Less invasive surfactant administration is associated with improved pulmonary outcomes in spontaneously breathing preterm infants.

AIM: Providing less invasive surfactant administration (LISA) to spontaneously breathing preterm infants has been reported to reduce mechanical ventilation and bronchopulmonary dysplasia (BPD) in randomised controlled trials. This large cohort study compared these outcome measures between LISA-treated infants and controls. METHODS: Infants receiving LISA, who were born before 32 gestational weeks and enrolled in the German Neonatal Network, were matched to control infants by gestational age, umbilical cord pH, Apgar-score at 5 min, small for gestational age status, antenatal treatment with steroids, gender and highest supplemental oxygen during the first 12 h of life. Outcome data were compared with chi-square and Mann-Whitney U-tests and adjusted for multiple comparisons. RESULTS: Between 2009 and 2012, 1103 infants were treated with LISA at 37 centres. LISA infants had lower rates of mechanical ventilation (41% versus 62%, p < 0.001), postnatal dexamethasone treatment (2.5% versus 7%, p < 0.001), BPD (12% versus 18%, p = 0.001) and BPD or death (14% versus 21%, p < 0.001) than the controls. CONCLUSION: Surfactant treatment of spontaneously breathing infants was associated with lower rates of mechanical ventilation and BPD. Additional large-scale randomised controlled trials are needed to assess the possible long-term benefits of LISA.

Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial.

BACKGROUND: Surfactant is usually given to mechanically ventilated preterm infants via an endotracheal tube to treat respiratory distress syndrome. We tested a new method of surfactant application to spontaneously breathing preterm infants to avoid mechanical ventilation. METHOD: In a parallel-group, randomised controlled trial, 220 preterm infants with a gestational age between 26 and 28 weeks and a birthweight less than 1·5 kg were enrolled in 12 German neonatal intensive care units. Infants were independently randomised in a 1:1 ratio with variable block sizes, to standard treatment or intervention, and randomisation was stratified according to centre and multiple birth status. Masking was not possible. Infants were stabilised with continuous positive airway pressure and received rescue intubation if necessary. In the intervention group, infants received surfactant treatment during spontaneous breathing via a thin catheter inserted into the trachea by laryngoscopy if they needed a fraction of inspired oxygen more than 0·30. The primary endpoint was need for any mechanical ventilation, or being not ventilated but having a partial pressure of carbon dioxide more than 65 mm Hg (8·6 kPa) or a fraction of inspired oxygen more than 0·60, or both, for more than 2 h between 25 h and 72 h of age. Analysis was by intention to treat. This study is registered, number ISRCTN05025922. FINDINGS: 108 infants were assigned to the intervention group and 112 infants to the standard treatment group. All infants were analysed. On day 2 or 3 after birth, 30 (28%) infants in the intervention group were mechanically ventilated versus 51 (46%) in the standard treatment group (number needed to treat 6, 95% CI 3-20, absolute risk reduction 0·18, 95% CI 0·30-0·05, p=0·008). 36 (33%) infants in the intervention group were mechanically ventilated during their stay in the hospital compared with 82 (73%) in the standard treatment group (number needed to treat: 3, 95% CI 2-4, p<0·0001). The intervention group had significantly fewer median days on mechanical ventilation, (0 days. IQR 0-3 vs 2 days, 0-5) and a lower need for oxygen therapy at 28 days (30 infants [30%] vs 49 infants [45%], p=0·032) compared with the standard treatment group. We recorded no differences between groups for mortality (seven deaths in the intervention group vs five in the standard treatment group) and serious adverse events (21 vs 28). INTERPRETATION: The application of surfactant via a thin catheter to spontaneously breathing preterm infants receiving continuous positive airway pressure reduces the need for mechanical ventilation. FUNDING: German Ministry of Research and Technology, University of Lübeck, and Chiesi Pharmaceuticals.

Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial.

IMPORTANCE: Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). OBJECTIVE: To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. INTERVENTION: LISA via a thin catheter. MAIN OUTCOMES AND MEASURES: Survival without BPD at 36 weeks' gestational age. RESULTS: Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). CONCLUSIONS AND RELEVANCE: LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN64011614.

Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study.

