest hypothermia initiated at 30 min post-ischemia does not confer neuroprotection.

Numerous studies using adult animal models suggest that dichloroacetate (DCA) may have neuroprotective properties by virtue of its ability to increase rates of metabolism and, therefore, clearance of brain lactic acidosis, which may accumulate during cerebral ischemia. We tested the hypothesis that postischemic DCA administration affects lactate and acid clearance to different extents in immature versus mature brain. 31P and 1H magnetic resonance spectroscopy were used to measure intracellular acid and lactate clearance rates in vivo in newborn and 1-month-old swine after a 14-min episode of transient near-complete global ischemia. Simultaneous monitoring of extracellular lactate efflux and clearance was measured in the same animals by in vivo microdialysis. Plasma glucose concentrations were elevated in order to study animals with severe cerebral lactic acidosis. Maximal levels of brain lactosis (16-20 micromol/g) and acidosis (PHintracellular 5.8-6.0) were reached during the first 10 min of recovery and were the same in age groups and in subgroups either acting as controls or treated with DCA (200 mg/kg) given from the last minute of ischemia to 5-7 min after ischemia. For newborns, DCA administration improved the postischemic clearance rate of cerebral acidosis and cerebral phosphocreatine, with similar trends for the clearance of lactosis and increased rates of recovery of nucleotide triphosphates, compared with controls. In contrast, DCA administration in 1-month-olds resulted in a modest trend for improvement of cerebral lactate clearance, but did not affect acid clearance or the recovery rate of phosphocreatine or nucleotide triphosphates. Extracellular brain lactate concentrations had similar relative increases and rates of decline for subgroups of either age treated with DCA versus controls. The results of this study indicate that postischemic DCA administration helps to resolve cerebral acidosis to a greater degree in immature than more mature brain, suggesting that DCA may have cerebroprotective properties for neonatal hypoxic-ischemic encephalopathy.

This randomized, controlled trial had as its goal to determine whether whole-body cooling, begun within 6 hours of birth and continuing for 72 hours, reduces disability and mortality in term infants with moderate or severe encephalopathy. Infants entered into the study had a gestational age of 36 weeks or longer, were admitted with either severe acidosis or perinatal complications, and required resuscitation at birth. They were randomized to usual care or whole-body cooling and were reassessed neurodevelopmentally at age 18 to 22 months. The 102 infants assigned to hypothermia were placed on a blanket precooled to 5°C and the esophageal temperature, measured with a probe, was reduced to 33.5°C. A second blanket then was attached to the cooling system decrease variability in esophageal temperature. A skin probe monitored the temperature of the abdominal-wall skin. At both sites, temperature was monitored continuously and recorded every 15 minutes for 4 hours and then hourly for 8 hours. After 72 hours, the set point of the automatic control on the cooling system was increased by 0.5°C per hour. After 6 hours, the esophageal probe was removed and warming continued until the set point of the warmer reached 36.5°C. The 106 control infants were exposed to an overhead radiant warmer to maintain an abdominal-wall skin temperature of 36.5°C to 37.0°C. The incidence of death or moderate/severe disability was 44% in treated infants and 62% of control infants (risk ratio [RR], 0.72; 95% confidence interval [CI], 0.54-0.95). Approximately one fourth of actively treated infants (24%) and 37% of control infants died (RR, 0.68; 95% CI, 0.44-1.05). No increase in major disability was observed in surviving infants. Cerebral palsy occurred in 19% of the hypothermia group and 30% of control infants (RR, 0.68; 95% CI, 0.38-1.22). These results suggest that whole-body cooling, or hypothermia, is a safe and effective means of limiting mortality and reducing disability in newborn infants with moderate or severe encephalopathy.

