The investment case for preventing NICU-associated infections.

BACKGROUND: Nosocomial [hospital-associated or neonatal intensive care unit (NICU)-associated] infections occur in as many as 10 to 36% of very low-birth-weight infants cared for in NICUs. OBJECTIVE: To determine the potentially avoidable, incremental costs of care associated with NICU-associated bloodstream infections. STUDY DESIGN: This retrospective study included all NICU admissions of infants weighing 401 to 1500 g at birth in the greater Cincinnati region from January 1, 2005, through December 31, 2007. Nonphysician costs of care were compared between infants who developed at least one bacterial bloodstream infection prior to NICU discharge or death and infants who did not. Costs were adjusted for clinical and demographic characteristics that are present in the first 3 days of life and are known associates of infection. RESULTS: Among 900 study infants with no congenital anomaly and no major surgery, 82 (9.1%) developed at least one bacterial bloodstream infection. On average, the cost of NICU care was $16,800 greater per infant who experienced NICU-associated bloodstream infection. CONCLUSION: Potentially avoidable costs of care associated with bloodstream infection can be used to justify investments in the reliable implementation of evidence-based interventions designed to prevent these infections.

Cytokines and neurodevelopmental outcomes in extremely low birth weight infants.

OBJECTIVE: To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants. STUDY DESIGN: Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1ß; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants. RESULTS: IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-ß, soluble IL rα, macrophage inflammatory protein 1ß) were found to be altered on days 0-4 in infants who developed CP. CONCLUSIONS: CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.

Understanding variation in vitamin A supplementation among NICUs.

OBJECTIVE: We examined and characterized variation among NICUs in the use of vitamin A supplementation for the prevention of bronchopulmonary dysplasia in extremely low birth weight infants. METHODS: An historical cohort study of extremely low birth weight infants admitted within 7 days after birth to NICUs participating in the Pediatric Health Information System database, between January 1, 2005, and March 31, 2008, was performed. NICU medical directors were surveyed to determine attitudes and decision-making regarding adoption of vitamin A supplementation. The proportion of infants receiving vitamin A at each center was measured over time. Patient and hospital characteristics associated with vitamin A use were examined. RESULTS: Among 4184 eligible infants cared for in 30 NICUs, 1005 infants (24%) received vitamin A. Eighteen centers (60%) used vitamin A for some patients. Infants discharged in 2007 (odds ratio: 2.7 [95% confidence interval: 1.4-5.3]) and 2008 (odds ratio: 2.8 [95% confidence interval: 1.4-5.8]), compared with 2005, were more likely to receive vitamin A. NICU medical directors from centers using vitamin A, compared with centers that did not adopt vitamin A supplementation, reported stronger beliefs in the efficacy of vitamin A to reduce the incidence of bronchopulmonary dysplasia (83% vs 33%; P = .03) and in the ease with which vitamin A could be implemented (75% vs 22%; P = .02). CONCLUSIONS: Although the use of vitamin A is increasing, marked variation across NICUs remains. Provider attitudes and system characteristics seem to influence vitamin A adoption.

Early CPAP versus surfactant in extremely preterm infants.

BACKGROUND: There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS: We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS: A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS: The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

Intensive home visiting is associated with decreased risk of infant death.

OBJECTIVE: The goal was to test the hypothesis that participation in a community-based home-visiting program is associated with a decreased risk of infant death. METHODS: A retrospective, case-control design was used to compare the risk of infant death among participants in Cincinnati's Every Child Succeeds program and control subjects matched for gestational age at birth, previous pregnancy loss, marital status, and maternal age. The likelihood of infant death, adjusted for level of prenatal care, maternal smoking, maternal education, race, and age, was determined with multivariate logistic regression. The interaction between race and program participation and the effect of home visiting on the risk of preterm birth were explored. RESULTS: Infants whose families did not receive home visiting (n = 4995) were 2.5 times more likely to die in infancy compared with infants whose families received home visiting (n = 1665). Black infants were at least as likely to benefit from home visiting as were nonblack infants. No effect of program participation on the risk of preterm birth was observed. CONCLUSION: The current study is consistent with the hypothesis that intensive home visiting reduces the risk of infant death.

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.