OBJECTIVE: To determine whether bovine surfactant given in cases of severe pediatric acute respiratory distress syndrome (ARDS) improves oxygenation. DESIGN: Single-center study with 19 patients, followed by a multicenter randomized comparison of surfactant with a standardized treatment algorithm. Primary endpoint PaO(2)/FIO(2) at 48 h, secondary endpoints: PaO(2)/FIO(2) at 2, 4, 12, and 24 h, survival, survival without rescue, days on ventilator, subgroups analyzed by analysis of variance to identify patients who might benefit from surfactant. SETTING: Multicenter study in 19 reference centers for ARDS. PATIENTS: Children after the 44th postconceptional week and under 14 years old, admitted for at least 4 h, ventilated for 12-120 h, and without heart failure or chronic lung disease. In the multicenter study 35 patients were recruited; 20 were randomized to the surfactant group and 15 to the nonsurfactant group. Decreasing recruitment of patients led to a preliminary end of this study. INTERVENTIONS: Administration of 100 mg/kg bovine surfactant intratracheally under continuous ventilation and PEEP, as soon as the PaO(2)/FIO(2) ratio dropped to less than 100 for 2 h (in the pilot study increments of 50 mg/kg as long as the PaO(2)/FIO(2) did not increase by 20%). A second equivalent dose within 48 h was permitted. RESULTS: In the pilot study the PaO(2)/FIO(2) increased by a mean of 100 at 48 h (n=19). A higher PaO(2)/FIO(2) ratio was observed in the surfactant group 2 h after the first dose (58 from baseline vs. 9), at 48 h there was a trend towards a higher ratio (38 from baseline vs. 22). The rate of rescue therapy was significantly lower in the surfactant group. Outcome criteria were not affected by a second surfactant dose (n=11). A significant difference in PaO(2)/FIO(2) in favor of surfactant at 48 h was found in the subgroup with an initial PaO(2)/FIO(2) ratio higher than 65 and in patients without pneumonia. CONCLUSIONS. Surfactant therapy in severe ARDS improves oxygenation immediately after administration. This improvement is sustained only in the subgroup of patients without pneumonia and that with an initial PaO(2)/FIO(2) ratio higher than 65

Epidemic microclusters of blood-culture proven sepsis in very-low-birth weight infants: experience of the German Neonatal Network.

INTRODUCTION: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. METHODS: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. RESULTS: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. DISCUSSION: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

Multiple hepatic mesenchymal hamartomas in a premature associated with placental mesenchymal dysplasia.

Placental mesenchymal dysplasia (PMD) is an uncommon disorder that has to be differentiated histologically from a partial mole. In contrast to a hydatitiform mole, PMD can coexist with a viable fetus. Placental mesenchymal dysplasia is characterized by placentomegaly and dilatation of the chorionic vessels. In our case, multiple hepatic mesenchymal hamartomas in a preterm were associated with PMD. This association is an extremely rare anomaly. Mesenchymal hamartomas occur in 5% of all primary liver tumors in children and are generally benign lesions.

Detection of bocavirus DNA in nasopharyngeal aspirates of a child with bronchiolitis.

We describe a case of bronchiolitis associated with the newly detected human bocavirus (hBoV) in a child with a suspected Noonan syndrome. This is the first report of a bronchiolitis probably linked to hBoV that required intensive care while being accompanied by a congenital heart disease and a history of several episodes of severe respiratory symptoms.

Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis.

Chorioamnionitis and funisitis are associated with preterm labor and postnatal morbidity. Activation of endothelium resulting in up-regulation of adhesion molecules seems to be a key mechanism in development of organ damage. We investigated whether chorioamnionitis with or without funisitis in preterm infants induced expression and shedding of adhesion molecules in the umbilical cord and resulted in increased concentrations of E-selectin, intercellular adhesion molecule (ICAM)-1, IL-1beta, IL-6, and IL-8 in the cord blood. Data were obtained by using immunohistochemistry and ELISA. Thirty-two preterm infants were divided into three groups according to histology: chorioamnionitis with funisitis, chorioamnionitis without funisitis, and controls without signs of inflammation. ICAM-1 expression on arterial endothelium was higher with funisitis compared with chorioamnionitis alone or with the control group. Similar results for ICAM-1 expression were found in venous endothelium, vascular walls, Wharton's jelly, and amnion epithelium. Endothelial E-selectin and vascular cell adhesion molecule (VCAM)-1 expression was only induced significantly with funisitis. Serum-concentrations of soluble ICAM-1 were higher with funisitis compared with chorioamnionitis alone or control group. Similarly, concentrations of soluble E-selectin, IL-1beta, IL-6, and IL-8 were increased exclusively with funisitis. In conclusion, only chorioamnionitis with funisitis was associated with systemic inflammation and endothelial activation with up-regulation and shedding of umbilical cord adhesion molecules. We speculate that this activation of endothelium may not be limited to the umbilical cord but may also involve other organs resulting in neonatal morbidity. This underlines the importance of funisitis as a risk factor for adverse outcome.

Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth.

Chorioamnionitis and funisitis are associated with neonatal morbidity and mortality. We hypothesized that chorioamnionitis may stress fetal endothelium, activate proinflammatory gene transcription. and affect angiogenic homeostasis in fetal capillaries. Placentas from preterm infants were stained for heat-shock protein 70, nuclear factor-kappaB, hypoxia-inducible factor-1alpha, and vascular endothelial growth factor (VEGF). VEGF receptors (VEGF-R) 1 and 2 as well as the receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE-2), which is involved in vascular remodeling, were quantified. Immunohistochemistry was analyzed by counting positive capillaries in placental terminal villi. Staining intensity was quantified by a three-step semiquantitative scale. The samples were divided into three matched groups according to histology: chorioamnionitis with funisitis ("funisitis"), chorioamnionitis without funisitis ("chorioamnionitis"), and control group with no inflammation. In tissues from the funisitis or chorioamnionitis group, heat-shock protein 70 expression was increased over the control group. More nuclear factor-kappaB-positive nuclei of endothelial cells in capillaries were counted in the funisitis and chorioamnionitis groups. Expression of VEGF and VEGF-R1 and -R2 were reduced in cases of funisitis or chorioamnionitis in comparison with controls. Hypoxia-inducible factor-1alpha expression tended to be slightly lower in the funisitis and chorioamnionitis groups but did not reach statistical significance. We speculate that cellular stress and changes in angiogenic homeostasis induced by proinflammatory activation of fetal endothelium in chorioamnionitis may not be limited to the placenta but may also involve other fetal organs.

Blood transfusion in anemic infants with apnea of prematurity.

We found recently that blood transfusions had no effect on bradycardia and hypoxemia, the clinically important components of apnea of prematurity, in mildly anemic infants. Here, we wanted to know whether this also holds true for more severely anemic patients. Nineteen preterm infants, median gestational age at birth 25 (range 22-30) weeks, age at the time of study 5.5 (range 1-13) weeks, for whom a blood transfusion was ordered because of recurrent episodes of bradycardia and/or hypoxemia in conjunction with anemia (median hemoglobin level 78 g/l, range 63-98 g/l) were investigated. One infant received two transfusions and was thus studied twice. 4-hour recordings of pulse oximeter saturation (SpO(2)), pulse waveforms, electrocardiogram, breathing movements, and nasal airflow were performed immediately before transfusion of 20 ml/kg packed red blood cells and again 24 h later. The recordings were analyzed for baseline heart and respiratory rates and SpO(2), all measured during regular breathing, as well as for apnea (>/=20 s), bradycardia (heart rate <2/3 of baseline for >/=4 s), and episodic desaturation (SpO(2) /=4 s). There was no significant change in the combined frequency of bradycardia and desaturation, the primary study end point - median 6.4/h (range 3.0-13.5/h) before versus 4.6/h (range 0.6-15.7/h) after transfusion -, although there was slightly less bradycardia - 0.8/h (range 0.0-8.8/h) versus 0.7/h (range 0.0-5.1/h; p < 0.05). Baseline heart and respiratory rates decreased, respectively, from 163/min (range 140-182/min) and 58/min (range 34-98/min) to 152/min (range 134-172/min) and 55/min (range 36-82/min; p < 0.01). We conclude that blood transfusions significantly reduced heart and respiratory rates in these anemic infants, but had little effect on apnea of prematurity.

Soluble Fas (CD95/Apo-1), soluble Fas ligand, and activated caspase 3 in the cerebrospinal fluid of infants with posthemorrhagic and nonhemorrhagic hydrocephalus.