To determine whether small for gestational age (SGA) infants born at27 weeks gestational age (GA) are at increased risk for mortality, morbidity, and growth and neurodevelopmental impairment at 18-22 months corrected age.This was a retrospective cohort study from National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-Up Studies. Infants born at27 weeks GA between January 2006 and July 2008 were included. SGA was defined as birth weight10th percentile for GA based on Olsen growth curves. Infants with birth weight ≥ 10th percentile for GA were classified as non-SGA. Maternal and infant characteristics, neonatal outcomes, and neurodevelopmental data were compared in SGA and non-SGA infants. Neurodevelopmental impairment was defined as any of the following: cognitive score70 on the Bayley Scales of Infant Development III, moderate or severe cerebral palsy, bilateral hearing loss (with and without amplification), or blindness (bilateral vision20/200). Logistic regression analysis was applied to evaluate the associations between SGA status and death or neurodevelopmental impairment.The SGA group comprised 385 infants; the non-SGA group, 2586 infants. Compared with mothers of non-SGA infants, mothers of SGA infants were more likely to have a high school education, prenatal care, cesarean delivery, pregnancy-induced hypertension, and antenatal corticosteroid exposure. Compared with non-SGA infants, SGA infants had higher mortality and were more likely to have postnatal growth failure, prolonged mechanical ventilation, and postnatal steroid use. SGA status was associated with increased risk of death or neurodevelopmental impairment (OR, 3.91; 95% CI, 2.91-5.25; P.001).SGA status in infants born at27 weeks GA is associated with an increased likelihood of postnatal steroid use, mortality, growth failure, and neurodevelopmental impairment at 18-22 months corrected age.

Objectives To describe and compare the incidence of late-onset sepsis (LOS) and demographic and clinical characteristics associated with LOS in very low birth weight (VLBW) infants from singleton and multiple births, and to examine the heritability of susceptibility to LOS among VLBW twins by comparing same-sex and unlike-sex twin pairs. Study design The study group comprised infants with birth weight 401-1500 g seen at clinical centers of the Eunice Kennedy Shriver National Institute of Child and Human Development Neonatal Research Network between 2002 and 2008. Only the first episode of LOS was included in our analysis. Stepwise logistic regression models were fitted separately for singleton and multiple pregnancies to examine the maternal and neonatal factors associated with LOS. LOS due solely to gram-negative bacteria in singleton and multiple pregnancies was also examined in separate models. The heritability of LOS was estimated by examining the concordance of LOS in twins from same-sex and unlike-sex pairs. Results LOS occurred in 25.0% (3797 of 15 178) of singleton and 22.6% (1196 of 5294) of multiple-birth VLBW infants. Coagulase-negative staphylococci were the most common infecting organisms, accounting for 53.2% of all LOS episodes in singletons and 49.2% in multiples. Escherichia coli and Klebsiella species were the most commonly isolated gram-negative organisms, and Candida albicans was the most commonly isolated fungus. Concordance of LOS did not differ significantly between same-sex and unlike-sex twin pairs. Conclusion LOS remains a common problem in VLBW infants. The incidence of LOS is similar for singleton and multiple-birth infants. The similar concordance of LOS in same-sex and unlike-sex twin pairs provides no evidence that susceptibility to LOS among VLBW infants is genetically determined.

SEVERAL algorithms for the calculation of ionized intracellular magnesium concentration from the chemical shifts of MgATP were compared, using in vivo 31 P NMR data obtained from swine brain during and following hypoxic ischemia plus i.v. MgSO 4 infusion. This analysis reveals that both the absolute ionized intracellular magnesium and relative changes in magnesium may vary widely between algorithms used. The calculated intracellular pH, used in algorithms to determine ionized magnesium concentration was found to be a critical parameter that governs the extent of these differences.