Race, gender, and clinical risk index for babies (CRIB) score as predictors of severe retinopathy of prematurity.

PURPOSE: To determine whether race, gender, and the Clinical Risk Index for Babies (CRIB) illness severity score are predictors of threshold or severe prethreshold retinopathy of prematurity warranting surgery (ROP warranting surgery) and whether racial and gender differences in ROP are correlated with racial and gender differences in illness severity. METHODS: This was a retrospective analysis of premature infants 401-1250 g at birth that were admitted to the University Hospital of Cincinnati (January 1998 to May 2003). Birth weight, gestational age, multiple birth, birth in the study hospital or elsewhere, race, gender, CRIB score, and eye findings were abstracted. The outcome variable was ROP warranting surgery. RESULTS: Of 299 patients (596 eyes) with adequate eye and CRIB data, 35 patients (11.7%) [66 eyes; 11.1%] developed ROP warranting surgery. Multiple logistic regression analysis showed that higher CRIB score (P < 0.0001; odds ratio [OR] 1.21), male gender (P < 0.005; OR: 2.68), nonblack race (P < 0.0005; OR: 4.32), lower gestational age, and multiple birth are predictive factors for ROP warranting surgery. Because birth weight and gestational age comprise 2 of the 6 components of the CRIB score, a CRIB subscore (CRIBSUB) consisting of the remaining 4 components was tested and remained a significant predictor (P < 0.00001). Birth weight was a significant predictor when CRIBSUB was in the model but not when the CRIB score was used. The CRIB score was a predictor of neonatal mortality, but race and gender did not predict the CRIB score or neonatal mortality. CONCLUSIONS: Nonblack race, male gender, and higher CRIB illness severity scores are predictors of ROP warranting surgery. In our population, there were no racial or gender differences in neonatal mortality or CRIB scores to explain the racial and gender differences in severity of ROP.

Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis.

OBJECTIVES: Necrotizing enterocolitis (NEC) is a significant complication for the premature infant. However, subsequent neurodevelopmental and growth outcomes of extremely low birth weight (ELBW) infants with NEC have not been well described. We hypothesized that ELBW infants with surgically managed (SurgNEC) are at greater risk for poor neurodevelopmental and growth outcomes than infants with medically managed NEC (MedNEC) compared with infants without a history of NEC (NoNEC). The objective of this study was to compare growth, neurologic, and cognitive outcomes among ELBW survivors of SurgNEC and MedNEC with NoNEC at 18 to 22 months' corrected age. METHODS: Multicenter, retrospective analysis was conducted of infants who were born between January 1, 1995, and December 31, 1998, and had a birth weight <1000 g in the National Institute of Child Health and Human Development Neonatal Research Network Registry. Neurodevelopment and growth were assessed at 18 to 22 months' postmenstrual age. chi2, t test, and logistic regression analyses were used. RESULTS: A total of 2948 infants were evaluated at 18 to 22 months, 124 of whom were SurgNEC and 121 of whom were MedNEC. Compared with NoNEC, both SurgNEC and MedNEC infants were of lower birth weight and had a greater incidence of late sepsis; SurgNEC but not MedNEC infants were more likely to have received a diagnosis of cystic periventricular leukomalacia and bronchopulmonary dysplasia and been treated with postnatal steroids. Weight, length, and head circumference <10 percentile at 18 to 22 months were significantly more likely among SurgNEC but not MedNEC compared with NoNEC infants. After correction for anthropometric measures at birth and adjusted age at follow-up, all growth parameters at 18 to 22 months for SurgNEC but not MedNEC infants were significantly less than for NoNEC infants. SurgNEC but not MedNEC was a significant independent risk factor for Mental Developmental Index <70 (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.05-2.50), Psychomotor Developmental Index <70 (OR: 1.95; 95% CI: 1.25-3.04), and neurodevelopmental impairment (OR: 1.78; 95% CI: 1.17-2.73) compared with NoNEC. CONCLUSIONS: Among ELBW infants, SurgNEC is associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months' corrected age compared with NoNEC. MedNEC does not seem to confer additional risk. SurgNEC is likely to be associated with greater severity of disease.

Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: a feasibility trial.

