2% chlorhexidine-70% isopropyl alcohol versus 10% povidone-iodine for insertion site cleaning before central line insertion in preterm infants: a randomised trial.

OBJECTIVE: To determine whether 2% chlorhexidine gluconate-70% isopropyl alcohol (CHX-IA) is superior to 10% aqueous povidone-iodine (PI) in preventing catheter-related blood stream infection (CR-BSI) when used to clean insertion sites before placing central venous catheters (CVCs) in preterm infants. DESIGN: Randomised controlled trial. SETTING: Two neonatal intensive care units (NICUs). PATIENTS: Infants <31 weeks' gestation who had a CVC inserted. INTERVENTIONS: Insertion site was cleaned with CHX-IA or PI. Caregivers were not masked to group assignment. MAIN OUTCOME MEASURES: Primary outcome was CR-BSI determined by one microbiologist who was masked to group assignment. Secondary outcomes included skin reactions to study solution and thyroid dysfunction. RESULTS: We enrolled 304 infants (CHX-IA 148 vs PI 156) in whom 815 CVCs (CHX-IA 384 vs PI 431) were inserted and remained in situ for 3078 (CHX-IA 1465 vs PI 1613) days. We found no differences between the groups in the proportion of infants with CR-BSI (CHX-IA 7% vs PI 5%, p=0.631), the proportion of CVCs complicated by CR-BSI or the rate of CR-BSI per 1000 catheter days. Skin reaction rates were low (<1% CVC insertion episodes) and not different between the groups. More infants in the PI group had raised thyroid-stimulating hormone levels and were treated with thyroxine (CHX-IA 0% vs PI 5%, p=0.003). CONCLUSIONS: We did not find a difference in the rate of CR-BSI between preterm infants treated with CHX-IA and PI, and more infants treated with PI had thyroid dysfunction. However, our study was not adequately powered to detect a difference in our primary outcome and a larger trial is required to confirm our findings. TRIAL REGISTRATION: This study was registered with the EU clinical trials register before the first patient was enrolled (Eudract 2011-002962-19). (https://www.clinicaltrialsregister.eu).

The Association of Vitamin D Status with Acute Respiratory Morbidity in Preterm Infants.

OBJECTIVE: To assess the association between serum 25-hydroxyvitamin D (25OHD) levels and outcomes in preterm infants (<32 weeks gestation). STUDY DESIGN: Serum 25OHD was measured in mothers and their infants within 24 hours of birth, before the start of enteral vitamin D supplementation, and at discharge from the neonatal intensive care unit. We evaluated the associations between vitamin D status and various early preterm outcomes. RESULTS: Ninety-four preterm infants and their mothers were included; 92% of the infants had a 25OHD level≤50 nmol/L (20 ng/mL), and 64% had a 25OHD level<30 nmol/L (12 ng/mL). A low 25OHD level (<30 nmol/L) in preterm infants at birth was associated with increased oxygen requirement (P=.008), increased duration of intermittent positive-pressure ventilation during resuscitation at delivery (P=.032), and greater need for assisted ventilation (P=.013). CONCLUSION: We observed a high prevalence of low 25OHD (<30 nmol/L), and found an association between vitamin D status and acute respiratory morbidity in preterm infants after birth.

Neutrophil and monocyte toll-like receptor 4, CD11b and reactive oxygen intermediates, and neuroimaging outcomes in preterm infants.

BACKGROUND: Activated leukocytes and infection are implicated in neonatal brain injury. Leukocyte surface receptors are increased in stroke models and may be targets for future adjunctive therapies. METHODS: Serial blood samples were analyzed from preterm infants (n = 51; <32 wk gestation) on days 0, 1, 2, and 7 of life. Monocyte and neutrophil activation were evaluated via flow cytometry at baseline and following endotoxin stimulation ex vivo by measuring CD11b (activation), toll-like receptor 4 (TLR-4; endotoxin recognition) expression, and intracellular reactive oxygen intermediate (ROI) production (function). RESULTS: Control preterm infants with normal neuroimaging had elevated baseline CD11b and TLR-4 expression and ROI production compared with adults as well as a robust immune response following endotoxin stimulation. Preterm infants with abnormal neuroimaging had increased neutrophil TLR-4 and ROI compared with all controls. CONCLUSION: Preterm infants have a robust immune response compared with adults. Increased TLR-4 expression in preterm infants with abnormal neuroimaging is similar to findings in adult stroke. In addition, ROI production may cause tissue injury. The modulation of these responses may be beneficial in preterm inflammatory disorders.