Newborn and 1-mo-old swine were exposed to identical durations (18 min) and degrees of hypoxia (O2 content = 4 mL/dL), to examine the effects of hypoxia on cerebral energy metabolism and intracellular pH (pHi) in vivo, using 31P and 1H nuclear magnetic resonance spectroscopy. Hypoxia produced the same extent of reductions in phosphocreatine (PCr) (63 +/- 28% and 65 +/- 10%, newborns and 1-mo-olds, respectively) and pHi (6.93 +/- 0.06 and 6.89 +/- 0.06, respectively) for either age group. The magnitude of changes in PCr, lactate, and pHi was larger for subgroups of data collected when cardiovascular instability was present, suggesting that hypotension and possibly reduced cerebral perfusion contributed to cerebral energy failure and lactic-acidosis for either age group. There were no correlations between the blood plasma glucose concentration at 18 min of hypoxia and the extent of change in PCr, lactate, or pHi for either age group. During a subsequent period of complete ischemia induced via cardiac arrest after 20 min hypoxia, the decline in PCr and nucleoside triphosphate (NTP), and increase in lactate followed similar rates compared with previously studied age-matched animals that were normoxic before ischemia. The rate constants for the change in PCr, NTP, and lactate followed similar rates compared with previously studied age-matched animals that were normoxic before ischemia. The rate constants for the change in PCr, NTP, and lactate during ischemia showed no correlation with the blood plasma glucose concentration measured immediately before cardiac arrest. These results suggest that cerebral glycolytic rates and energy utilization during ischemia are unaffected by a preceding interval of hypoxia and that hyperglycemia does not delay cerebral energy failure during hypoxia or combined hypoxic-ischemia.

In neonatal and adult animals, modest reduction in brain temperature (2-3 degrees C) during ischemia and hypoxia-ischemia provides partial or complete neuroprotection. One potential mechanism for this effect is a decrease in brain energy utilization rate with consequent preservation of brain ATP, as occurs with profound hypothermia. To determine the extent to which modest hypothermia is associated with a decrease in brain energy utilization rate, in vivo 31P and 1H magnetic resonance spectroscopy (MRS) was used to measure the rate of change in brain concentration of phosphocreatine, nucleoside triphosphate, and lactate after complete ischemia induced by cardiac arrest in 11 piglets (8-16 d). Pre-ischemia metabolite concentrations and MRS-determined rate constants were used to calculate the initial flux of high energy phosphate equivalents (d[approximately P]/dt, brain energy utilization rate). Baseline physiologic and MRS measurements were obtained at 38.2 degrees C and repeated after brain temperature was adjusted between 28 and 41 degrees C. This was followed by measurement of d[approximately P]/dt during complete ischemia at 1-2 degrees C increments within this temperature range. Adjusting brain temperature did not alter any systemic variable except for heart rate which directly correlated with brain temperature (r = 0.95, p < 0.001). Before ischemia brain temperature inversely correlated with phosphocreatine (r = -0.89, p < 0.001), and reflected changes in the phosphocreatine-ATP equilibrium, because brain temperature inversely correlated with intracellular pH (r = -0.77, p = 0.005). Brain temperature and d[approximately P]/dt were directly correlated and described by a linear relationship (slope = 0.61, intercept = -12, r = 0.92, p < 0.001). A reduction in brain temperature from normothermic values of 38.2 degrees C was associated with a decline in d[approximately P]/dt of 5.3% per 1 degree C, and therefore decreases in d[approximately P]/dt during modest hypothermia represent a potential mechanism contributing to neuroprotection.