Hydrocephalus may result in loss of tissue associated with neuronal degeneration, axonal damage, and reactive gliosis. The soluble form of the anti-apoptotic regulator Fas (sFas) and the pro-apoptotic factors soluble FasL (sFasL) and activated caspase 3 were studied in the cerebrospinal fluid of infants with hydrocephalus. Fifteen preterm infants with posthemorrhagic hydrocephalus undergoing serial reservoir puncture and seven term or near-term infants with nonhemorrhagic hydrocephalus and shunt surgery were included in the study. Twenty-four age-matched patients with lumbar puncture for the exclusion of meningitis served as controls. Elevated levels of sFas were observed in infants with posthemorrhagic hydrocephalus [median (range), 131 ng/mL (51-279 ng/mL)] and in nonhemorrhagic hydrocephalus [127 ng/mL (35-165 ng/mL)]. sFas concentrations were highest in a subgroup of eight patients with posthemorrhagic hydrocephalus developing periventricular leukomalacia [164 ng/mL (76-227 ng/mL)]. In contrast, in 24 control infants, sFas was low, in 15 cases below detection limit (0.5 ng/mL) and in nine cases, 24 ng/mL (20-43 ng/mL). sFasL and activated caspase 3 did not differ from control infants in all groups of patients. Increased intrathecal release of sFas in the cerebrospinal fluid of infants with hydrocephalus may serve as an indicator of brain injury from progressive ventricular dilatation.

Vascular endothelial growth factor and transforming growth factor-beta1 are highly expressed in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus.

The expression of specific growth factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) is of importance during brain development and in the pathogenesis of neurodegenerative disorders. VEGF and TGF-beta1 was studied in the cerebrospinal fluid (CSF) of neonates with posthemorrhagic hydrocephalus (PHHC) and nonhemorrhagic hydrocephalus. For determining the interference of inflammatory cytokine interaction with the expression of VEGF and TGF-beta1, IL-6 and IL-10 CSF concentrations were measured. Eighteen neonates who had PHHC and underwent serial reservoir puncture and nine neonates who had congenital nonhemorrhagic hydrocephalus (CHC) and underwent first shunt surgery were included in the study. CSF samples of 11 neonates with lumbar puncture for the exclusion of meningitis served as control subjects. VEGF, TGF-beta1, IL-6, and IL-10 concentrations in the CSF were measured by ELISA technique. VEGF concentrations in the CSF of patients with PHHC were significantly higher (median: 377 pg/mL; range: 101-1301 pg/mL) when compared with patients with CHC (median: 66 pg/mL; range: 3-1991; p < 0.001) and control subjects (median: 2 pg/mL; range: 0-12 pg/mL; p < 0.0001). TGF-beta1 CSF concentrations did not differ from control infants in all groups. Median IL-6 and IL-10 concentrations in the CSF were found to be low in all patient groups. Increased release of VEGF in the CSF of neonates with PHHC and nonhemorrhagic hydrocephalus may serve as an indicator of brain injury from progressive ventricular dilation. TGF-beta1 CSF concentrations are not elevated in the phase of acute fibroproliferative reactions in patients with PHHC.

Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g.

OBJECTIVE: To investigate whether recombinant erythropoietin (rhEPO) reduces the need for transfusion in extremely low birth weight (ELBW) infants (birth weight 500-999 g) and to determine the optimal time for treatment. METHODS: In a blinded multicenter trial, 219 ELBW infants were randomized on day 3 to one of 3 groups: early rhEPO group (rhEPO from the first week for 9 weeks, n = 74), late rhEPO group (rhEPO from the fourth week for 6 weeks, n = 74), or control group (no rhEPO, n = 71). All infants received enteral iron (3-9 mg/kg/day) from the first week. The rhEPO beta dose was 750 IU/kg/week. Success was defined as no transfusion and hematocrit levels never below 30%. RESULTS: Success rate was 13% in the early rhEPO group, 11% in the late rhEPO group, and 4% in the control group (P =.026 for early rhEPO versus control group). Median transfusion volume was 0.4 versus 0.5 versus 0.7 mL/kg/day (P =.02) and median donor exposure was 1.0 versus 1.0 versus 2.0 (P =.05) in the early rhEPO group, the late rhEPO group, and the control group, respectively. Infection risk was not increased and weight gain was not delayed with rhEPO beta. CONCLUSION: Early rhEPO beta treatment effectively reduces the need for transfusion in ELBW infants.