A randomized trial of nasal prong or face mask for respiratory support for preterm newborns.

BACKGROUND AND OBJECTIVE: Resuscitation guidelines recommend that respiratory support should be given to newborns via a face mask (FM) in the delivery room (DR). Respiratory support given to preterm newborns via a single nasal prong (SNP; ie, short nasal tube, nasopharyngeal tube) may be more effective. We wished to determine whether giving respiratory support to preterm newborns with a SNP rather than a FM reduces the rate of intubation in the DR. METHODS: Infants <31 weeks' gestation were randomized just before delivery to SNP (endotracheal tube shortened to 5 cm) or FM. Randomization was stratified by gestation (<28 weeks, 28-30(+6)). Infants with apnea, respiratory distress, and/or heart rate <100 received positive pressure ventilation with a T-piece. The primary outcome was intubation and mechanical ventilation in the DR. Infants in both groups were intubated for heart rate <100 and/or apnea despite PPV and not solely for surfactant administration. All other aspects of treatment in the DR and NICU were the same. Relevant secondary outcomes were recorded and data were analyzed by using the intention-to-treat principle. RESULTS: One hundred forty-four infants were enrolled. The rate of intubation in the DR was the same in both groups (11/72 [15%] vs 11/72 [15%], P = 1.000]. Infants assigned to SNP had lower SpO2 at 5 minutes and received a higher maximum concentration of oxygen in the DR. There were no significant differences in other secondary outcomes. CONCLUSIONS: Giving respiratory support to newborn infants <31 weeks' gestation via a SNP, compared with a FM, did not result in less intubation and ventilation in the DR.

A randomized trial of exothermic mattresses for preterm newborns in polyethylene bags.

BACKGROUND AND OBJECTIVE: Hypothermia on admission to the NICU is associated with increased mortality in preterm infants. Many newborns are hypothermic on admission despite using polyethylene bags (PBs). Using exothermic mattresses (EMs) in addition to PBs may reduce hypothermia but increase hyperthermia. We wished to determine whether placing preterm newborns in PBs on EMs in the DR results in more infants with rectal temperature outside the range 36.5 to 37.5°C on NICU admission. METHODS: Infants <31 weeks were randomly assigned before birth to treatment with or without an EM. All infants were placed in a PB and under radiant heat immediately after birth and brought to NICU in a transport incubator. Infants randomly assigned to EM were placed on a mattress immediately after delivery and remained on it until admission. Randomization was stratified by gestational age. Rectal temperature was measured with a digital thermometer on NICU admission. RESULTS: The data safety monitoring committee recommended stopping for efficacy after analyzing data from half the planned sample. We report data for 72 infants enrolled at this time. Fewer infants in PBs on EMs had temperatures within the target range (15/37 [41%] vs 27/35 [77%], P = .002) and more had temperatures >37.5°C (17/37 [46%] vs 6/35 [17%], P = .009). CONCLUSIONS: In very preterm newborns, using EMs in addition to PBs in the DR resulted in more infants with temperatures outside the normal range and more hyperthermia on NICU admission.

Vitamin D nutritional status in preterm infants and response to supplementation.