To determine whether the incidence of neurosonographic and neurologic abnormalities is higher in cocaine-exposed infants at birth.In utero exposure to cocaine was investigated in 39 term and near-term infants with positive urine screens for cocaine only and 39 matched control infants without drug exposure admitted to the regular term newborn nursery. Serial evaluations were performed on each infant on postnatal days 1 and 2 and included a cranial sonogram, a neurologic and behavioral assessment for drug withdrawal, and Doppler interrogation of the anterior and middle cerebral arteries.There were no differences between groups in neurosonographic abnormalities. Grade I or II intraventricular hemorrhage occurred in 11% of cocaine-exposed and 11% of control infants. There were no cases of grade III intraventricular hemorrhage, cystic periventricular leukomalacia, or neonatal stroke. Head size was smaller in cocaine-exposed infants, ie, 32.7 +/- 0.1 cm versus 33.8 +/- 0.1 cm. The neurologic examination was similar between groups with regard to tone, reflexes, and cranial nerves. Behavioral scores were higher on both days, in cocaine-exposed versus control infants, ie, 4.4 +/- 0.5 versus 2.7 +/- 0.03 on day 1 and 5.0 +/- 0.5 versus 1.71 +/- 0.31 on day 2. Cerebral blood flow velocity measurements in the anterior cerebral artery were similar between groups on both days of examination. However, cocaine-exposed infants demonstrated a significant increase in flow velocity from day 1 to day 2, ie, 0.48 +/- 0.03 to 0.57 +/- 0.04. There was a concomitant decrease in the pulsatility index from day 1 to day 2 in the cocaine-exposed, ie, 0.74 +/- 0.02 to 0.69 +/- 0.02, but not in the control infants. No differences were noted in the flow velocities in the middle cerebral arteries between groups.Term and near-term infants admitted to a regular nursery who are exposed to cocaine in utero: (1) do not exhibit an increased incidence of neurosonographic abnormalities; (2) do exhibit altered behavior consistent with drug withdrawal; and (3) do demonstrate changes in flow velocity in the anterior cerebral artery consistent with the vasoconstrictive effects of the drug. However, these changes were not accompanied by changes in the neurologic examination or altered care. The long-term neurodevelopmental implications of these subtle abnormalities in the neonatal period remain to be determined.

Background and Purpose A 2.9°C reduction in the intraischemic rectal temperature of neonatal piglets is associated with less brain damage compared with animals with normothermic rectal temperatures. This investigation studied one potential mechanism for this observation: better maintenance of energy stores and less brain acidosis secondary to reduced metabolic activity associated with modest hypothermia. Methods 31 P MR spectroscopy was used to study piglets before, during, and after 15 minutes of partial brain ischemia with intraischemic rectal temperatures of either 38.3±0.4°C (n=10, normothermic) or 35.4±0.5°C (n=10, hypothermic). Animals were followed up for up to 72 hours after ischemia and were evaluated clinically and by brain histology. Results Values for pH i remained 0.15 to 0.20 pH units greater in modestly hypothermic than in normothermic piglets during ischemia and the initial 30 minutes after ischemia ( P =.049, group effect). Phosphocreatine, β-ATP, and inorganic phosphorus were similar between groups. The relationship between the intraischemic energy state and subsequent clinical evidence of brain damage (irrespective of group assignment) revealed lower pH i over the last 7 minutes of ischemia for abnormal compared with normal piglets (5.98±0.22 versus 6.39±0.24, respectively; P =.002). In contrast, intraischemic β-ATP (41±19% versus 57±21% of control) and inorganic phosphorus (273±31% versus 224±92% of control) for abnormal and normal piglets, respectively, did not differ between groups. Conclusions Intraischemic modest hypothermia attenuates the severity of brain acidosis during and 30 minutes after ischemia compared with normothermic animals and supports the concept that attenuated brain acidosis is a potential mechanism by which hypothermia may reduce ischemic brain damage.

The goal of this study was to evaluate the potential of using the difference between the 1H NMR frequencies of water and N-acetylaspartic acid (NAA) to measure brain temperature noninvasively. All water-suppressed and non-water-suppressed 1H NMR spectra were obtained at a field strength of 4.7 T using a surface coil. Experiments performed on model solutions revealed a decrease in the difference between NMR frequencies for NAA and water as a linear function of increasing temperature from 14 to 45 degrees C. Changing pH in the range 5.5-7.6 produced no discernible trends for concurrent changes in the slope and intercept of the linear relationship. There were minor changes in slope and intercept for solutions containing 80 or 100 mg of protein/ml versus no protein, but these changes were not considered to be of sufficient magnitude to deter the use of this approach to measure brain temperature. The protein content of swine cerebral cortex was found to remain constant from newborn to 1 month old (78 +/- 12 mg/g; n = 41). Therefore, data collected for the model solution containing 80 mg of protein/ml were used as a calibration curve to calculate brain temperature in eight swine during control, hypothermia, ischemia, postischemia, or death, over a temperature range of 23-40 degrees C. A plot of 61 temperatures determined from 1H NMR versus temperatures measured from an optical fiber probe sensor implanted 1 cm into the cerebral cortex showed excellent linear agreement (slope = 1.00 +/- 0.03, r2 = 0.96). We conclude that 1H NMR spectroscopy presents a practical means of making noninvasive measurements of brain temperature with an accuracy of better than +/- 1 degree C.

