Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia.

We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO (2) response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO (2) of 39 +/- 50 mm Hg versus a mean decrease of 11 +/- 15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.

Inhaled nitric oxide for premature infants with severe respiratory failure.

BACKGROUND: Inhaled nitric oxide is a controversial treatment for premature infants with severe respiratory failure. We conducted a multicenter, randomized, blinded, controlled trial to determine whether inhaled nitric oxide reduced the rate of death or bronchopulmonary dysplasia in such infants. METHODS: We randomly assigned 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1500 g, and with respiratory failure more than four hours after treatment with surfactant to receive placebo (simulated flow) or inhaled nitric oxide (5 to 10 ppm). Infants with a response (an increase in the partial pressure of arterial oxygen of more than 10 mm Hg) were weaned according to protocol. Treatment with study gas was discontinued in infants who did not have a response. RESULTS: The rate of death or bronchopulmonary dysplasia was 80 percent in the nitric oxide group, as compared with 82 percent in the placebo group (relative risk, 0.97; 95 percent confidence interval, 0.86 to 1.06; P=0.52), and the rate of bronchopulmonary dysplasia was 60 percent versus 68 percent (relative risk, 0.90; 95 percent confidence interval, 0.75 to 1.08; P=0.26). There were no significant differences in the rates of severe intracranial hemorrhage or periventricular leukomalacia. Post hoc analyses suggest that rates of death and bronchopulmonary dysplasia are reduced for infants with a birth weight greater than 1000 g, whereas infants weighing 1000 g or less who are treated with inhaled nitric oxide have higher mortality and increased rates of severe intracranial hemorrhage. CONCLUSIONS: The use of inhaled nitric oxide in critically ill premature infants weighing less than 1500 g does not decrease the rates of death or bronchopulmonary dysplasia. Further trials are required to determine whether inhaled nitric oxide benefits infants with a birth weight of 1000 g or more.

Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.

BACKGROUND: Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain. METHODS: We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability. RESULTS: Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20). CONCLUSIONS: Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.

Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants.

BACKGROUND: It is uncertain whether the rates and causes of early-onset sepsis (that occurring within 72 hours after birth) among very-low-birth-weight infants have changed in recent years, since antibiotics have begun to be used more widely during labor and delivery. METHODS: We studied 5447 very-low-birth-weight infants (those weighing between 401 and 1500 g) born at centers of the Neonatal Research Network of the National Institute of Child Health and Human Development between 1998 and 2000 who had at least one blood culture in the first three days of life and compared them with 7606 very-low-birth-weight infants born at centers in the network between 1991 and 1993. RESULTS: Early-onset sepsis (as confirmed by positive blood cultures) was present in 84 infants in the more recent birth cohort (1.5 percent). As compared with the earlier birth cohort, there was a marked reduction in group B streptococcal sepsis (from 5.9 to 1.7 per 1000 live births of infants weighing 401 to 1500 g, P<0.001) and an increase in Escherichia coli sepsis (from 3.2 to 6.8 per 1000 live births, P=0.004); the overall rate of early-onset sepsis was not significantly changed. Most E. coli isolates from the recent birth cohort (85 percent) were resistant to ampicillin, and mothers of infants with ampicillin-resistant E. coli infections were more likely to have received intrapartum ampicillin than were those with ampicillin-sensitive strains (26 of 28 with sensitivity data vs. 1 of 5, P=0.01). Infants with early-onset sepsis were more likely to die than uninfected infants (37 percent vs. 13 percent, P<0.001), especially if they were infected with gram-negative organisms. CONCLUSIONS: Early-onset sepsis remains an uncommon but potentially lethal problem among very-low-birth-weight infants. The change in pathogens over time from predominantly gram-positive to predominantly gram-negative requires confirmation by ongoing surveillance.

Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide.

OBJECTIVES: We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group. STUDY DESIGN: Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness. RESULTS: Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43). CONCLUSIONS: In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

Trends in neonatal morbidity and mortality for very low birthweight infants.