Little is known about vitamin D status in preterm infants and their response to supplementation. To investigate this, we assessed serum 25-hydroxyvitamin D (25OHD) levels using RIA in a consecutive sample of stable preterm very low birth weight (VLBW) infants (born ≤ 32 weeks gestation or birth weight ≤ 1·5 kg), and we explored associated factors. Serum 25OHD level was first assessed once infants were tolerating feeds (n 274). If this first 25OHD level was below 50 nmol/l (20 ng/ml), which is the level associated with covering requirements in terms of skeletal health in the majority, then we recommended prolonged augmented vitamin D intake ( ≥ 10 µg (400 IU) daily) from a combination of fortified feeds and vitamin supplements and follow-up re-assessment at approximately 6 weeks corrected age (n 148). The first assessment, conducted at a median for chronological age of 18 (interquartile range (IQR) 11-28) d, found that 78 % had serum 25OHD levels below 50 nmol/l. Multivariable analysis demonstrated that the determinants of serum 25OHD levels were duration of vitamin D supplementation and gestational age at birth (r 2 0·215; P< 0·001). At follow-up, after a median of 104 (IQR 78-127) d, 87 % achieved levels ≥ 50 nmol/l and 8 % had levels >125 nmol/l, a level associated with potential risk of harm. We conclude that low 25OHD levels are an issue for preterm VLBW infants, warranting early nutritional intervention. In infants with serum 25OHD levels < 50 nmol/l, a vitamin D intake of ≥ 10 µg (400 IU) daily achieves target levels in the majority; however, further work is needed to determine the exact dose to safely meet target levels without overcorrection.

Isolated acute non-cystic white matter injury in term infants presenting with neonatal encephalopathy.

We discuss possible aetiological factors, MRI evolution of injury and neuro-developmental outcomes of neonatal encephalopathy (NE). Thirty-six consecutive infants diagnosed with NE were included. In this cohort, four infants (11%) were identified with injury predominantly in the deep white matter on MRI who were significantly of younger gestation, lower birthweight with higher Apgars at one and five minutes compared to controls. Placental high grade villitis of unknown aetiology (VUA) was identified in all four of these infants. Our hypothesis states VUA may induce white matter injury by causing a local inflammatory response and/or oxidative stress during the perinatal period. We underline the importance of continued close and systematic evaluation of all cases of NE, including examination of the placenta, in order to come to a better understanding of the clinical presentation, the patterns of brain injury and the underlying pathophysiological processes.

Randomized trial of prongs or mask for nasal continuous positive airway pressure in preterm infants.

OBJECTIVE: To determine whether nasal continuous positive airway pressure (NCPAP) given with nasal prongs compared with nasal mask reduces the rate of intubation and mechanical ventilation in preterm infants within 72 hours of starting therapy. METHODS: Infants <31 weeks' gestation treated with NCPAP were randomly assigned to receive it via either prongs or mask. Randomization was stratified by gestational age (<28 weeks, 28-30 weeks) and according to whether NCPAP was started as a primary treatment for respiratory distress or postextubation. Infants were intubated and ventilated if they fulfilled 2 or more of 5 failure criteria (worsening signs of respiratory distress; recurrent apnea treated with mask positive pressure ventilation; fraction of inspired oxygen >0.4 to keep oxygen saturation >88% sustained for 30 minutes; pH <7.2 on 2 blood gases ≥ 30 minutes apart; Pco(2) >9 kPa [68 mm Hg] on 2 blood gases ≥ 30 minutes apart) within 72 hours of starting therapy. The groups were treated the same in all other respects. We recorded relevant secondary outcomes and analyzed data by using the intention-to-treat principle. RESULTS: We enrolled 120 infants. Thirty-two of 62 (52%) infants randomly assigned to prongs were intubated within 72 hours, compared with 16/58 (28%) of those randomly assigned to mask (P = .007). There were no statistically significant differences between the groups in any secondary outcomes. CONCLUSIONS: In premature infants, NCPAP was more effective at preventing intubation and ventilation within 72 hours of starting therapy when given via nasal masks compared with nasal prongs.

MR imaging of term infants with hypoxic-ischaemic encephalopathy as a predictor of neurodevelopmental outcome and late MRI appearances.