To the Editor .— The important study by Shalak et al1 unfortunately left me confused and perplexed. Their stated purpose was to determine if any of the cytokines “were correlated with short-term neonatal neurologic outcomes including depression at birth … and hypoxic-ischemic encephalopathy.” They have indeed found such a correlation but have, I believe, misdiagnosed “hypoxic-ischemic encephalopathy” (HIE). The authors state that HIE and/or seizures were defined in accordance with recommendations of the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. These criteria are unfortunately stated out of context. The presence of the findings of low Apgar scores at …

The increasingly widespread use of antibiotics during labor and delivery raises the question of whether the incidence or causes of early onset sepsis (within 72 hours of birth) in very-low-birth-weight (VLBW) infants havechanged. The study population included 5447 VLBW infants, weighing from 401 to 1500 g at birth in the years 1998-2000, who had at least one blood culture in the first 3 days of life. They were compared with 7606 VLBW infants born during 1991-1993. Early onset sepsis was diagnosed in 84 study infants for a rate of 15.4 per 1000 live births. The rate in 1991-1993 had been 19.3 per 1000 births. Approximately 60% of infections in the recent cohort were due to Gram-negative organisms, and 44% were attributed to Escherichia coli. In contrast, Gram-negative organisms caused a majority of the earlier infections. The rate of infection by group B streptococci fell from 5.9 to 1.7 per 1000 live births, whereas that of E. coli infection rose from 3.2 to 6.8 per 1000. All but 2% of cases occurred in infants weighing more than 500 g, and the gestational age at birth was similar in the two periods. In the later period, 85% of E. coli isolates were resistant to ampicillin, whereas all 26 isolates tested were sensitive to third-generation cephalosporins. Maternal antibiotic use during hospitalization could not be related to either the risk of E. coli or group B streptococcal sepsis or the risk of death from either of these infections. After adjusting for gestational age, septic infants were at significantly increased risk of respiratory distress syndrome, severe intraventricular hemorrhage/periventricular leukomalacia, and bronchopulmonary dysplasia. Septic infants also were likelier than others to die within 4 months of birth, again adjusting for gestational age. Infants with Gram-negative sepsis were likelier to die than those infected by a Gram-positive organism, but the difference was significant only within 3 days after birth. Early onset sepsis, especially that caused by Gram-negative organisms, remains an important cause of neonatal death.

Objective To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants. Study design This was a cohort study of infants with a birth weight ≤1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI). Results A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes. Conclusion Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.

Objective The study goal was to evaluate maternal and neonatal risk factors associated with post-neonatal intensive care unit (NICU) discharge mortality among extremely low birth weight (ELBW) infants. Study design This is a retrospective analysis of ELBW ( Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network sites between January 2000 and June 2007. Infants were tracked until death or 18 to 22 months' corrected age. Infants who died between NICU discharge and the 18- to 22-month follow-up visit were classified as post-NICU discharge mortality (P-NDM). Association of maternal and infant risk factors with P-NDM was determined using logistic regression analysis. A prediction model with 6 significant predictors was developed and validated. Results There were 5364 infants who survived to NICU discharge; 557 (10%) infants were lost to follow-up, and 107 infants died following NICU discharge. P-NDM rate was 22.3 per 1000 ELBW infants. In the prediction model, African American race, unknown maternal health insurance, and hospital stay ≥120 days significantly increased risk, and maternal exposure to intrapartum antibiotics was associated with decreased risk of P-NDM. Conclusion We identified African American race, unknown medical insurance, and prolonged NICU stay as risk factors associated with P-NDM among ELBW infants.