OBJECTIVE: Although earlier studies have suggested that early continuous airway positive pressure (CPAP) may be beneficial in reducing ventilator dependence and subsequent chronic lung disease in the extremely low birth weight (ELBW) infant, the time of initiation of CPAP has varied, and there are no prospective studies of infants who have received CPAP or positive end-expiratory pressure (PEEP) from initial resuscitation in the delivery room (DR). Current practice for the ELBW infant includes early intubation and the administration of prophylactic surfactant, often in the DR. The feasibility of initiating CPAP in the DR and continuing this therapy without intubation for surfactant has never been determined prospectively in a population of ELBW infants. This study was designed to determine the feasibility of randomizing ELBW infants of <28 weeks' gestation to CPAP/PEEP or no CPAP/PEEP during resuscitation immediately after delivery, avoiding routine DR intubation for surfactant administration, initiating CPAP on neonatal intensive care unit (NICU) admission, and assessing compliance with subsequent intubation criteria. METHODS: Infants who were of <28 weeks' gestation, who were born in 5 National Institute of Child Health and Human Development Neonatal Research Network NICUs from July 2002 to January 2003, and for whom a decision had been made to provide full treatment after birth were randomized to receive either CPAP/PEEP or not using a neonatal T-piece resuscitator (NeoPuff). Infants would not be intubated for the sole purpose of surfactant administration in the DR. After admission to the NICU, all nonintubated infants were placed on CPAP and were to be intubated for surfactant administration only after meeting specific criteria: a fraction of inspired oxygen of >0.3 with an oxygen saturation by pulse oximeter of <90% and/or an arterial oxygen pressure of <45 mm Hg, an arterial partial pressure of carbon dioxide of >55 mm Hg, or apnea requiring bag and mask ventilation. RESULTS: A total of 104 infants were enrolled over a 6-month period: 55 CPAP and 49 control infants. No infant was intubated in the DR for the exclusive purpose of surfactant administration. Forty-seven infants were intubated for resuscitation in the DR: 27 of 55 CPAP infants and 20 of 49 control infants. Only 4 of the 43 infants who had a birth weight of <700 g and 3 of the 37 infants of <25 weeks' gestation were resuscitated successfully without positive pressure ventilation, and no difference was observed between the treatment groups. All infants of 23 weeks' gestation required intubation in the DR, irrespective of treatment group, whereas only 3 (14%) of 21 infants of 27 weeks' required such intubation. For infants who were not intubated in the DR, 36 infants (16 CPAP infants and 20 control infants) were subsequently intubated in the NICU by day 7, in accordance with the protocol. Overall, 80% of studied infants required intubation within the first 7 days of life. The care provided for 52 (95%) of 55 CPAP infants and 43 (88%) of the 49 control infants was in compliance with the study protocol, with an overall compliance of 91%. CONCLUSIONS: This study demonstrated that infants could be randomized successfully to a DR intervention of CPAP/PEEP compared with no CPAP/PEEP, with intubation provided only for resuscitation indications, and subsequent intubation for prespecified criteria. Forty-five percent (47 of 104) of infants <28 weeks' gestation required intubation for resuscitation in the DR. CPAP/PEEP in the DR did not affect the need for intubation at birth or during the subsequent week. Overall, 20% of infants did not need intubation by 7 days of life. This experience should be helpful in facilitating the design of subsequent prospective studies of ventilatory support in ELBW infants.

The impact of a clinical guideline on imaging children with hypertrophic pyloric stenosis.

PURPOSE: The purpose of the study was to evaluate the impact of a clinical pathway on the volume of imaging studies performed in children with suspected clinical diagnosis of hypertrophic pyloric stenosis. The pathway suggested referral to surgeons for clinical evaluation for palpation of the olive prior to ordering imaging studies. Only those children in whom the olive could not be palpated would be referred for imaging, and it was anticipated that imaging volume would be reduced following guideline implementation. MATERIALS AND METHODS: The database of the Health Policy and Clinical Effectiveness Department was used to evaluate all patients who had surgery for hypertrophic pyloric stenosis. The presence of a palpable olive and the type of imaging were evaluated both prior to and after the implementation of the clinical guideline. RESULTS: Prior to the guideline, 85 infants had surgery for pyloric stenosis, with 83 of the 85 (97%) having imaging. After the implementation of the guideline, 90 infants had surgery for pyloric stenosis with 84 of 90 patients imaged (92%). A chi-square analysis demonstrated no significant difference in the percentage of children imaged in the two groups (P = 0.104). Approximately one in five children referred for vomiting were diagnosed with hypertrophic pyloric stenosis. CONCLUSION: No significant change in imaging volume occurred following initiation of a guideline which recommended clinical evaluation for palpation of the olive prior to ordering imaging studies. Multiple factors probably contributed to the lack of demonstrated changes.