BACKGROUND: Morbidity attributable to hypoxic-ischaemic injury (HIE) in the perinatal period remains problematic, and timely and accurate assessment of the degree of injury is required for clinical management and prognosis. Conventional MR sequences typically appear normal in the first 48 h post HIE. While diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps register the injury earlier, perhaps within the first 24 h, it has been suggested that there may be a propensity at that early stage to underestimate the lesion severity or extent. OBJECTIVE: To assess whether MR imaging that included DWI, measured ADC values and T1- and T2-weighted sequences ultimately correlated with either neurodevelopmental outcome or with late MR imaging at 2 years of age. In addition, we wished to compare the performance of MR imaging with cranial US imaging. MATERIALS AND METHODS: All infants presenting with HIE who had an MRI within 10 days of life were eligible for enrollment and subsequently underwent a full neurodevelopmental assessment at 2 years of age. All children underwent repeat MRI at this time. All neonates had at least one cranial US study. The US findings were categorized as normal, abnormalities confined to the cerebral cortex and subcortical white matter, isolated central grey matter hyperechogenicity, and central hyperechogenicity combined with cerebral cortical/subcortical changes. All MRI studies were retrospectively reviewed by three radiologists. The patterns of injury on the early DWI and ADC maps and early T1- and T2-W studies were recorded as diffuse, central, watershed or atypical. The patterns of signal abnormality were assessed using a scoring system that yielded four separate scores [basal ganglia (BG), watershed (W), BG/W and summation (S)] for the three sets of images, a total of 12 scores in all. The appearance of the posterior limb of the internal capsule (PLIC) on T1-W inversion recovery sequences and of the corpus callosum on all sequences was also documented. After detailed neurodevelopmental assessment at 2 years of age, infants were classified into two groups according to whether they had a favourable or unfavourable outcome. RESULTS: Of the 26 infants, 6 infants died before formal assessment at the age of 2 years. A further 5 infants had moderate to severe cerebral palsy in addition to severe cognitive impairment. The remaining 15 infants were categorized in the favourable outcome group. The US appearance performed well in terms of predicting final outcome (P = 0.005). The pattern of ischaemia seen on early MRI was a significant predictor of outcome (P < 0.0001). The BG, BG/W and S scores of the diffusion imaging were significantly associated with outcome (P < 0.0001, P < 0.0001 and P = 0.0005 respectively). DWI was predictive of outcome group (P < 0.0001), as were the early T1- and T2-W sequences (P = 0.002) and cranial US (P = 0.005). Assessment of the PLIC in infants with watershed or atypical patterns of ischaemia was found to be less reliable in predicting outcome. The measured ADC value in the PLIC was significantly reduced in those children who had an unfavourable outcome (P = 0.03). CONCLUSION: While early MRI performed better than cranial US, the sonography findings were useful. The pattern of ischaemia on early MRI was a good predictor of prognosis. All infants with watershed or atypical patterns had a favourable outcome. The majority of infants with central patterns of ischaemia had an unfavourable outcome and all infants with a diffuse pattern had an unfavourable outcome. DWI was predictive of outcome group, as were early T1- and T2-W sequences and cranial US.

Mediastinal and neck kaposiform hemangioendothelioma: report of three cases.

Kaposiform hemangioendothelioma is an aggressive vascular tumor, named for its striking histologic resemblance to Kaposi sarcoma and locally invasive growth. Mortality is high, and ranges from 10% to 24% for all kaposiform hemangioendothelioma lesions, with a significantly higher mortality for deep soft-tissue or visceral lesions occurring in infants less than 6 months. Mediastinal and neck kaposiform hemangioendothelioma in particular merit special discussion, as involvement of these critical anatomic locations results in significant site-specific therapeutic challenges due to invasion of vital structures, inherent delays in establishing histopathologic confirmation, and difficulties in monitoring disease status. We report our experience with three cases of mediastinal and neck kaposiform hemangioendothelioma, emphasizing the unique diagnostic and management challenges, variable response to treatment and outcome of this anatomic variant of kaposiform hemangioendothelioma.

Ontogeny of the eotaxins in human lung.

