Outcomes following candiduria in extremely low birth weight infants.

BACKGROUND: Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants. METHODS: Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18-22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling. RESULTS: Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2-5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia. CONCLUSIONS: These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.

Empiric antifungal therapy and outcomes in extremely low birth weight infants with invasive candidiasis.

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.

Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory failure.

BACKGROUND: Inhaled nitric oxide (iNO) is a potent and selective pulmonary vasodilator that decreases pulmonary resistance, and improves ventilation-perfusion matching, thereby improving oxygenation and reducing the need for more invasive therapies. Despite the efficacy of iNO at reducing the use of extracorporeal membrane oxygenation, significant concern remains over the potential toxicity from oxidative derivatives and methemoglobinemia. At present, there is no universal agreement on the lowest effective starting dose. Reported initial doses in the neonatal literature have ranged from 1 to 80 ppm. PURPOSE: To determine if the initial dose of iNO altered the incidence of adverse outcome. METHODS: A cohort of neonates who received iNO for treatment of hypoxic respiratory failure and were entered into the Duke Neonatal Nitric Oxide Registry were evaluated. Neonates with congenital anomalies were excluded. This registry collects data from 36 centers that voluntarily report their experiences with iNO. From this database, the starting dose was recorded and the clinical course was followed. Adverse outcomes were prospectively defined and monitored in the database and included: methemoglobinemia, chronic lung disease, treatment with extracorporeal membrane oxygenation, or death. RESULTS: Data on 476 patients were analyzed. Based on starting doses, records were sorted into three groups: a low-dose group (LDG; <18 ppm, n=57), a mid-dose group (MDG; 18 to 22 ppm, n=320), and a high-dose group (HDG; >22 ppm, n=99). ANOVA showed no statistically significant differences among the groups except for PaO(2)/FiO(2) (p<0.05). Neonates in the high starting dose group were more often classified as treatment failures (21% in the LDG, 27% in the MDG, and 38% in the HDG, p=0.04) and treated with extracorporeal membrane oxygenation (19% in the LDG, 23% in the MDG, and 34% in the HDG, p=0.05) compared to the lower dose groups. In addition, survival without the need for oxygen at 30 days or at discharge was higher in the lower dose groups (93% in the LDG, 84% in the MDG, and 76% in the HDG, p=0.03). Logistic regression, however, showed that the starting dose of iNO did not significantly influence these outcomes when corrected for the degree of hypoxemia (PaO(2)/FiO(2)) at the start of therapy (p>0.1). High initial doses of iNO (>22 ppm) were associated with higher levels of methemoglobin (p< 0.05). There were no differences in mortality or length of hospital stay between the groups. CONCLUSIONS: There is significant variation in the starting dose of iNO between centers. Our retrospective study shows no evidence that higher doses improve outcome. A low concentration of iNO (<18 ppm) should be considered to minimize the potential toxicity of methemoglobin. Furthermore, a well-designed, prospective trial should be undertaken to further define the optimal starting dose.

Enrollment of extremely low birth weight infants in a clinical research study may not be representative.

BACKGROUND AND OBJECTIVE: The Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT) antenatal consent study demonstrated that mothers of infants enrolled in the SUPPORT trial had significantly different demographics and exposure to antenatal steroids compared with mothers of eligible, but not enrolled infants. The objective of this analysis was to compare the outcomes of bronchopulmonary dysplasia, severe retinopathy of prematurity, severe intraventricular hemorrhage or periventricular leukomalacia (IVH/PVL), death, and death/severe IVH/PVL for infants enrolled in SUPPORT in comparison with eligible, but not enrolled infants. METHODS: Perinatal characteristics and neonatal outcomes were compared for enrolled and eligible but not enrolled infants in bivariate analyses. Models were created to test the effect of enrollment in SUPPORT on outcomes, controlling for perinatal characteristics. RESULTS: There were 1316 infants enrolled in SUPPORT; 3053 infants were eligible, but not enrolled. In unadjusted analyses, enrolled infants had significantly lower rates of death before discharge, severe IVH/PVL, death/severe IVH/PVL (all < 0.001), and bronchopulmonary dysplasia (P = .003) in comparison with eligible, but not enrolled infants. The rate of severe retinopathy of prematurity was not significantly different. After adjustment for perinatal factors, enrollment in the trial was not a significant predictor of any of the tested clinical outcomes. CONCLUSIONS: The results of this analysis demonstrate significant outcome differences between enrolled and eligible but not enrolled infants in a trial using antenatal consent, which were likely due to enrollment bias resulting from the antenatal consent process. Additional research and regulatory review need to be conducted to ensure that large moderate-risk trials that require antenatal consent can be conducted in such a way as to ensure the generalizability of results.