Hypothermia is a frequent occurrence in newborns, and thermoregulatory management is a fundamental part of medical stabilization. Although modest reduction in brain temperature (2-3 degrees C) before ischemia provides neuroprotection in adults, the effect of modest hypothermia on immature brain has not been examined. Nine-day-old swine were exposed to 15 min of incomplete global brain ischemia, with intraischemic rectal temperatures of either 38.3 +/- 0.4 degrees C (n = 10, normothermic) or 35.4 +/- 0.5 degrees C (n = 10, hypothermic). The relationship between rectal and brain temperature was delineated in preliminary experiments on four swine. Animals with intraischemic rectal temperatures maintained at either 39.5 degrees C or 35.5 degrees C were associated with a similar magnitude of difference in brain temperature. Therefore, rectal temperature was used to monitor brain temperature for 20 animals studied subsequently. Ischemia was induced by combining neck compression with hemorrhagic hypotension and resulted in similar group values for mean arterial pressure and changes in pH and blood gases at the completion of ischemia. A clinical overall performance score and brain tissue structure were evaluated after 72 h (or earlier if animals died prematurely). Hypothermic animals had less severe stages of impairment compared with the normothermic group (p = 0.023). Hypothermic piglets had less histologic damage in the neocortex at 0.5 cm beneath the brain surface (p = 0.048), the caudate nucleus (p = 0.038), and the pons/midbrain (p = 0.04) and the same direction of effect in neocortex at 1 cm beneath the surface (p = 0.07) and the cerebellum (p = 0.07) as compared with normothermic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Since systemic glucose concentration is an important determinant of ischemic brain metabolism in neonates, we sought to determine if the systemic glucose concentration influences brain metabolic alterations following repeated partial ischemia. A group of hyperglycemic piglets (n = 12) were compared to a group of modestly hypoglycemic piglets (n = 12) using in vivo 2H and 31P magnetic resonance spectroscopy to simultaneously measure cerebral blood flow and phosphorylated metabolites before, during and 30 min after two 10-min episodes of ischemia (i.e. Recovery 1 and 2). For both groups, beta-ATP levels at Recovery 1 and 2 were lower than Control (91 +/- 11 and 83 +/- 15% of Control, respectively for both groups combined, P = 0.002 vs Control). Inorganic phosphorus was elevated in hyperglycemic piglets at Recovery 1 and 2 (117 +/- 15 and 118 +/- 10% of Control). In contrast, in modestly hypoglycemic piglets inorganic phosphorus progressively rose from Recovery 1 (131 +/- 24% of Control) to Recovery 2 (149 +/- 37% of Control), and differed from the hyperglycemic group (P = 0.02). These changes did not correlate with post-ischemic cerebral blood flow, cerebral O2 delivery or cerebral glucose delivery. In both groups phosphocreatine and intracellular pH returned to Control values during Recovery 1 and 2. The progressive increase in inorganic phosphorus post-ischemia in hypoglycemic piglets suggests that modest hypoglycemia during and following repeated partial ischemia adversely affects immediate brain metabolic recovery.

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

To evaluate the association between early hypocarbia and 18- to 22-month outcome among neonates with hypoxic-ischemic encephalopathy.Data from the National Institute of Child Health and Human Development Neonatal Research Network randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy were used for this secondary observational study. Infants (n = 204) had multiple blood gases recorded from birth to 12 hours of study intervention (hypothermia versus intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18 to 22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO(2) and cumulative exposure to PCO(2)35 mm Hg. The relationship between cumulative PCO(2)35 mm Hg (calculated as the difference between 35 mm Hg and the sampled PCO(2) multiplied by the duration of time spent35 mm Hg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), and time to spontaneous respiration and ventilator days; results were expressed as odds ratios and 95% confidence intervals. Alternative models of CO(2) concentration were explored to account for fluctuations in CO(2).Both minimum PCO(2) and cumulative PCO(2)35 mm Hg were associated with poor outcome (P.05). Moreover, death/disability increased with greater cumulative exposure to PCO(2)35 mm Hg.Hypocarbia is associated with poor outcome after hypoxic-ischemic encephalopathy.