The ontogeny of the C-C chemokines eotaxin-1, eotaxin-2, and eotaxin-3 has not been fully elucidated in human lung. We explored a possible role for eotaxin in developing lung by determining the ontogeny of eotaxin-1 (CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), and the eotaxin receptor, CCR3. We tested discarded surgical samples of developing human lung tissue using quantitative RT-PCR (QRT-PCR) and immunostaining for expression of CCL11, CCL24, CCL26, and CCR3. We assessed possible functionality of the eotaxin-CCR3 system by treating lung explant cultures with exogenous CCL11 and analyzing the cultures for evidence of changes in proliferation and activation of ERK1/2, a signaling pathway associated with CCR3. QRT-PCR analyses of 22 developing lung tissue samples with gestational ages 10-23 wk demonstrated that eotaxin-1 mRNA is most abundant in developing lung, whereas mRNAs for eotaxin-2 and eotaxin-3 are minimally detectable. CCL11 mRNA levels correlated with gestational age (P < 0.05), and immunoreactivity was localized predominantly to airway epithelial cells. QRT-PCR analysis detected CCR3 expression in 16 of 19 developing lung samples. Supporting functional capacity in the immature lung, CCL11 treatment of lung explant cultures resulted in significantly increased (P < 0.05) cell proliferation and activation of the ERK signaling pathway, which is downstream from CCR3, suggesting that proliferation was due to activation of CCR3 receptors by CCL11. We conclude that developing lung expresses the eotaxins and functional CCR3 receptor. CCL11 may promote airway epithelial proliferation in the developing lung.

Bombesin-like peptides modulate alveolarization and angiogenesis in bronchopulmonary dysplasia.

RATIONALE: The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstrated elevated bombesin-like peptide levels in infants that later developed BPD. In the 140-day hyperoxic baboon model of BPD, anti-bombesin antibody 2A11 abrogated lung injury. OBJECTIVES: To test the hypothesis that bombesin-like peptides mediate BPD in extremely premature baboons (born at Gestational Day 125 and given oxygen pro re nata [PRN], called the 125-day PRN model), similar to "modern-day BPD." METHODS: The 125-day animals were treated with 2A11 on Postnatal Day 1 (P1), P3, and P6. On P14 and P21, lungs were inflation-fixed for histopathologic analyses of alveolarization. Regulation of angiogenesis by bombesin was evaluated using cultured pulmonary microvascular endothelial cells. MEASUREMENTS AND MAIN RESULTS: In 125-day PRN animals, urine bombesin-like peptide levels at P2-3 are directly correlated with impaired lung function at P14. Gastrin-releasing peptide (the major pulmonary bombesin-like peptide) mRNA was elevated eightfold at P1 and remained high thereafter. At P14, 2A11 reduced alveolar wall thickness and increased the percentage of secondary septa containing endothelial cells. At P21, 2A11-treated 125-day PRN animals had improved alveolarization according to mean linear intercepts and number of branch points per millimeter squared. Bombesin promoted tubulogenesis of cultured pulmonary microvascular endothelial cells, but cocultured fetal lung mesenchymal cells abrogated this effect. CONCLUSIONS: Early bombesin-like peptide overproduction in 125-day PRN animals predicted alveolarization defects weeks later. Bombesin-like peptide blockade improved septation, with the greatest effects at P21. This could have implications for preventing BPD in premature infants.

Altered gene expression patterns in intrauterine growth restriction: potential role of hypoxia.

OBJECTIVE: Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). In our study, microarray technology was used to identify genes, which may impair placentation resulting in IUGR. STUDY DESIGN: The RNA was isolated from both IUGR term placentas and normal term placentas. Microarray experiments were used to identify differentially expressed genes between the 2 cohorts. Real-time quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry were used in follow-up experiments. RESULTS: Microarray experiments identified increased expression of certain genes including leptin, soluble vascular endothelial growth factor receptor, human chorionic gonadotropin, follistatin-like 3, and hypoxia-inducible factor 2alpha in the IUGR. Real-time quantitative polymerase chain reaction confirmed these results. CONCLUSION: The upregulation of soluble vascular endothelial growth factor receptor and hypoxia-inducible factor 2alpha at this period in pregnancy indicate that placental angiogenesis is altered in IUGR and that hypoxia is a major contributor to maldevelopment of the placental vasculature.