OBJECTIVE: To document the mortality and morbidity of infants weighing 501-1500 g at birth according to gestational age, birthweight, and sex. STUDY DESIGN: Prospective collection of perinatal events and neonatal course to 120 days of life, discharge, or death from January 1990 through December 2002 for infants born at 16 participating centers of the National Institute of Child Health & Human Development Neonatal Research Network. RESULTS: Compared with 1995-1996, for 1997-2002 the survival of infants with birthweight of 501-1500 g increased by 1 percentage point (from 84% to 85%). Survival without major neonatal morbidity remained static, at 70%; this includes bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Survival increased for multiple births (26%, up from 22%), antenatal corticosteroid use (79%, up from 71%), and maternal antibiotics (70%, up from 62%) (P < .05). From 1997 to 2002, birthweight-specific survival was 55% for infants weighing 501-750 g, 88% for 751-1000 g, 94% for 1001-1250 g, and 96% for 1251-1500 g. More females survived. The incidence of NEC (7%), severe IVH (12%), and late-onset septicemia (22%) remained essentially unchanged, but BPD decreased slightly, from 23% to 22%. The use of postnatal corticosteroids declined from 20% in 1997-2000 to 12% in 2001-2002. Growth failure (weight <10th percentile) at 36 weeks' postmenstrual age decreased from 97% in 1995-1996 to 91% in 1997-2002. CONCLUSION: There have been no significant increases in survival without neonatal and long-term morbidity among VLBW infants between 1997 and 2002. We speculate that to improve survival without morbidity requires determining, disseminating, and applying best practices using therapies currently available, and also identifying new strategies and interventions.

Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants.

BACKGROUND: Glutamine is one of the most abundant amino acids in both plasma and human milk and may be conditionally essential in premature infants. However, glutamine is not provided by standard intravenous amino acid solutions. OBJECTIVE: We assessed the effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants receiving parenteral nutrition (PN). DESIGN: A total of 141 infants with birth weights of 401-1000 g were randomly assigned to receive a standard intravenous amino acid solution that did not contain glutamine or an isonitrogenous amino acid solution with 20% of the total amino acids as glutamine. Blood samples were obtained just before initiation of study PN and again after the infants had received study PN (mean intake: 2.3 +/- 1.0 g amino acids x kg(-1) x d(-1)) for approximately 10 d. RESULTS: Infants randomly assigned to receive glutamine had mean plasma glutamine concentrations that increased significantly and were approximately 30% higher than those in the control group in response to PN (425 +/- 182 and 332 +/- 148 micromol/L for the glutamine and control groups, respectively). There was no significant difference between the 2 groups in the relative change in plasma glutamate concentration between the baseline and PN samples. In both groups, there were significant decreases in plasma phenylalanine and tyrosine between the baseline and PN samples; the decrease in tyrosine was greater in the group that received glutamine. CONCLUSIONS: In extremely low-birth-weight infants, parenteral glutamine supplementation can increase plasma glutamine concentrations without apparent biochemical risk. Currently available amino acid solutions are likely to be suboptimal in their supply of phenylalanine, tyrosine, or both for these infants.

Growth failure in the preterm infant: can we catch up?

Postnatal growth failure is extremely common in the very low birth weight and extremely low birth weight infant. Recent data from the National Institute of Child and Human Development (NICHD) Neonatal Research Network indicates that 16% of extremely low birth weight infants are small for gestational age at birth, but by 36 weeks corrected age, 89% have growth failure. Follow-up at 18 to 22 months corrected age shows that 40% still have weights, lengths, and head circumferences less than the 10th percentile. Growth failure is associated with an increased risk of poor neurodevelopmental outcome. Inadequate postnatal nutrition is an important factor contributing to growth failure, as most extremely low birth weight infants experience major protein and energy deficits during the neonatal intensive care unit hospitalization, in spite of the fact that nutrition sufficient to support intrauterine growth rates can generally be provided safely. Aggressive nutritional support--parenteral and enteral--is well tolerated in the extremely low birth weight infant and is effective in improving growth. Continued provision of appropriate nutrition (premature formula or fortified human milk) is important throughout the neonatal intensive care unit stay. After discharge, nutrient-enriched postdischarge formula should be continued for approximately 9 months post-term. Exclusively breast-fed infants require additional supplementation/fortification postdischarge as well. Additional trials are needed to address a number of important questions concerning the role of nutrition and growth on ultimate development.

Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants.

OBJECTIVE: To demonstrate the association between fluid intake and weight loss during the first 10 days of life and the risk of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. STUDY DESIGN: A retrospective analysis of data from a cohort of ELBW infants enrolled in the Neonatal Research; 1,382 infants with birth weight between 401 and 1,000 g were randomized. The daily fluid intake and weight loss during the first 10 days of life were compared between the infants who survived without BPD and those who either died or developed BPD. Demographic and clinical neonatal variables were also compared. Multivariate logistic regression was used to analyze the effect of fluid intake and weight loss on death or BPD, controlling for demographic and clinical factors that are significantly associated with BPD by univariate analysis. RESULTS: 585 infants survived without BPD and 797 infants either died or developed BPD. Univariate analysis showed that the daily fluid intakes were higher (day 2-10) and weight loss less (day 6-9) in the group of infants who either died or developed BPD. In addition, lower birth weight, lower gestational age, male gender, lower 1 and 5-minute Apgar Scores, higher oxygen requirement at 24 hours of age, longer duration of assisted ventilation, use of postnatal steroids for BPD and presence of severe intraventricular hemorrhage, proven necrotizing enterocolitis, patent ductus arteriosus, and late onset sepsis, were associated with higher incidence of death or BPD. The adjusted risk of higher fluid intake and less weight loss during the first 10 days of life remained significantly related to death or BPD. CONCLUSION: In this cohort of ELBW infants treated during the post surfactant era, higher fluid intake and less weight loss during the first 10 days of life were associated with an increased risk of BPD. The finding suggests that careful attention to fluid balance might be an important means to reduce the incidence of BPD.

Enterobacter sakazakii is a rare cause of neonatal septicemia or meningitis in VLBW infants.

To determine the rates of Enterobacter sakazakii (ES) infections among very low birth weight infants, culture data from the National Institute of Child Health and Human Development Neonatal Research Network were reviewed. Only one case of ES sepsis was identified among 10660 neonates. These data suggest that outside of the epidemic situation, ES is very rare in very low birth weight infants.

Neurodevelopmental outcome of premature infants after antenatal phenobarbital exposure.

OBJECTIVE: We previously demonstrated that antenatal phenobarbital does not decrease the risk of intracranial hemorrhage or early death in premature infants. The objective of the present study was to evaluate the impact of antenatal phenobarbital exposure on the neurodevelopmental outcome of premature infants born to women who were participating in the randomized clinical trial of antenatal phenobarbital exposure. STUDY DESIGN: Infants were evaluated at 18 to 22 months corrected age with a standard neurologic examination and the Bayley scales of infant development measuring the mental developmental index and the psychomotor developmental index. RESULTS: Of the 578 infants <34 weeks of gestational age who were born to women who were enrolled in the primary study, 7 infants died after discharge from the neonatal intensive care unit, and 135 infants were lost to follow-up. Infants who were lost to follow-up had a higher mean birth weight and gestational age and a lower maternal education, but the rates of intracranial hemorrhage were comparable to those infants who were evaluated. Among the infants who were evaluated (n = 436; 76%), the mean birth weight and gestational age, maternal education, and frequency and distribution of intracranial hemorrhage were similar in the antenatal phenobarbital exposed and placebo groups. Eighteen infants (8%) in the antenatal phenobarbital exposed group and 21 infants (11%) in the placebo group had cerebral palsy (P = not significant). There was no difference between the 2 groups in either the median Bayley II mental developmental index (85 in the antenatal phenobarbital and 86 in the placebo group) or the Psychomotor Developmental Index (91 in the antenatal phenobarbital and 91 in the placebo group). Infants with intracranial hemorrhage (23%) had significantly lower mental developmental index and psychomotor developmental index scores than infants with no intracranial hemorrhage, independent of antenatal phenobarbital exposure. In the total cohort of 436 infants, the presence of intracranial hemorrhage or periventricular leukomalacia was associated with lower mental developmental index and psychomotor developmental index scores; the presence of increasing birth weight, maternal education, and a complete course of antenatal steroids was associated with a higher mental developmental index score. CONCLUSION: Antenatal phenobarbital exposure did not favorably or adversely affect the neurodevelopmental outcome of premature infants at 18 to 22 months of age.