This study examined the effect of hypercarbia on cerebral agonal glycolytic rates and brain lactate accumulation after complete ischemia induced by cardiac arrest. Before cardiac arrest, the blood plasma glucose concentration in seven newborn (113 d postconception; normal gestation, 115 d) and seven 1-mo-old (144 d postconception) piglets was adjusted to a specific value (range, 1 to 64 mM), and then inspired ventilation gases were changed to 10:50:40 CO2:O2:N2 for 20 min. The agonal glycolytic rate was measured by monitoring the rate of cerebral lactate formation in vivo using proton nuclear magnetic resonance spectroscopy, and postmortem brain lactate concentrations were measured biochemically in tissue extracts obtained 40 to 45 min after cardiac arrest. These data were compared with 21 normocarbic piglets of similar age, nine examined as part of the present study and 12 examined previously (Corbett RJT, Laptook AR, Ruley JI, Garcia D: Pediatr Res 30:579-586, 1991). There was a nonlinear relationship between the final postmortem brain lactate concentration and preischemia blood plasma glucose concentration that was most prominent in newborn piglets and previously had gone unnoticed. When analyzed using a steady-state model for glucose transport, this relationship revealed that normocarbic newborns had a lower preischemia affinity constant for the transport mechanism for glucose (2.8 +/- 1.5 mM) and lower cerebral glucose utilization rate relative to transport rate (0.12 +/- 0.04), compared with 1-mo-olds (4.5 +/- 1.4 mM and 0.30 +/- 0.03, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Ischemia-induced changes in 31P NMR relaxation were examined in 16 piglets. NMR spectra were acquired under control conditions and during complete cerebral ischemia induced via cardiac arrest. Changes in T1 were assessed directly in six animals during control conditions and after 30–45 min of complete ischemia when changes in brain P1 levels had reached a plateau. The T1 for P1 did not change, i.e., 2.3 ± 0.5 s during control conditions versus 2.4 ± 1.0 s during ischemia. To evaluate phosphocreatine and ATP, two types of spectra, with a long (25-s) or short (1-s) interpulse delay time, were collected during the first 10 min of ischemia (n = 10). Both types of spectra showed the same time course of changes in phosphocreatine and ATP levels, implying that the T1 relaxation times do not change during ischemia. There were no changes in the linewidths of phosphocreatine, ATP, or P1 during ischemia, implying that the T*2 values remain constant. Our results suggest that the 31P T1 and T*2 for phosphocreatine, Pi, and ATP do not change during ischemia, and therefore changes in 31P NMR peak intensity accurately reflect changes in metabolite concentrations.

Our investigation sought to determine whether neonatal brain ischemic vascular and metabolic effects were altered by repeated episodes of ischemia. We studied twelve piglets using in vivo magnetic resonance spectroscopy to obtain multiple, simultaneous measurements of cerebral blood flow and phosphorylated metabolites from the same tissue volume. The relationship between cerebral blood flow and energy metabolism was examined over a range of reduced cerebral blood flow (90-10% of control). Three episodes of partial ischemia were studied, each lasting 10 minutes and separated by 45 minutes. During each interval of ischemia, plots of the percent reduction in cerebral blood flow versus the percent change in phosphorylated metabolites (phosphocreatine, inorganic phosphorus) or unit change in intracellular pH did not differ in slope and intercept. The relationship between beta-ATP and cerebral blood flow during repeated ischemia revealed similar slopes, but a lower intercept during the third interval of ischemia (p = 0.029). After ischemia, cerebral blood flow was reduced as a function of the severity of the preceding ischemia. After each interval of ischemia, phosphocreatine and intracellular pH were unchanged from preischemic values. Inorganic phosphorus remained elevated after ischemia (117 +/- 16 and 118 +/- 11% of control, p less than 0.005, following the first and second intervals of ischemia), and beta-ATP was restored to progressively lower values (92 +/- 10 and 83 +/- 11% of control, p less than 0.025). Calculated free ADP decreased after ischemia and correlated with the postischemic level of beta-ATP (r = 0.63, p = 0.001). These results demonstrate that the relationship between cerebral blood flow and metabolism was reasonably preserved during repeated partial ischemia. However, following ischemia, alterations occurred in both cerebral blood flow and metabolism. These alterations may reflect a relative inhibition of ATP production by metabolic regulators such as ADP on either glycolysis or oxidative phosphorylation or both.