Antenatal consent in the SUPPORT trial: challenges, costs, and representative enrollment.

OBJECTIVES: The purposes of this study were to quantify the time and effort involved in obtaining prenatal consent for the Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT) and to determine whether the enrolled infants were representative of the eligible population. METHODS: Eligible subjects were likely to deliver in the SUPPORT gestational age window (24-27(6/7)] weeks). Data included who approached the subjects for consent, how often they approached, the duration of each contact, whether consent was obtained, and whether subjects were enrolled in the trial. Eligible, nonenrolled infants entered into the Neonatal Research Network Generic Database throughout the period of SUPPORT enrollment were compared with enrolled infants. RESULTS: A total of 2826 women were identified at 18 sites, 2228 were approached for consent, and 1219 (54.7%) agreed. For 76.9% of those approached, <3 visits (mean: 2.0 +/- 1.2 visits) were required to complete the consent process. Of the 659 infants with consent who were delivered within the study window, 611 were enrolled. Mothers who received a neonatal consultation were more likely to give consent (P < .001). The proportion of infants not exposed to steroids was significantly greater in the nonapproached group than in the approached group (20.0% vs 3.4%; P < .0001). CONCLUSION: In a trial that involved preterm infants and required prenatal consent, >5 women were identified as being likely to deliver in the SUPPORT gestational age window for each 1 who delivered an enrolled infant.

Neonatal candidiasis: epidemiology, risk factors, and clinical judgment.

OBJECTIVE: Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight (<1000-g) infants. We quantified risk factors that predict infection in premature infants at high risk and compared clinical judgment with a prediction model of invasive candidiasis. METHODS: The study involved a prospective observational cohort of infants≤1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis. RESULTS: Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from ≥1 of these sources: blood (n=96); cerebrospinal fluid (n=9); urine obtained by catheterization (n=52); or other sterile body fluid (n=10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled≥50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. CONCLUSION: Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.

Impact of a physiologic definition on bronchopulmonary dysplasia rates.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the endpoint of many intervention trials in neonatology, yet the outcome measure when based solely on oxygen administration may be confounded by differing criteria for oxygen administration between physicians. We previously reported a technique to standardize the definition of BPD between sites by using a timed room-air challenge in selected infants. We hypothesized that a physiologic definition of BPD would reduce the variation in observed rates of BPD among different neonatal centers. Methodology. A total of 1598 consecutive inborn premature infants (501-1249 g birth weight) who remained hospitalized at 36 weeks' postmenstrual age were prospectively assessed and assigned an outcome with both a clinical definition and physiologic definition of BPD. The clinical definition of BPD was oxygen supplementation at exactly 36 weeks' postmenstrual age. The physiologic definition of BPD was assigned at 36 +/- 1 weeks' postmenstrual age and included 2 distinct subpopulations. First, neonates on positive pressure support or receiving >30% supplemental oxygen with saturations between 90% and 96% were assigned the outcome BPD and not tested further. Second, those receiving < or =30% oxygen or effective oxygen >30% with saturations >96% underwent a room-air challenge with continuous observation and oxygen-saturation monitoring. Outcomes of the room-air challenge were "no BPD" (saturations > or =90% during weaning and in room air for 30 minutes) or "BPD" (saturation <90%). At the conclusion of the room-air challenge, all infants were returned to their baseline oxygen levels. Safety (apnea, bradycardia, increased oxygen use) and outcomes of the physiologic definition versus the clinical definition were assessed. RESULTS: A total of 560 (35.0%) neonates were diagnosed with BPD by the clinical definition of oxygen use at 36 weeks' postmenstrual age. The physiologic definition diagnosed BPD in 398 (25.0%) neonates in the cohort. All infants were safely studied. There were marked differences in the impact of the definition on BPD rates between centers (mean reduction: 10%; range: 0-44%). Sixteen centers had a decrease in their BPD rate, and 1 center had no change in their rate. CONCLUSIONS: The physiologic definition of BPD reduced the overall rate of BPD and reduced the variation among centers. Significant center differences in the impact of the physiologic definition were seen, and differences remained even with the use of this standardized definition. The magnitude of the change in BPD rate is comparable to the magnitude of treatment effects seen in some clinical trials in BPD. The physiologic definition of BPD facilitates the measurement of BPD as an outcome in clinical trials and the comparison between and within centers over time.