Contributions of infertility treatment to very-low-birth-weight multiple birth infants receiving neonatal intensive care.

OBJECTIVE: This study was undertaken to determine proportions of very-low-birth-weight (VLBW) multiple birth infants receiving neonatal intensive care whose mothers received various types of infertility treatment and to evaluate infertility treatment-associated morbidity and mortality. STUDY DESIGN: Study infants were multiples with birth weight 401 to 1500 g cared for in Cincinnati neonatal intensive care units from January 1996 to December 2000. Data were obtained retrospectively from the National Institute for Child Health and Human Development Neonatal Research Network registry. Use of infertility treatment (in vitro fertilization, injection or oral ovulation, and intrauterine insemination) was determined by maternal interview or chart review. The generalized estimating equation approach to logistic regression was used. RESULTS: The study included 382 infants of 212 mothers: 201=spontaneous conception (53%), 93=in vitro fertilization (24%), 55=injection (14%), 15=oral (4%), and 18=intrauterine insemination (5%). Neither gestational age nor birth weight differed between groups. More female (58%, P=.003) and white infants (95%, P<.001) resulted from infertility treatment-induced pregnancies than from spontaneous pregnancies. Advancing gestational age significantly decreased odds for all outcomes. CONCLUSION: Of VLBW multiples receiving neonatal intensive care, 47% are associated with infertility treatment. Infertility treatment does not influence outcomes in VLBW multiples.

Early bubble CPAP and outcomes in ELBW preterm infants.

OBJECTIVE: To test whether the introduction of early bubble continuous positive airway pressure (CPAP) results in improved respiratory outcomes in extremely low birth-weight infants. STUDY DESIGN: Outcomes of all infants between 401 and 1000 g born in a level 3 neonatal intensive care units (NICU) between July 2000 and October 2001 (period 2) were compared using historical controls (period 1). Early bubble (CPAP) was prospectively introduced in the NICU during period 1. Univariate and adjusted comparisons were made across time periods. RESULTS: Delivery room intubations, days on mechanical ventilation and use of postnatal steroids decreased (p<0.001) in period 2, while mean days on CPAP, number of babies on CPAP at 24 hours (p<0.001) and mean weight at 36 weeks corrected gestation also increased (p<0.05) after introduction of early bubble CPAP. CONCLUSIONS: Early bubble CPAP reduced delivery room intubations, days on mechanical ventilation, postnatal steroid use and was associated with increased postnatal weight gain with no increased complications.

Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants.

OBJECTIVE: To determine whether minimal ventilation decreases death or bronchopulmonary dysplasia (BPD). STUDY DESIGN: Infants with birth weight 501 g to 1000 g and mechanically ventilated before 12 hours were randomly assigned to minimal ventilation (partial pressure of carbon dioxide [PCO(2)] target >52 mm Hg) or routine ventilation (PCO(2) target <48 mm Hg) and a tapered dexamethasone course or saline placebo for 10 days, using a 2 x 2 factorial design. The primary outcome was death or BPD at 36 weeks' postmenstrual age. RESULTS: After enrollment of 220 patients, the trial was halted because of unanticipated nonrespiratory adverse events related to dexamethasone therapy. The relative risk for death or BPD at 36 weeks in the minimal versus routine ventilation groups was 0.93 (95% CI, 0.77-1.12; P =.43). Ventilator support at 36 weeks was 1% in the minimal versus 16% in the routine group (P <.01). Major morbidities and long-term outcome were comparable in both treatment groups. CONCLUSIONS: With the sample size studied, minimal ventilation did not reduce the incidence of death or BPD. The reduced ventilator support at 36 weeks in the minimal ventilation group warrants further study of this intervention.

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.