The purpose of this study was to investigate the effect of plasma glucose concentration on cerebral agonal glycolytic rates in piglets of different ages. Twenty-four piglets were divided into four different age groups corresponding to 113, 121, 128, and 145 d postconception (normal gestation = 115 d). For each group the agonal glycolytic rate was measured by monitoring the rate of cerebral lactate accumulation after total ischemia. Ischemia was induced by cardiac arrest, and the rate of lactate formation was measured in vivo using proton nuclear magnetic resonance spectroscopy. Before cardiac arrest, the blood plasma glucose concentration for individual piglets was adjusted to a specific value in the range 1–30 mM. The dependence of agonal glycolytic rate upon blood glucose concentration was analyzed for each age group, using the Michaelis-Menten equation to evaluate Vmax, the maximal rate of glucose utilization, and Km the concentration of plasma glucose at which the half maximal rate of utilization occurs. Vmax for the two youngest age groups of piglets had significantly different (p < 0.05) values compared with each other (1.38 ± 0.17 and 1.92 ± 0.64 μmol·g-1·min-1, respectively) and with the two older groups of animals (2.99 ± 0.52 and 3.42 ± 0.65 μmol·g-1·min-1, respectively). The Km values determined for the two youngest age groups (0.79 ± 0.70 and 1.79 ± 0.33 mM, respectively) also were significantly lower than for the two older age groups (4.96 ± 2.90 and 4.82 ± 2.96 mM, respectively). We conclude that throughout the first 2 wk of life there are marked increases in the cerebral glycolytic capacity. It follows, therefore, that rates of lactate formation in newborns are not as strongly accelerated by increased blood glucose compared with older piglets. During combined hyperglycemia and severe ischemia, newborns will not be exposed to harmful levels of cerebral lactate as rapidly as 2− to 4-wk-old piglets. However, despite the differences in glycolytic rates, all four age groups showed similar potentials to generate high cerebral lactate concentrations. Furthermore, the final brain lactate concentration showed the same linear correlation with preischemia plasma glucose concentration for all four age groups. The implications of this study are that piglets of any age have the same potential to generate high concentrations of brain lactate, although newborns will reach this level more slowly than older animals.

This report demonstrates the feasibility of using deuterium (2H) and phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy to make multiple simultaneous determinations of changes in cerebral blood flow, brain intracellular pH, and phosphorylated metabolites for individual animals. In vivo spectra were obtained from the brains of newborn piglets immediately following an intracarotid bolus injection of deuterium oxide. Experiments were performed at magnetic field strengths of 1.9 T (2H NMR only) or 4.7 T (interleaved 2H and 31P NMR). The rate of clearance of deuterium signal was used to calculate cerebral perfusion rates (CBFdeuterium) during a stable control physiologic state and conditions known to alter blood flow. CBFdeuterium values measured at 1.9 T under conditions of control (normocarbia, normotension), hypercarbia, hypocarbia, and varying degrees of ischemia induced by hypotension showed a significant positive correlation with values measured simultaneously using radiolabeled microspheres (CBFdeuterium = 0.4 × CBFmicrospheres + 8; r = 0.8). Simultaneous interleaved 2H and 31P NMR measurements under control conditions indicate that brain energy metabolites and intracellular pH remained at constant levels during the time course of the administration and clearance of deuterium oxide. Also, brain phosphorylated metabolites and intracellular pH did not differ significantly from their preinjection levels. Under control physiologic conditions, CBFdeuterium varied by ±6% and phosphorylated metabolite levels did not show a significant change with time, as measured from 15 blood flow determinations collected over 4 h. The results indicate that CBFdeuterium determinations have excellent reproducibility and do not affect brain energy metabolite levels. The procedures described here have the potential to bring a novel methodology to bear on investigating the relationship between cerebral perfusion and energy status during conditions such as ischemia or asphyxia.