Brenda B. Poindexter

Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death

Objective:To determine the association between human milk (HM) intake and risk of necrotizing enterocolitis (NEC) or death among infants 401 to 1000 g birth weight.Study Design:Analysis of 1272 infants in the National Institute of Child Health and Human Development Neonatal Network Glutamine Trial was performed to determine if increasing HM intake was associated with decreased risk of NEC or death. HM intake was defined as the proportion of HM to total intake, to enteral intake and total volume over the first 14 days. Known NEC risk factors were included as covariates in Cox proportional hazard analyses for duration of survival time free of NEC.Result:Among study infants, 13.6% died or developed NEC after 14 days. The likelihood of NEC or death after 14 days was decreased by a factor of 0.83 (95% confidence interval, CI 0.72, 0.96) for each 10% increase in the proportion of total intake as HM. Each 100 ml kg−1 increase in HM intake during the first 14 days was associated with decreased risk of NEC or death (hazard ratio, HR 0.87 (95% CI 0.77, 0.97)). There appeared to be a trend towards a decreased risk of NEC or death among infants who received 100% HM as a proportion to total enteral intake (HM plus formula), although this finding was not statistically significant (HR 0.85 (95% CI 0.60, 1.19)).Conclusion:These data suggest a dose-related association of HM feeding with a reduction of risk of NEC or death after the first 2 weeks of life among extremely low birth weight infants.

Aggressive vs. conservative phototherapy for infants with extremely low birth weight

BACKGROUND It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less). METHODS We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments. RESULTS Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g. CONCLUSIONS Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin‐structure infections (including those caused by community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA‐MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one‐compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)0.75 × (PMA3.1/(43.63.1 + PMA3.1)); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age‐based dosing.

Impact of Nutrition on Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) remains a common morbidity of prematurity. Although the pathogenesis of BPD is recognized to be both multifactorial and complex, the role of nutrition in the pathophysiology of BPD is typically limited to management after a diagnosis has been made. Infants born small for gestational age and those who experience postnatal growth failure are more likely to have BPD. Therapies for lung disease, such as fluid restriction, diuretics, and corticosteroids, can negatively impact postnatal growth. Future research is needed to optimize nutritional strategies in the neonatal intensive care unit and following hospital discharge.

Catecholamine-resistant hypotension and myocardial performance following patent ductus arteriosus ligation

Objective:We performed a multicenter study of preterm infants, who were about to undergo patent ductus arteriosus ligation, to determine whether echocardiographic indices of impaired myocardial performance were associated with subsequent development of catecholamine-resistant hypotension following ligation.Study Design:A standardized treatment approach for hypotension was followed at each center. Infants were considered to have catecholamine-resistant hypotension if their dopamine infusion was >15 μg kg–1min–1. Echocardiograms and cortisol measurements were obtained between 6 and 14 h after the ligation (prior to the presence of catecholamine-resistant hypotension).Result:Forty-five infants were enrolled, 10 received catecholamines (6 were catecholamine-responsive and 4 developed catecholamine-resistant hypotension). Catecholamine-resistant hypotension was not associated with decreased preload, shortening fraction or ventricular output. Infants with catecholamine-resistant hypotension had significantly lower levels of systemic vascular resistance and postoperative cortisol concentration.Conclusion:We speculate that low cortisol levels and impaired vascular tone may have a more important role than impaired cardiac performance in post-ligation catecholamine-resistant hypotension.

Reliability of Echocardiographic Indicators of Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia

Objectives To determine the assessment and inter‐rater reliability of echocardiographic evaluations of pulmonary vascular disease (PVD) in preterm infants at risk for bronchopulmonary dysplasia. Study design We prospectively studied echocardiograms from preterm infants (birthweights 500‐1250 g) at 7 days of age and 36 weeks postmenstrual age (PMA). Echocardiograms were assessed by both a cardiologist on clinical service and a single research cardiologist. Interpretations were reviewed for inclusion of determinants of PVD and assessed for inter‐rater reliability using the Prevalence Adjusted Bias Adjusted Kappa Score (PABAK). Results One hundred eighty and 188 matching research and clinical echocardiogram reports were available for the 7‐day and 36‐week PMA studies. At least one of the specific qualitative measures of PVD was missing from 54% of the clinical reports. PVD was diagnosed at 7 days in 31% and 20% of research and clinical interpretations, respectively (PABAK score of 0.54). At 36 weeks, PH was diagnosed in 15.6% and 17.8% of research and clinical interpretations, respectively (PABAK score of 0.80). Conclusions Although all qualitative variables of PVD are not consistently provided in echocardiogram reports, the inter‐rater reliability of cardiologists evaluating measures of PVD revealed strong agreement, especially at 36 weeks PMA. We speculate that establishment of a protocol for echocardiographic evaluation may improve the identification of PVD in preterm infants.

Nutrition for the Extremely Preterm Infant

With advancements in the care of preterm infants, the goals in nutritional care have expanded from survival and mimicking fetal growth to optimizing neurodevelopmental outcomes. Inadequate nutritional support may be a risk factor for major complications of prematurity; conversely, higher disease burden is a risk for growth restriction. Early complete parenteral nutrition support, including intravenous lipid emulsion, should be adopted, and the next challenge that should be addressed is parenteral nutrition customized to fit the specific needs and metabolism of the extremely preterm infant. Standardized feeding protocols should be adopted.

Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

ABSTRACT Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)

Characteristics of extremely low-birth-weight infant survivors with unimpaired outcomes at 30 months of age

Objective:To evaluate characteristics of unimpaired outcome in extremely low-birth-weight (ELBW) survivors.Study design:ELBW infants (n=714) with 30 months’ assessments were analyzed. Logistic regression was used to develop a model for the binary outcome of unimpaired versus impaired outcome.Result:Thirty-three percent of infants had an unimpaired outcome. Seventeen percent of ELBW survivors had a Bayley II Mental Developmental Index score of ⩾101 and 2% had a score of ⩾116. Female gender, use of antenatal steroids (ANS), maternal education ⩾high school and the absence of major neonatal morbidities were independent predictors of unimpaired outcome. The likelihood of an unimpaired outcome in the presence of major neonatal morbidities was higher in infants exposed to ANS.Conclusion:The majority of unimpaired ELBW survivors had cognitive scores shifted toward the lower end of the normal distribution. Exposure to ANS was associated with higher likelihood of an unimpaired outcome in infants with major neonatal morbidities.

Outcomes of preterm infants following discussions about withdrawal or withholding of life support

Objectives To describe the frequency of postnatal discussions about withdrawal or withholding of life‐sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes. Study design This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22‐28 weeks of gestation who survived >12 hours during 2011‐2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In‐hospital and 18‐ to 26‐month outcomes were evaluated. Results WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22‐24 weeks (27.0%) compared with 27‐28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of ≤24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%‐29.9%) as did WWLST (5.2%‐20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator. Conclusions Wide center variations in WWLST discussions occur, especially at ≤24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor. Trial registration ClinicalTrials.gov: NCT00063063.