Risk factors for early death among extremely low-birth-weight infants.

OBJECTIVE: The purposes of this study were to compare the clinical characteristics of extremely low birth-weight infants (501-1000 g birth weight) who die early (<12 hours of age) with those of infants who die >12 hours after birth and infants who survive to neonatal intensive care unit discharge and to develop a model of risk for early death. STUDY DESIGN: Perinatal data were prospectively collected on 5986 infants in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from March 1993 through December 1997. Maternal and neonatal characteristics of infants who died early were compared with infants who survived and infants who died beyond 12 hours of age. A model for risk for early death was developed by logistic regression analysis, with results expressed as odds ratio with 95% CI. RESULTS: Mothers of infants who died early were more likely to be delivered in an inborn setting and experience labor and were less likely to have hypertension or preeclampsia, to receive antenatal corticosteroids, or to be delivered by cesarean birth than mothers of infants who died >12 hours after birth or infants who survived. Infants who died early were more likely to have lower Apgar scores and lower gestational age/birth weight and were less likely to be intubated at birth and to receive mechanical ventilation and surfactant therapy than infants who died >12 hours after birth or infants who survived. Greater risk for early death versus survival to neonatal intensive care unit discharge was associated with the lack of surfactant administration (odds ratio, 8.6; 95% CI, 6.3-11.9), lack of delivery room intubation (odds ratio, 5.3; 95% CI, 3.5-8.1), lack of antenatal corticosteroid use (odds ratio, 2.3; 95% CI, 1.6-3.2), lower 1-minute Apgar score (odds ratio, 2.0; 95% CI, 1.8-2.2), male sex (odds ratio, 1.7; 95% CI, 1.3-2.3), multiple gestation (odds ratio, 1.7; 95% CI, 1.2-2.5), no tocolytics (odds ratio, 1.7; 95% CI, 1.2-2.3), lower gestational age per week (odds ratio, 1.4; 95% CI, 1.3-1.6), and lower birth weight per 50 g (95% CI, 1.2-1.4). CONCLUSION: Early death (<12 hours of age) among extremely low-birth-weight infants may reflect an assessment of non-viability by obstetricians and neonatologists.

Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network.

OBJECTIVE: Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401-1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998-2000). METHODS: The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998. RESULTS: Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%). CONCLUSIONS: Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.

Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants.

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 degrees 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 degrees C (mean +/- standard deviation) around the set point of 33.5 degrees C were reduced to 0.7 +/- 0.2 degrees 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 degrees 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 degrees 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 <6 hours of age to a constant esophageal temperature using servo control and provides no evidence that hypothermia involved greater hazard than benefit.

To tap or not to tap: high likelihood of meningitis without sepsis among very low birth weight infants.

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 chi2 tests and adjusted comparisons using regression models. RESULTS: Of 9641 VLBW infants who survived >3 days, 2877 (30%) had > or = 1 LPs, and 6056 (63%) had > or = 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.

Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants.

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.